Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo
Open accessAbstract
Proteomic analysis of histones has shown that they are subject to a superabundance of acylations, which extend far beyond acetylation, to include: crotonylation, propionylation, butyrylation, malonylation, succinylation, β-hydroxybutyrylation and 2-hydroxyisobutyrylation. To date, much of the functional data has focussed on histone crotonylation which, similar to acetylation, has been associated with positive gene regulation and is added by the acyltransferase, p300. Although Sirtuins 1–3, along with HDAC3, have been shown to possess decrotonylase activity in vitro, there is relatively little known about the regulation of histone crotonylation in vivo. Here we show that Histone Deacetylase 1 and 2 (HDAC1/2), the catalytic core of numerous co-repressor complexes, are important histone decrotonylase enzymes. A ternary complex of HDAC1/CoREST1/LSD1 is able to hydrolyse both histone H3 Lys18-acetyl (H3K18ac) and H3 Lys18-crotonyl (H3K18cr) peptide substrates. Genetic deletion of HDAC1/2 in ES cells increases global levels of histone crotonylation and causes an 85% reduction in total decrotonylase activity. Furthermore, we mapped H3K18cr in cells using ChIP-seq, with and without HDAC1/2, and observed increased levels of crotonylation, which largely overlaps with H3K18ac in the vicinity of transcriptional start sites. Collectively, our data indicate that HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo.
AI snapshot
Written from the paper’s full text.
TL;DR
HDAC1/2-containing complexes act as histone decrotonylases in vitro and in mouse ES cells; deletion of HDAC1/2 increases global H3K18ac and H3K18cr and reduces total decrotonylase activity by 85%. ChIP-seq shows H3K18cr overlaps H3K18ac near transcription start sites and increases at active/bivalent genes upon HDAC1/2 loss.
Key findings
- A recombinant HDAC1/CoREST1/LSD1 ternary complex hydrolysed both H3K18ac and H3K18cr peptides, with a lower initial rate for decrotonylation than deacetylation; InsP6 increased the initial deacetylation rate 3.2-fold and decrotonylation rate 1.8-fold. HDAC3/SMRT/GPS2/TBL1 also showed decrotonylase activity, with an initial rate 2.4-fold lower for H3K18cr than H3K18ac.
- In ES cells, LBH589 treatment increased H3K18cr 3.2-fold and H3K18ac 2.6-fold in a dose-dependent manner; both marks doubled within 2 hours.
- HDAC1/2 double knockout ES cells showed 2.3-fold higher H3K18ac and 2.2-fold higher H3K18cr, plus 1.8-fold higher total H3 crotonylation and 1.7-fold higher H4 crotonylation; total decrotonylase activity was reduced by 85%, while deacetylase activity was 56% of control.
- ChIP-seq in control and HDAC1/2 DKO ES cells showed H3K18cr peaks near TSS overlapping H3K18ac; loss of HDAC1/2 increased average H3K18ac and H3K18cr around TSS, with up to 4-fold increases in H3K18cr at loci such as Lactb and Anapc5, and increased H3K18cr correlated with upregulated genes (p < 0.0001) and GO enrichment overlap (R² = 0.929, p < 0.0001).
Methods
- In vitro deacetylase/decrotonylase assays used Caliper EZ Reader II with 500 nM recombinant HDAC1/CoREST1/LSD1 or HDAC3/SMRT/GPS2/TBL1 complexes and fluorescein-labelled H3K18ac, H3K18cr, and H4K16ac peptides, with or without InsP6.
- Cell assays used mouse ES cells and HEK-293T cells; conditional Hdac1/2 deletion was induced with 1 µM tamoxifen (OHT), HDAC inhibition with LBH589, and activity measured with Boc-Lys(Ac)-AMC and Boc-Lys(Cr)-AMC substrates, plus quantitative western blotting and co-immunoprecipitation with HDAC2/LSD1 antisera.
- ChIP-seq for H3K18ac and H3K18cr was performed in control and DKO ES cells using native ChIP and Illumina HiSeq4000 75 bp sequencing; reads were mapped to mm9, peaks called with MACS, and analyses used deepTools and DAVID, with data deposited at GEO GSE116019.
Limitations
- Paper-stated: prior in vitro studies with isolated recombinant enzymes may not reflect physiological activity, and class-I HDAC activity in vivo depends on binding to complex partners; the paper also notes that in vitro decrotonylation was slower than deacetylation, whereas cellular recovery showed little difference, possibly due to isolated histone-tail peptides versus intact nucleosomes or cooperating factors.
- Evident: the in vitro assays use peptide substrates rather than intact nucleosomes, and the genetic and ChIP-seq findings are largely in mouse ES cells, so generalizability to other cell types or tissues is not established here.
- Evident: some in vitro data are from n = 2 technical replicates (Fig. 1), and although HDAC3 knockout showed no significant global change in H3K18ac/H3K18cr, the paper states this does not preclude locus-specific regulation.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 46 cited sources checked · 0 supported · 0 flagged
- Findingown data
Both H3K18ac and H3K18cr are hydrolysed by HDAC1/CoREST1/LSD1 at a reduced rate compared with H4K16Ac.
“Interestingly, both H3K18 modifications were hydrolysed at a reduced rate compared to H4K16Ac (Fig. 1C), indicating that there may be a hierarchy of acylated sites among histone tails.”
Quote in the paperSubstantial claim - Findingown data
The initial rate of H3K18cr decrotonylation by HDAC1/CoREST1/LSD1 is lower than the initial rate of H3K18ac deacetylation.
“HDAC1 was able to deacylate both H3K18ac and H3K18cr substrates (Fig. 1A,B), although the initial rate of decrotonylation was lower than deacetylation.”
Quote in the paperSubstantial claim - Findingown data
A purified ternary complex of HDAC1/CoREST1/LSD1 is able to hydrolyse both H3K18ac and H3K18cr peptide substrates.
“A ternary complex of HDAC1/CoREST1/LSD1 is able to hydrolyse both histone H3 Lys18-acetyl (H3K18ac) and H3 Lys18-crotonyl (H3K18cr) peptide substrates.”
- Also stated in: § HDAC1 functions as a histone decrotonylase whose activity is modulated by inositol phosphates · plain
“HDAC1 was able to deacylate both H3K18ac and H3K18cr substrates (Fig. 1A,B), although the initial rate of decrotonylation was lower than deacetylation.”
Quote in the paperSubstantial claim - Also stated in: § HDAC1 functions as a histone decrotonylase whose activity is modulated by inositol phosphates · plain
- Findingown data
H3K18cr is enriched at active genes such as Nanog and Pou5f1 in ES cells.
“We also observed an enrichment for H3K18cr at active genes, such Nanog and Pou5f1 (Fig. 4B) consistent with a role for histone crotonylation in active gene expression9,39.”
Quote in the paperNot a substantial claim- Rests on an assumption: The H3K18cr antibody used for native ChIP specifically detects H3K18cr.
- Findingown data
Cross-referencing 1,445 genes up-regulated in DKO cells to ChIP-seq data reveals a strong correlation between increased transcription and increased H3K18cr (p < 0.0001).
“Cross-referencing the 1,445 genes up-regulated genes in DKO cells to our ChIP-seq dataset revealed a strong correlation between increased transcription and an increase in H3K18cr (Fig. 5A, p < 0.0001) and H3K18ac (p < 0.0001) levels.”
Quote in the paperSubstantial claim
- Findingown data
Genetic deletion of HDAC1/2 in ES cells increases global levels of histone crotonylation.
“Genetic deletion of HDAC1/2 in ES cells increases global levels of histone crotonylation and causes an 85% reduction in total decrotonylase activity.”
Quote in the paperSubstantial claim- Rests on an assumption: The changes in histone crotonylation levels upon HDAC1/2 deletion are due to loss of HDAC1/2 decrotonylase activity rather than indirect effects on other enzymes.
- Findingown data
Individual genes Htra1, Hes6 and Nagk, whose expression increased 2.7, 1.6 and 2.1-fold respectively, show corresponding increases in H3K18ac and H3K18cr levels.
“Individual genes, such as Htra1, Hes6 and Nagk, whose expression increased 2.7, 1.6 and 2.1-fold respectively, showed corresponding increases in H3K18ac and H3K18cr levels (Supplementary Fig. S4).”
Quote in the paperNot a substantial claim - Findingown data
HDAC1/2 and HDAC3, in recombinant purified co-repressor complexes, are active decrotonylase enzymes in vitro.
“In this study, we show that HDAC1/2 and HDAC3 are active decrotonylase enzymes in vitro using recombinant purified co-repressor complexes (Fig. 1A and Supplementary Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
A time course of LBH589 treatment shows both H3K18ac and H3K18cr levels double within 2 hours.
“A time course of LBH589 treatment revealed that both H3K18ac and H3K18cr levels double within 2 hours (Fig. 2D), indicating that the dynamics of acetylation/crotonylation are similar in cells.”
Quote in the paperSubstantial claim - Findingown data
Increased levels of both H3K18ac and H3K18cr are observed at bivalent genes in ES cells.
“Intriguingly, we also observed increased levels of both H3K18ac and H3K18cr at bivalent genes (Fig. 5B), that is, poised genes marked with both H3K4me3 and H3K27me3 in ES cells35,36, suggesting a role for HDAC1/2 in controlling the activity of developmentally regulated genes prior to ES cell differentiation.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [35] Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326, https://doi.org/10.1016/j.cell.2006.02.041 (2006). source
Not checked in the free run.
- cites [36] Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560, https://doi.org/10.1038/nature06008 (2007). source
Not checked in the free run.
- Findingown data
Genetic deletion of HDAC1/2 in ES cells causes an 85% reduction in total decrotonylase activity.
“Genetic deletion of HDAC1/2 in ES cells increases global levels of histone crotonylation and causes an 85% reduction in total decrotonylase activity.”
Quote in the paperSubstantial claim- Rests on an assumption: The changes in histone crotonylation levels upon HDAC1/2 deletion are due to loss of HDAC1/2 decrotonylase activity rather than indirect effects on other enzymes.
- Findingown data
HDAC2 and LSD1 related complexes immunoprecipitated from ES cells demonstrate substantial decrotonylase activity.
“Both HDAC2 and LSD1 related complexes demonstrated substantial decrotonylase activity (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
Treatment of ES cells with LBH589 increases H3K18ac levels 2.6-fold in a dose-dependent manner.
“Treatment of ES cells with LBH589, a broad spectrum inhibitor of Zn2+-HDAC enzymes (HDACs 1–11) increased the levels of both H3K18cr (3.2-fold) and H3K18ac (2.6-fold) in a dose dependent manner (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
GO analysis of the top 10% of genes enriched for either H3K18cr or H3K18ac upon HDAC1/2 deletion reveals functional enrichment for genes with roles in embryonic morphogenesis and embryo development.
“Consistent with this mechanism, gene ontology (GO) analysis of the top 10% of genes enriched for either H3K18cr or H3K18ac upon HDAC1/2 deletion (Fig. 4B; red line), revealed functional enrichment for genes with roles in embryonic morphogenesis and embryo development (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
In the absence of HDAC1/2, decrotonylase activity is significantly decreased.
“In the absence of HDAC1/2 we observed a significant decrease in both deacetylase (Fig. 3C) and decrotonylase (Fig. 3D) activity.”
Quote in the paperSubstantial claim - Findingown data
Cross-referencing 1,445 genes up-regulated in DKO cells to ChIP-seq data reveals a strong correlation between increased transcription and increased H3K18ac (p < 0.0001).
“Cross-referencing the 1,445 genes up-regulated genes in DKO cells to our ChIP-seq dataset revealed a strong correlation between increased transcription and an increase in H3K18cr (Fig. 5A, p < 0.0001) and H3K18ac (p < 0.0001) levels.”
Quote in the paperSubstantial claim - Findingown data
Elevated H3K18ac and H3K18cr levels after HDAC1/2 loss appear largely at pre-existing sites rather than de novo loci.
“These elevated levels appear be largely at pre-existing sites of acetylation/crotonylation rather than de novo loci (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
Loss of HDAC1/2 does not alter HDAC3 protein levels in DKO cells.
“To assess whether loss of HDAC1/2 altered the expression of other decrotonylases, we examined HDAC3 protein levels in DKO cells, but found no change (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Following deletion of HDAC1/2 in ES cells, total H3 crotonylation increases 1.8-fold.
“Moreover, using a pan-crotonyl antibody, we were able to detect a 1.8-fold and 1.7-fold increase in total H3 and H4 crotonylation (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
HDAC activity is 56% of control levels in HDAC1/2 DKO cells.
“Indeed, decrotonylation activity was reduced by 85% compared to controls, while HDAC activity was only 56% of control levels (Fig. 3E).”
Quote in the paperSubstantial claim - Findingown data
HDAC3 knockout cells show no significant changes in H3K18ac and H3K18cr levels.
“In addition, we also examined H3K18ac and H3K18cr levels in HDAC3 knockout cells and found no significant changes (Supplementary Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Following deletion of HDAC1/2 in ES cells, H3K18ac increases 2.3-fold.
“Following deletion of HDAC1/2, quantitative western blotting revealed a 2.3-fold and 2.2-fold increase in H3K18ac and H3K18cr, respectively (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
In the absence of HDAC1/2, deacetylase activity is significantly decreased.
“In the absence of HDAC1/2 we observed a significant decrease in both deacetylase (Fig. 3C) and decrotonylase (Fig. 3D) activity.”
Quote in the paperSubstantial claim - Findingown data
Decrotonylation activity is reduced by 85% in HDAC1/2 DKO cells compared with controls.
“Indeed, decrotonylation activity was reduced by 85% compared to controls, while HDAC activity was only 56% of control levels (Fig. 3E).”
Quote in the paperSubstantial claim - Findingown data
Treatment of ES cells with LBH589 increases H3K18cr levels 3.2-fold in a dose-dependent manner.
“Treatment of ES cells with LBH589, a broad spectrum inhibitor of Zn2+-HDAC enzymes (HDACs 1–11) increased the levels of both H3K18cr (3.2-fold) and H3K18ac (2.6-fold) in a dose dependent manner (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
At specific gene loci such as Lactb or Anapc5, H3K18cr increases up to 4-fold following HDAC1/2 deletion.
“At specific gene loci, such as Lactb or Anapc5 (Fig. 4D), we observed increases in H3K18cr of up to 4-fold following HDAC1/2 deletion.”
Quote in the paperSubstantial claim - Findingown data
Following deletion of HDAC1/2 in ES cells, H3K18cr increases 2.2-fold.
“Following deletion of HDAC1/2, quantitative western blotting revealed a 2.3-fold and 2.2-fold increase in H3K18ac and H3K18cr, respectively (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Following deletion of HDAC1/2 in ES cells, total H4 crotonylation increases 1.7-fold.
“Moreover, using a pan-crotonyl antibody, we were able to detect a 1.8-fold and 1.7-fold increase in total H3 and H4 crotonylation (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Loss of HDAC1/2 results in little or no detectable decrotonylation activity in ES cell extracts.
“However, this was not observed for decrotonylase activity, where loss of HDAC1/2 resulted in little or no detectable decrotonylation activity (Fig. 3D).”
Quote in the paperSubstantial claim - Findingown data
In cells, the rate of decrotonylation is little different from the rate of deacetylation.
“when we examined the rate of decrotonylation in cells (inhibitor treatment followed by wash-out and recovery, Supplementary Fig. S2C), we found there was little difference between deacetylation and decrotonylation rates.”
Quote in the paperSubstantial claim - Findingown data
An HDAC1/CoREST1/LSD1 ternary complex and an HDAC3/SMRT/GPS2/TBL1 quaternary complex are able to turnover H3K18cr, albeit at a reduced rate compared to the equivalent acetylated substrate.
“we show that an HDAC1/CoREST1/LSD1 ternary (Fig. 1) and HDAC3/SMRT/GPS2/TBL1 (Supplementary Fig. S1B) quaternary complex are able to turnover H3K18cr, albeit at a reduced rate compared to the equivalent acetylated substrate.”
Quote in the paperSubstantial claim - Premisereasoning
In vitro studies with recombinant enzymes produced in isolation do not fully address the physiological role of lysine-crotonylation erasers in a cellular context.
“However, these studies were performed in vitro with recombinant enzymes produced in isolation and therefore do not fully address the physiological role of Lys-cr erasers in a cellular context.”
Quote in the paperSubstantial claim - Premisecitation
Both lysine acetylation and lysine crotonylation share p300 as a common writer.
“Both Lys-ac and Lys-cr share a common ‘writer’ in the acyltransferase and co-activator protein, p3009.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Molecular cell 58, 203–215, https://doi.org/10.1016/j.molcel.2015.02.029 (2015). source
Not checked in the free run.
- Premisecitation
HDAC1/2 have been implicated in the regulation of histone crotonylation levels in cells.
“Recently, HDAC1/2 have been implicated in the regulation of histone crotonylation levels in cells21,22.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [21] Wei, W. et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res 27, 898–915, https://doi.org/10.1038/cr.2017.68 (2017). source
Not checked in the free run.
- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
- Interpretationown data
Both HDAC1 and HDAC3 containing complexes are active decrotonylases.
“Together these data demonstrate that both HDAC1 and HDAC3 containing complexes are active decrotonylases.”
Quote in the paperSubstantial claim- Rests on an assumption: The HDAC1/CoREST1/LSD1 ternary complex is representative of HDAC1/2-containing co-repressor complexes for decrotonylase activity.
- Premisecitation
Previous studies failed to detect significant decrotonylase activity for HDAC1/2.
“Previous studies failed to detect significant decrotonylase activity for HDAC1/23,18 and this may be because they were using recombinant enzymes generated in isolation.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028, https://doi.org/10.1016/j.cell.2011.08.008 (2011). source
Not checked in the free run.
- cites [18] Madsen, A. S. & Olsen, C. A. Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro. Angew Chem Int Ed Engl 51, 9083–9087, https://doi.org/10.1002/anie.201203754 (2012). source
Not checked in the free run.
- Interpretationown data
HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo.
“Collectively, our data indicate that HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo.”
- Also stated in: § Introduction · hedged
“Collectively, these data indicate that HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: The HDAC1/CoREST1/LSD1 ternary complex is representative of HDAC1/2-containing co-repressor complexes for decrotonylase activity.
- Rests on an assumption: ES cells are a valid model for in vivo regulation of histone crotonylation.
- Also stated in: § Introduction · hedged
- Interpretationown data
HDAC1/2 are important histone decrotonylase enzymes.
“Here we show that Histone Deacetylase 1 and 2 (HDAC1/2), the catalytic core of numerous co-repressor complexes, are important histone decrotonylase enzymes.”
Quote in the paperSubstantial claim- Rests on an assumption: The HDAC1/CoREST1/LSD1 ternary complex is representative of HDAC1/2-containing co-repressor complexes for decrotonylase activity.
- Interpretationown data
HDAC1/2 are the dominant decrotonylases in ES cells.
“These results demonstrate that HDAC1/2 are the dominant decrotonylases in ES cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The HDAC1/CoREST1/LSD1 ternary complex is representative of HDAC1/2-containing co-repressor complexes for decrotonylase activity.
- Interpretationown data
Histone crotonylation plays a role in active gene expression.
“consistent with a role for histone crotonylation in active gene expression9,39.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9] Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Molecular cell 58, 203–215, https://doi.org/10.1016/j.molcel.2015.02.029 (2015). source
Not checked in the free run.
- cites [39] Montellier, E., Rousseaux, S., Zhao, Y. & Khochbin, S. Histone crotonylation specifically marks the haploid male germ cell gene expression program: post-meiotic male-specific gene expression. Bioessays 34, 187–193, https://doi.org/10.1002/bies.201100141 (2012). source
Not checked in the free run.
- Interpretationcitation
Total decrotonylase activity correlates with the total amount of HDAC1/2.
“This difference in activity suggests that HDAC2 acts as a histone decrotonylase, consistent with data from Wei et al.21 and that total decrotonylase activity (similar to deacetylase) correlates with the total amount of HDAC1/2.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Wei, W. et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res 27, 898–915, https://doi.org/10.1038/cr.2017.68 (2017). source
Not checked in the free run.
- Interpretationown data
The difference in activity between HDAC1-KO; HDAC2-Het and DKO cells suggests HDAC2 acts as a histone decrotonylase.
“This difference in activity suggests that HDAC2 acts as a histone decrotonylase, consistent with data from Wei et al.21 and that total decrotonylase activity (similar to deacetylase) correlates with the total amount of HDAC1/2.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Wei, W. et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res 27, 898–915, https://doi.org/10.1038/cr.2017.68 (2017). source
Not checked in the free run.
- Interpretationown data
HDAC1/2 may control the activity of developmentally regulated genes prior to ES cell differentiation.
“Intriguingly, we also observed increased levels of both H3K18ac and H3K18cr at bivalent genes (Fig. 5B), that is, poised genes marked with both H3K4me3 and H3K27me3 in ES cells35,36, suggesting a role for HDAC1/2 in controlling the activity of developmentally regulated genes prior to ES cell differentiation.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [35] Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326, https://doi.org/10.1016/j.cell.2006.02.041 (2006). source
Not checked in the free run.
- cites [36] Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560, https://doi.org/10.1038/nature06008 (2007). source
Not checked in the free run.
- Interpretationown data
There is a concomitant relationship between HDAC1/2 gene regulation and histone crotonylation levels.
“This demonstrates a concomitant relationship between HDAC1/2 gene regulation and histone crotonylation levels.”
Quote in the paperSubstantial claim - Interpretationown data
The reduction in total decrotonylase activity caused by HDAC1/2 deletion in ES cells is the first genetic link between HDACs and decrotonylase activity in cells.
“this is the first genetic link between HDACs and decrotonylase activity in cells”
Quote in the paperSubstantial claim - Premisecitation
The activity of class-I HDACs in vivo is dependent upon binding to an activating partner as part of a multi-protein complex, as typified by HDAC1/CoREST/LSD1 and HDAC3/SMRT/GPS2/TBL1.
“The activity of class-I HDACs in vivo is dependent upon binding to an activating partner, part of a multi-protein complex19,20, as typified by HDAC1/CoREST/LSD1 and HDAC3/SMRT/GPS2/TBL1.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Kelly, R. D. & Cowley, S. M. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochemical Society transactions 41, 741–749, https://doi.org/10.1042/BST20130010 (2013). source
Not checked in the free run.
- cites [20] Millard, C. J., Watson, P. J., Fairall, L. & Schwabe, J. W. Targeting Class I Histone Deacetylases in a “Complex” Environment. Trends Pharmacol Sci 38, 363–377, https://doi.org/10.1016/j.tips.2016.12.006 (2017). source
Not checked in the free run.
- May combine two claims. 21
- Classified as probably not a substantial claim. 16
May combine two claims.
Findingown dataAt the assay endpoint, percentage conversion of H3K18cr by HDAC1/CoREST1/LSD1 is reduced compared with H3K18ac, suggesting crotonyl-lysine is turned over more slowly.
“At the end-point of the assay we were also able to measure the percentage conversion of each substrate, which was similarly reduced for H3K18cr compared to H3K18ac, suggesting that the crotonyl-lysine is turned over more slowly than the corresponding acetyl mark.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAddition of InsP6 increases the initial rate of deacetylation and decrotonylation by HDAC1/CoREST/LSD1 3.2-fold and 1.8-fold respectively.
“The initial rate of deacetylation and decrotonylation was increased 3.2-fold and 1.8-fold respectively by the addition of InsP6 to the HDAC1/CoREST/LSD1 complex (Fig. 1A,B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExtracts from ES cells and HEK-293T cells display robust decrotonylase activity that correlates with protein concentration upon extended incubation (>6 hours).
“Upon using extended incubation times (>6 hours) extracts from both ES cells and HEK-293T cells displayed robust decrotonylase activity which correlated with protein concentration (Fig. 2A,B).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationThe HDAC3/SMRT/GPS2/TBL1 complex displays significant decrotonylase activity against H3K18cr peptide, with an initial rate 2.4-fold lower than for H3K18ac.
“Consistent with previously published data18 HDAC3 also displayed significant activity against the H3K18cr peptide (Supplementary Fig. 1B), although similar to HDAC1, with an initial rate which was 2.4-fold lower than the H3K18ac substrate.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Madsen, A. S. & Olsen, C. A. Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro. Angew Chem Int Ed Engl 51, 9083–9087, https://doi.org/10.1002/anie.201203754 (2012). source
Not checked in the free run.
May combine two claims.
Findingown dataDeletion of HDAC1/2 in ES cells causes a small but significant increase in H3K18cr in the vicinity of transcriptional start sites, which is more pronounced at specific promoters such as Lactb and Anapc5.
“In contrast, we observed a small but significant increase in H3K18cr in the vicinity of TSS upon deletion of HDAC1/2 of in ES cells (Fig. 4A), which is more pronounced at specific promoters (Lactb and Anapc5, Fig. 4D).”
Quote in the paperSubstantial claim- Rests on an assumption: The H3K18cr antibody used for native ChIP specifically detects H3K18cr.
May combine two claims.
Findingown dataLoss of HDAC1/2 increases H3K18cr levels, which largely overlap with H3K18ac in the vicinity of transcriptional start sites.
“Furthermore, we mapped H3K18cr in cells using ChIP-seq, with and without HDAC1/2, and observed increased levels of crotonylation, which largely overlaps with H3K18ac in the vicinity of transcriptional start sites.”
Quote in the paperSubstantial claim- Rests on an assumption: The changes in histone crotonylation levels upon HDAC1/2 deletion are due to loss of HDAC1/2 decrotonylase activity rather than indirect effects on other enzymes.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataHDAC1/2 themselves and their related complex components Sin3A and LSD1 all map within the vicinity of transcriptional start sites.
“This is perhaps unsurprising since HDAC1/2 themselves (Fig. 4C) and their related complex components, Sin3A37 and LSD138, all map within the vicinity of TSS.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [37] Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348, https://doi.org/10.1038/nature10066 (2011). source
Not checked in the free run.
- cites [38] Whyte, W. A. et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482, 221–225, https://doi.org/10.1038/nature10805 (2012). source
Not checked in the free run.
May combine two claims.
Findingown dataPlotting FDR of enriched GO terms for both H3K18ac and H3K18cr shows an R2 = 0.929 correlation (p < 0.0001), indicating significant overlap in function of these two acylations in ES cells.
“Furthermore, by plotting the false discovery rate (FDR) of enriched GO terms for both H3K18ac and H3K18cr we observed an R2 = 0.929 correlation (p < 0.0001), indicating a significant overlap in the function of these two acylations in ES cells (Fig. 5D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGenetic deletion of HDAC1/2 from mouse ES cells causes an 85% reduction in total decrotonylase activity, showing HDAC1/2 to be critical enzymes in the regulation of H3K18cr levels.
“We have shown that deletion of HDAC1/2 in ES cells caused an 85% reduction in total decrotonylase activity; this is the first genetic link between HDACs and decrotonylase activity in cells.”
- Also stated in: § Discussion · boosted
“Furthermore, genetic deletion of HDAC1/2 from ES cells reveals them to be critical enzymes in the regulation of H3K18cr levels, in terms of total decrotonylase activity (Fig. 3) and the regulation of histone crotonylation at specific genomic loci (Fig. 4).”
Quote in the paperSubstantial claim- Also stated in: § Discussion · boosted
May combine two claims.
Findingown dataLoss of HDAC1/2 increases average levels of both H3K18ac and H3K18cr around the TSS, with a more pronounced increase for H3K18ac.
“Loss of HDAC1/2 increases the average levels of both H3K18ac and H3K18cr around the TSS (Ctrl vs DKO), with a more pronounced increase observed for H3K18ac.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn contrast to previously published data, increased histone crotonylation upon loss of HDAC1/2 activity largely overlaps with H3K18ac at TSS and correlates with gene activity.
“In contrast to previously published data22, we observed increased levels of histone crotonylation upon loss of HDAC1/2 activity which largely overlaps with H3K18ac at TSS and correlates with gene activity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
- Rests on an assumption: The changes in histone crotonylation levels upon HDAC1/2 deletion are due to loss of HDAC1/2 decrotonylase activity rather than indirect effects on other enzymes.
May combine two claims.
FindingcitationH3K18cr levels peak in the vicinity of transcription start sites and significantly overlap with H3K18ac.
“In line with previous findings9, we observed that H3K18cr levels peak in the vicinity of transcription start sites (TSS) with a significant overlap with H3K18ac (Fig. 4A).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Molecular cell 58, 203–215, https://doi.org/10.1016/j.molcel.2015.02.029 (2015). source
Not checked in the free run.
May combine two claims.
Findingown dataIn ES cells, H3K18ac and H3K18cr show a significant overlap in loci, with the increase in abundance upon HDAC1/2 deletion occurring at pre-existing sites.
“A comparison of H3K18ac and H3K18cr in ES cells revealed a significant overlap in loci, with the increase in abundance upon HDAC1/2 deletion occurring at pre-existing sites.”
Quote in the paperSubstantial claim- Rests on an assumption: The H3K18cr antibody used for native ChIP specifically detects H3K18cr.
May combine two claims.
Findingown dataHDAC1-KO; HDAC2-Het ES cells show increased H3K18ac (1.5-fold) and histone H3 crotonylation (1.5-fold; Pan-Cr), smaller than in DKO cells.
“HDAC1-KO; HDAC2-Het cells showed increased levels of H3K18ac (1.5-fold) and histone H3 crotonylation (1.5-fold; Pan-Cr; Supplementary Fig. S2B), although these increases are smaller than those observed in DKO cells (Fig. 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter LBH589 treatment for 24 hours and washout, there is little or no difference in recovery time between H3K18ac and H3K18cr, suggesting the rate of decrotonylation is similar to deacetylation in cells.
“Surprisingly, given the difference in initial rates measured using the caliper assay in vitro (Fig. 1), we detect little or no difference in the recovery time, suggesting that the rate of decrotonylation is similar to deacetylation in cells (Supplementary Fig. S2C).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHDAC inhibitor treatment reduces the average level of H3K18cr at transcriptional start sites.
“siRNA knockdown of HDAC1/221 or treatment with HDAC inhibitors22 caused increased levels of histone crotonylation; although counterintuitively, the average level of H3K18cr at transcriptional start sites (TSS) was reduced following HDAC inhibitor treatment22.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
May combine two claims.
PremisecitationsiRNA knockdown of HDAC1/2 or HDAC inhibitor treatment causes increased levels of histone crotonylation.
“siRNA knockdown of HDAC1/221 or treatment with HDAC inhibitors22 caused increased levels of histone crotonylation; although counterintuitively, the average level of H3K18cr at transcriptional start sites (TSS) was reduced following HDAC inhibitor treatment22.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [21] Wei, W. et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res 27, 898–915, https://doi.org/10.1038/cr.2017.68 (2017). source
Not checked in the free run.
- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLysine acetylation and lysine crotonylation are recognized by distinct readers, in bromodomains and Yeats domains respectively.
“However, Lys-ac and Lys-cr may be interpreted differently, since they are recognized by distinct readers, in the bromodomain10 and Yeats domain11 respectively.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [10] Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496, https://doi.org/10.1038/20974 (1999). source
Not checked in the free run.
- cites [11] Li, Y. et al. Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Molecular cell 62, 181–193, https://doi.org/10.1016/j.molcel.2016.03.028 (2016). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA study profiling substrate preferences of HDAC1-11 identified HDAC3 as a potential decrotonylase.
“A study profiling substrate preferences of HDAC1–11 identified HDAC3 as a potential decrotonylase18.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Madsen, A. S. & Olsen, C. A. Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro. Angew Chem Int Ed Engl 51, 9083–9087, https://doi.org/10.1002/anie.201203754 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSirtuins 1, 2 and 3 have been shown to be decrotonylases in vitro.
“Unsurprisingly, given the range of their potential substrates, sirtuins 1, 216 and 317 were shown to be decrotonylases in vitro.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [16] Feldman, J. L., Baeza, J. & Denu, J. M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. The Journal of biological chemistry 288, 31350–31356, https://doi.org/10.1074/jbc.C113.511261 (2013). source
Not checked in the free run.
- cites [17] Bao, X. et al. Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach. Elife 3, https://doi.org/10.7554/eLife.02999 (2014). source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationHDAC1 and HDAC2 form the catalytic core of multiple co-repressor complexes, including Sin3, NuRD, CoREST and MiDAC.
“HDAC1 and HDAC2 (HDAC1/2) are highly related deacetylases that form the catalytic core of multiple co-repressor complexes, including, Sin3, NuRD, CoREST and MiDAC19,20.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Kelly, R. D. & Cowley, S. M. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochemical Society transactions 41, 741–749, https://doi.org/10.1042/BST20130010 (2013). source
Not checked in the free run.
- cites [20] Millard, C. J., Watson, P. J., Fairall, L. & Schwabe, J. W. Targeting Class I Histone Deacetylases in a “Complex” Environment. Trends Pharmacol Sci 38, 363–377, https://doi.org/10.1016/j.tips.2016.12.006 (2017). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHistone lysine crotonylation is associated with active chromatin and overlaps with known sites of lysine acetylation.
“A number of functional studies have concentrated on histone lysine-crotonylation (Lys-cr) which is associated with active chromatin and overlaps with known sites of lysine-acetylation (Lys-ac)3,9.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [3] Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028, https://doi.org/10.1016/j.cell.2011.08.008 (2011). source
Not checked in the free run.
- cites [9] Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Molecular cell 58, 203–215, https://doi.org/10.1016/j.molcel.2015.02.029 (2015). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTreatment of HCT-116 cells with MS-275 increases global H3K18cr levels but reduces H3K18cr levels around transcriptional start sites.
“Although treatment of HCT-116 cells with MS-275 increased the global levels of H3K18cr, ChIP-seq showed a reduction in H3K18cr levels around transcriptional start sites22.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationClass-I HDACs regulate levels of histone decrotonylation in the intestine in response to short chain fatty acids generated by the gut microbiota.
“More recently, Fellows et. al. (2018) provided evidence that class-I HDACs regulate levels of histone decrotonylation in the intestine in response to short chain fatty acids generated by the microbiota of the gut22.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
May combine two claims.
Interpretationown dataIncreases in histone crotonylation at specific sites appear correlated with corresponding changes in H3K18ac, suggesting HDAC1/2 co-ordinately regulate both modifications at specific sites.
“These increases in histone crotonylation appear to be correlated with corresponding changes in H3K18ac, suggesting that HDAC1/2 co-ordinately regulate both histone modifications at specific sites.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOverexpression of class I HDACs (HDAC1, 2, 3 and 8) in HeLa cells decreases global histone crotonylation levels, whereas knockdown or HDAC inhibitor treatment produces the opposite effect.
“Wei et al.21 demonstrated that overexpression of class I HDACs (HDAC1, 2, 3 and 8) in HeLa cells were able to decrease global histone crotonylation levels, while knock-down or HDAC inhibitor treatment produced the opposite effect21.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Wei, W. et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res 27, 898–915, https://doi.org/10.1038/cr.2017.68 (2017). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHDAC1/2 map predominantly to transcription start sites with a positive correlation between binding and gene activity.
“This is not surprising, since HDAC1/2 map predominantly to TSS (Fig. 4C) with a positive correlation between binding and gene activity33,34.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031, https://doi.org/10.1016/j.cell.2009.06.049 (2009). source
Not checked in the free run.
- cites [34] Kurdistani, S. K., Robyr, D., Tavazoie, S. & Grunstein, M. Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nature genetics 31, 248–254, https://doi.org/10.1038/ng907 (2002). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe HDAC3/NCoR complex hydrolyses Lys-cr at a lower rate than Lys-ac, though still comparable to the deacetylase activities of HDAC8 and HDAC11.
“This is consistent with data from Madsen and Olson18, who showed that the HDAC3/NCoR complex also hydrolysed Lys-cr at a lower rate than Lys-ac, although still comparable to the deacetylase activities of HDAC8 and HDAC11.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Madsen, A. S. & Olsen, C. A. Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro. Angew Chem Int Ed Engl 51, 9083–9087, https://doi.org/10.1002/anie.201203754 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPurified HDAC1, 2 and 3 are able to reduce the levels of H3K18 butyrylation in vitro.
“Indeed, data from Fellows et al., showed that purified HDAC1, 2 and 3 are able to reduce the levels of H3K18 butyrlation in vitro22.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDecrotonylase activity has been described for HDAC1-3 and Sirtuins 1-3.
“To date, decrotonylase activity has been described for HDAC1-3 and Sirtuins 1-316–18,21,22.”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [16] Feldman, J. L., Baeza, J. & Denu, J. M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. The Journal of biological chemistry 288, 31350–31356, https://doi.org/10.1074/jbc.C113.511261 (2013). source
Not checked in the free run.
- cites [17] Bao, X. et al. Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach. Elife 3, https://doi.org/10.7554/eLife.02999 (2014). source
Not checked in the free run.
- cites [18] Madsen, A. S. & Olsen, C. A. Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro. Angew Chem Int Ed Engl 51, 9083–9087, https://doi.org/10.1002/anie.201203754 (2012). source
Not checked in the free run.
- cites [21] Wei, W. et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res 27, 898–915, https://doi.org/10.1038/cr.2017.68 (2017). source
Not checked in the free run.
- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAll in vitro HDAC and HDCR reactions were carried out in duplicate.
“All reactions were carried out in duplicate in 30 µl reaction volumes, performed at room temperature in 50 mM Tris pH 7.5, 50 mM NaCl, 5% glycerol.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMass-spectrometry data show an abundance of histone crotonylation sites in all four core histones.
“Mass-spectrometry data has shown that there are an abundance of histone crotonylation sites in all four core histones22,40.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [22] Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9, 105, https://doi.org/10.1038/s41467-017-02651-5 (2018). source
Not checked in the free run.
- cites [40] Tan, M. et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab 19, 605–617, https://doi.org/10.1016/j.cmet.2014.03.014 (2014). source
Not checked in the free run.
The paper relies on this without support.
The HDAC1/CoREST1/LSD1 ternary complex is representative of HDAC1/2-containing co-repressor complexes for decrotonylase activity.
“For this study we utilized the CoREST complex because we are able to generate a recombinant HDAC1/CoREST1/LSD1 ternary complex23, using full-length proteins, in a 1:1:1 ratio at milligram quantities.”
The paper relies on this without support.
ES cells are a valid model for in vivo regulation of histone crotonylation.
“Collectively, our data indicate that HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo.”
The paper relies on this without support.
The changes in histone crotonylation levels upon HDAC1/2 deletion are due to loss of HDAC1/2 decrotonylase activity rather than indirect effects on other enzymes.
“Since these observations imply HDAC1/2 are active decrontonylases, we assayed the remaining deacetylase and decrotonylase activity following HDAC1/2 deletion.”
The paper relies on this without support.
The H3K18cr antibody used for native ChIP specifically detects H3K18cr.
“Chromatin was immunoprecipitated using 8 μg H3K18ac (Catalog No: 39755; Active Motif) or 8 μg H3K18cr (PTM-Biolabs 517) conjugated to 50 μL Dynabeads Protein G overnight at 4 °C.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Histone modifications are dynamically regulated by coordinated enzyme systems referred to as writers, erasers, and readers, which deposit, remove, or recognize specific epigenetic marks.
“Histone modifications are dynamically regulated by coordinated enzyme systems commonly referred to as “writers,” “erasers,” and “readers,” which respectively deposit, remove, or recognize specific epigenetic marks (Kelly et al., 2018; Brancolini et al., 2022).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Kelly et al., 2018
Cites
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890 · see citing works
deepTools2: a next generation web server for deep-sequencing data analysis
Ramírez, F., Ryan, D. P., Grüning, B., Bhardwaj, V., Kilpert, F., Richter, A. S., Heyne, S., Dündar, F., & Manke, T. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw257 · Cited by 8,096 · see citing works
A bivalent chromatin structure marks key developmental genes in embryonic stem cells
Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.041 · Cited by 5,361 · see citing works
Genome-wide maps of chromatin state in pluripotent and lineage-committed cells
Mikkelsen, T. S., Ku, M., Jaffe, D. B., Issac, B., Lieberman, E., Giannoukos, G., Alvarez, P., Brockman, W., Kim, T.-K., Koche, R. P., et al. (2007) · Nature · doi:10.1038/nature06008 · Cited by 4,129 · see citing works
Haberland, M., Montgomery, R. L., & Olson, E. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2485 · Cited by 2,541 · see citing works
Sirtuins as regulators of metabolism and healthspan
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008 · see citing works
Tan, M., Luo, H., Lee, S., Jin, F., Yang, J. S., Montellier, E., Buchou, T., Cheng, Z., Rousseaux, S., Rajagopal, N., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.008 · Cited by 1,902 · see citing works
Structure and ligand of a histone acetyltransferase bromodomain
Dhalluin, C., Carlson, J. E., Zeng, L., He, C., Aggarwal, A. K., Zhou, M.-M., & Zhou, M.-M. (1999) · Nature · doi:10.1038/20974 · Cited by 1,732 · see citing works
Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase
Du, J., Zhou, Y., Su, X., Yu, J. J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J. H., Choi, B. H., et al. (2011) · Science · doi:10.1126/science.1207861 · Cited by 1,429 · see citing works
Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes
Wang, Z., Zang, C., Cui, K., Schones, D. E., Barski, A., Peng, W., & Zhao, K. (2009) · Cell · doi:10.1016/j.cell.2009.06.049 · Cited by 1,344 · see citing works
Metabolic regulation of gene expression through histone acylations
Sabari, B. R., Zhang, D., Allis, C. D., & Zhao, Y. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.140 · Cited by 1,134 · see citing works
TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity
Williams, K., Christensen, J., Pedersen, M. T., Johansen, J. V., Cloos, P. A. C., Rappsilber, J., & Helin, K. (2011) · Nature · doi:10.1038/nature10066 · Cited by 1,021 · see citing works
Histone core modifications regulating nucleosome structure and dynamics
Tessarz, P., & Kouzarides, T. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3890 · Cited by 1,018 · see citing works
Lysine glutarylation is a protein posttranslational modification regulated by SIRT5
Tan, M., Peng, C., Anderson, K. A., Chhoy, P., Xie, Z., Dai, L., Park, J., Chen, Y., Huang, H., Zhang, Y., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.014 · Cited by 844 · see citing works
Lysine propionylation and butyrylation are novel post-translational modifications in histones
Chen, Y., Sprung, R., Tang, Y., Ball, H., Sangras, B., Kim, S. C., Falck, J. R., Peng, J., Gu, W., & Zhao, Y. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m700021-mcp200 · Cited by 764 · see citing works
Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation
Xie, Z., Zhang, D., Chung, D., Tang, Z., Huang, H., Dai, L., Qi, S., Li, J., Colak, G., Chen, Y., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.036 · Cited by 744 · see citing works
Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractilityPreprint
Montgomery, R. L., Davis, C. A., Potthoff, M. J., Haberland, M., Fielitz, J., Qi, X., Hill, J. A., Richardson, J. A., & Olson, E. N. (2007) · Genes & Development · doi:10.1101/gad.1563807 · Cited by 716 · see citing works
Intracellular Crotonyl-CoA Stimulates Transcription through p300-Catalyzed Histone Crotonylation
Sabari, B. R., Tang, Z., Huang, H., Yong-Gonzalez, V., Molina, H., Kong, H. E., Dai, L., Shimada, M., Cross, J. R., Zhao, Y., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.02.029 · Cited by 659 · see citing works
Feldman, J. L., Baeza, J., & Denu, J. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.c113.511261 · Cited by 637 · see citing works
Lysine succinylation and lysine malonylation in histones
Xie, Z., Dai, J., Dai, L., Tan, M., Cheng, Z., Wu, Y., Boeke, J. D., & Zhao, Y. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.015875 · Cited by 613 · see citing works
Enhancer decommissioning by LSD1 during embryonic stem cell differentiation
Whyte, W. A., Bilodeau, S., Orlando, D. A., Hoke, H. A., Frampton, G. M., Foster, C. T., Cowley, S. M., & Young, R. A. (2012) · Nature · doi:10.1038/nature10805 · Cited by 602 · see citing works
Self-citationFellows, R., Denizot, J., Stellato, C., Cuomo, A., Jain, P., Stoyanova, E., Balázsi, S., Hajnády, Z., Liebert, A., Kazakevych, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02651-5 · Cited by 568 · see citing works
Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate
Watson, P. J., Fairall, L., Santos, G. M., & Schwabe, J. W. R. (2012) · Nature · doi:10.1038/nature10728 · Cited by 505 · see citing works
Self-citationLysine 2-hydroxyisobutyrylation is a widely distributed active histone mark
Dai, L., Peng, C., Montellier, E., Lu, Z., Chen, Y., Ishii, H., Debernardi, A., Buchou, T., Rousseaux, S., Jin, F., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1497 · Cited by 460 · see citing works
Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates
Millard, C. J., Watson, P. J., Celardo, I., Gordiyenko, Y., Cowley, S. M., Robinson, C. V., Fairall, L., & Schwabe, J. W. R. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.05.020 · Cited by 396 · see citing works
Self-citationMolecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain
Li, Y., Sabari, B. R., Panchenko, T., Wen, H., Zhao, D., Guan, H., Wan, L., Huang, H., Tang, Z., Zhao, Y., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.028 · Cited by 384 · see citing works
Bao, X., Wang, Y., Li, X., Li, X.-M., Liu, Z., Yang, T., Wong, C. F., Zhang, J., Hao, Q., & Li, X. D. (2014) · eLife · doi:10.7554/elife.02999 · Cited by 324 · see citing works
Wei, W., Liu, X., Chen, J., Gao, S., Lu, L., Zhang, H., Ding, G., Wang, Z., Chen, Z., Shi, T., et al. (2017) · Cell Research · doi:10.1038/cr.2017.68 · Cited by 304 · see citing works
Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation
Dovey, O. M., Foster, C. T., & Cowley, S. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000478107 · Cited by 298 · see citing works
Self-citationKelly, R. D. W., & Cowley, S. M. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130010 · Cited by 297 · see citing works
Self-citationHistone deacetylases 1 and 2 act in concert to promote the G1-to-S progressionPreprint
Yamaguchi, T., Cubizolles, F., Zhang, Y., Reichert, N., Kohler, H., Seiser, C., & Matthias, P. (2010) · Genes & Development · doi:10.1101/gad.552310 · Cited by 294 · see citing works
Genome-wide binding map of the histone deacetylase Rpd3 in yeast
Kurdistani, S. K., Robyr, D., Tavazoie, S., & Grunstein, M. (2002) · Nature Genetics · doi:10.1038/ng907 · Cited by 279 · see citing works
Goudarzi, A., Zhang, D., Huang, H., Barral, S., Kwon, O. K., Qi, S., Tang, Z., Buchou, T., Vitte, A.-L., Tie-ming, H., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.014 · Cited by 264 · see citing works
Immunoprecipitation of native chromatin: NChIP.
O'Neill, L., & Turner, B. (2003) · Methods · doi:10.1016/s1046-2023(03)00090-2 · Cited by 239 · see citing works
Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors
Kalin, J. H., Wu, M., Gómez, A. V., Song, Y., Das, J., Hayward, D., Adejola, N., Wu, M., Panova, I. P., Chung, H. J., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02242-4 · Cited by 239 · see citing works
Self-citationOverlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis
Wilting, R. H., Yanover, E., Heideman, M. R., Jacobs, H., Horner, J. W., van der Torre, J., DePinho, R. A., & Dannenberg, J. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.136 · Cited by 229 · see citing works
Histone propionylation is a mark of active chromatin
Kebede, A. F., Nieborak, A., Shahidian, L. Z., Gras, S. L., Richter, F. M., Aguilar‐Gómez, D., Baltissen, M. P. A., Mészáros, G., Magliarelli, H. D. F., Taudt, A., et al. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3490 · Cited by 203 · see citing works
Lysine-Specific Demethylase 1 Regulates the Embryonic Transcriptome and CoREST Stability
Foster, C. T., Dovey, O. M., Lezina, L., Luo, J., Gant, T. W., Barlev, N. A., Bradley, A., & Cowley, S. M. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00521-10 · Cited by 198 · see citing works
Self-citationTargeting Class I Histone Deacetylases in a “Complex” Environment
Millard, C. J., Watson, P. J., Fairall, L., & Schwabe, J. W. R. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.006 · Cited by 180 · see citing works
Self-citationStructure of p300 in complex with acyl-CoA variants
Kaczmarska, Z., Ortega, E. M., Goudarzi, A., Huang, H., KIM, S. ‐., Márquez, J. A., Zhao, Y., Khochbin, S., & Panne, D. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2217 · Cited by 174 · see citing works
Jamaladdin, S., Kelly, R. D., O’Regan, L., Dovey, O. M., Hodson, G. E., Millard, C. J., Portolano, N., Fry, A. M., Schwabe, J. W. R., & Cowley, S. M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321330111 · Cited by 164 · see citing works
Self-citationLamble, S., Batty, E. M., Attar, M., Buck, D., Bowden, R. J., Lunter, G. A., Crook, D. W., El‐Fahmawi, B., & Piazza, P. (2013) · BMC Biotechnology · doi:10.1186/1472-6750-13-104 · Cited by 149 · see citing works
Dovey, O. M., Foster, C. T., Conte, N., Edwards, S. A., Edwards, J. M., Singh, R., Vassiliou, G. S., Bradley, A., & Cowley, S. M. (2013) · Blood · doi:10.1182/blood-2012-07-441949 · Cited by 143 · see citing works
Self-citationMadsen, A. S., & Olsen, C. A. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201203754 · Cited by 122 · see citing works
Ridsdale, J., Hendzel, M. J., Delcuve, G. P., & Davie, J. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)34098-0 · Cited by 121 · see citing works
Montellier, E., Rousseaux, S., Zhao, Y., & Khochbin, S. (2012) · BioEssays · doi:10.1002/bies.201100141 · Cited by 116 · see citing works
Brand, M., Rampalli, S., Chaturvedi, C.-P., & Dilworth, F. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.8 · Cited by 99 · see citing works
A specific mutation in <i>TBL1XR1</i> causes Pierpont syndrome
Heinen, C. A., Jongejan, A., Watson, P. J., Redeker, B., Boelen, A., Boudzovitch-Surovtseva, O., Forzano, F., Hordijk, R., Kelley, R., Olney, A. H., et al. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2015-103233 · Cited by 73 · see citing works
Self-citationChromatin dynamics and histone modifications in intestinal microbiota-host crosstalk
Fellows, R., & Varga‐Weisz, P. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.12.005 · Cited by 71 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The interaction among gut microbes, the intestinal barrier and short chain fatty acids
Ma, J., Piao, X., Mahfuz, S. U., Long, S., & Wang, J. (2021) · Animal nutrition · doi:10.1016/j.aninu.2021.09.012 · Cited by 409 · see citing works
Liu, R., Wu, J., Guo, H., Yao, W., Li, S., Lu, Y., Jia, Y., Liang, X., Tang, J., & Zhang, H. (2023) · MedComm · doi:10.1002/mco2.292 · Cited by 287 · see citing works
Barnes, C. E., English, D. M., & Cowley, S. M. (2019) · Essays in Biochemistry · doi:10.1042/ebc20180061 · Cited by 225 · see citing works
Self-citationShort-chain fatty acids activate acetyltransferase p300
Thomas, S. P., & Denu, J. M. (2021) · eLife · doi:10.7554/elife.72171 · Cited by 159 · see citing works
Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy
Verza, F. A., Das, U., Fachin, A. L., Dimmock, J. R., & Marins, M. (2020) · Cancers · doi:10.3390/cancers12061664 · Cited by 147 · see citing works
Dai, S., Liu, P.-P., Li, X., Jiao, L., Teng, Z., & Liu, C. (2022) · Development · doi:10.1242/dev.200049 · Cited by 145 · see citing works
Functions and mechanisms of lysine crotonylation
Wan, J., Liu, H., Chu, J., & Zhang, H. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14650 · Cited by 138 · see citing works
Protein lysine crotonylation: past, present, perspective
Jiang, G., Li, C., Lü, M. K., Lu, K., & Li, H. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03987-z · Cited by 138 · see citing works
The Regulation and Function of Histone Crotonylation
Ntorla, A., & Burgoyne, J. R. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.624914 · Cited by 107 · see citing works
Lysine crotonylation is involved in hepatocellular carcinoma progression
Wan, J., Liu, H., & Ming, L. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.12.148 · Cited by 106 · see citing works
Yang, Y., Wen, R., Yang, N., Zhang, T., & Liu, C. (2023) · Molecular Medicine · doi:10.1186/s10020-023-00684-9 · Cited by 102 · see citing works
Kollenstart, L., de Groot, A. J. L., Janssen, G. M. C., Cheng, X., Vreeken, K., Martino, F., Côté, J., van Veelen, P. A., & van Attikum, H. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010302 · Cited by 95 · see citing works
Role of histone deacetylases and their inhibitors in neurological diseases
Zhang, L.-Y., Zhang, S.-Y., Wen, R., Zhang, T.-N., & Yang, N. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107410 · Cited by 84 · see citing works
Function and Mechanism of Novel Histone Posttranslational Modifications in Health and Disease
Xu, H., Wu, M., Ma, X., Huang, W. G., & Xu, Y. (2021) · BioMed Research International · doi:10.1155/2021/6635225 · Cited by 80 · see citing works
Chromatin dynamics and histone modifications in intestinal microbiota-host crosstalk
Fellows, R., & Varga‐Weisz, P. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.12.005 · Cited by 71 · see citing works
Dietary natural products as epigenetic modifiers in aging-associated inflammation and disease
Evans, L. W., Stratton, M. S., & Ferguson, B. S. (2020) · Natural Product Reports · doi:10.1039/c9np00057g · Cited by 70 · see citing works
Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice
Zhang, Y., Chen, Y., Zhang, Z., Tao, X., Xu, S., Zhang, X., Zurashvili, T., Lu, Z., Bayascas, J. R., Jin, L., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04725-9 · Cited by 66 · see citing works
Lucaciu, A., Brunkhorst, R., Pfeilschifter, J. M., Pfeilschifter, W., & Subburayalu, J. (2020) · Cells · doi:10.3390/cells9061515 · Cited by 65 · see citing works
HDACs and the epigenetic plasticity of cancer cells: target the complexity
Brancolini, C., Gagliano, T., & Minisini, M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108190 · Cited by 55 · see citing works
Histone post-translational modification and the DNA damage response
Song, H., Shen, R., Liu, X., Yang, X., Xie, K., Guo, Z., & Wang, D. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2022.04.002 · Cited by 54 · see citing works
The Function and related Diseases of Protein Crotonylation
Wang, S., Mu, G., Qiu, B., Wang, M., Yu, Z., Wang, W., Wang, J., & Yang, Y. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.58872 · Cited by 54 · see citing works
HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation
Xiao, Y., Hale, S. M., Awasthee, N., Meng, C., Zhang, X., Liu, Y., Ding, H., Huo, Z., Lv, D., Zhang, W., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.07.010 · Cited by 54 · see citing works
Effects of Histone Modification in Major Depressive Disorder
Wu, M.-S., Li, X., Liu, C., Xu, Q., Huang, J., Gu, S., & Chen, J. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210922150043 · Cited by 51 · see citing works
The mechanisms, regulations, and functions of histone lysine crotonylation
Xie, J., Ju, J., Zhou, P., Chen, H., Wang, S., Wang, K., Wang, T., Chen, Y.-C., Chen, Y.-C., & Wang, K. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01830-w · Cited by 51 · see citing works
Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease
Wang, R., Sun, H., Wang, G., & Ren, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197182 · Cited by 50 · see citing works
Sun, C., Xu, W., Zhao, Q.-W., Luo, S., Chen, X.-A., Li, Y., & Mao, X. (2020) · Communications Biology · doi:10.1038/s42003-020-0924-2 · Cited by 50 · see citing works
Histone crotonylation regulates neural stem cell fate decisions by activating bivalent promoters
Dai, S., Liu, P., Du, H., Liu, X., Xu, Y., Liu, C., Wang, Y.-Y., Teng, Z., & Liu, C. (2021) · EMBO Reports · doi:10.15252/embr.202052023 · Cited by 49 · see citing works
The Contribution of Histone Crotonylation to Tissue Health and Disease: Focus on Kidney Health
Martinez-Moreno, J. M., Fontecha‐Barriuso, M., Martín‐Sánchez, D., Sánchez-Niño, M. D., Ruiz‐Ortega, M., Sanz, A. B., & Ortíz, A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00393 · Cited by 41 · see citing works
Crotonylation and disease: Current progress and future perspectives
Yang, P., Qin, Y., Zeng, L., He, Y., Xie, Y., Cheng, X., Huang, W. G., & Cao, L. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115108 · Cited by 38 · see citing works
Substrate and Functional Diversity of Protein Lysine Post-translational Modifications
Hao, B., Chen, K., Zhai, L., Liu, M., Liu, B., & Tan, M. (2024) · Genomics Proteomics & Bioinformatics · doi:10.1093/gpbjnl/qzae019 · Cited by 39 · see citing works
Novel histone modifications and liver cancer: emerging frontiers in epigenetic regulation
Wang, Z., Liu, Z., Lv, M., Luan, Z., Li, T., & Hu, J. (2025) · Clinical Epigenetics · doi:10.1186/s13148-025-01838-8 · Cited by 39 · see citing works
Structural analyses of inositol phosphate second messengers bound to signaling effector proteins
Blind, R. D. (2019) · Advances in Biological Regulation · doi:10.1016/j.jbior.2019.100667 · Cited by 36 · see citing works
Post-translational acylation of proteins in cardiac hypertrophy
Liu, Y., Yang, Q., & He, G. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01150-1 · Cited by 38 · see citing works
Bahia, R. K., Hao, X., Hassam, R., Cseh, O., Bozek, D. A., Luchman, H. A., & Weiss, S. (2023) · Nature Communications · doi:10.1038/s41467-023-40776-y · Cited by 34 · see citing works
Nuclear position and local acetyl-CoA production regulate chromatin state
Willnow, P., & Teleman, A. A. (2024) · Nature · doi:10.1038/s41586-024-07471-4 · Cited by 34 · see citing works
P300 regulates histone crotonylation and preimplantation embryo development
Gao, D., Li, C., Liu, S., Xu, T., Lin, X., Tan, Y.-P., Gao, F.-M., Yi, L.-T., Zhang, J. V., Ma, J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50731-0 · Cited by 34 · see citing works
Yang, J., He, Z., Chen, C., Li, S., Qian, J., Zhao, J., & Fang, R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.696061 · Cited by 32 · see citing works
Resolving the deceptive isoform and complex selectivity of HDAC1/2 inhibitors
Payne, N. C., & Mazitschek, R. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.03.002 · Cited by 32 · see citing works
Epigenetic regulators controlling osteogenic lineage commitment and bone formation
Dashti, P., Lewallen, E. A., Gordon, J. A. R., Montecino, M. A., Davie, J., Stein, G. S., van Leeuwen, J. P. T. M., van der Eerden, B. C. J., & van Wijnen, A. J. (2024) · Bone · doi:10.1016/j.bone.2024.117043 · Cited by 30 · see citing works
González, B., Gancedo, S. N., Garazatua, S. A. J., Roldán, E. R. S., Vitullo, A. D., & González, C. R. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00216 · Cited by 30 · see citing works
Distinct biochemical properties of the class I histone deacetylase complexes
Lee, K., Whedon, S. D., Wang, Z. A., & Cole, P. A. (2022) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2022.102179 · Cited by 33 · see citing works
Reversible histone deacetylase activity catalyzes lysine acylation
Tsusaka, T., Najar, M. A., Schwarz, B. H., Bohrnsen, E., Osés-Prieto, J. A., Neudorf, H., Lee, C., Little, J. P., Burlingame, A. L., Bosio, C. M., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01869-5 · Cited by 29 · see citing works
Post-translational lysine ac(et)ylation in health, ageing and disease
Blasl, A., Schulze, S., Qin, C., Graf, L. G., Vogt, R., & Lammers, M. (2021) · Biological Chemistry · doi:10.1515/hsz-2021-0139 · Cited by 29 · see citing works
Regulatory Mechanism of Protein Crotonylation and Its Relationship with Cancer
Yang, S., Fan, X., & Yu, W. (2024) · Cells · doi:10.3390/cells13211812 · Cited by 27 · see citing works
Role of novel protein acylation modifications in immunity and its related diseases
Li, X., Yu, T., Li, X., He, X., Zhang, B., & Yang, Y. (2024) · Immunology · doi:10.1111/imm.13822 · Cited by 25 · see citing works
HDAC1 inhibits beige adipocyte-mediated thermogenesis through histone crotonylation of Pgc1a/Ucp1
Tian, D., Zeng, X., Gong, Y., Yin, Z., Zhang, J., & Wu, Z. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.110875 · Cited by 25 · see citing works
Huang, X., Pan, Q., Lin, Y., Gu, T., & Li, Y. (2020) · Plant Methods · doi:10.1186/s13007-020-0556-z · Cited by 24 · see citing works
Signalling Properties of Inositol Polyphosphates
Maffucci, T., & Falasca, M. (2020) · Molecules · doi:10.3390/molecules25225281 · Cited by 21 · see citing works
Protein acetylation in cardiac aging
Francois, A., Canella, A., Marcho, L. M., & Stratton, M. S. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.04.007 · Cited by 22 · see citing works
Xie, T., Dong, J., Zhou, X., Tang, D., Li, D., Chen, J., Chen, Y., Xu, H., Xue, W., Liu, D. J., et al. (2022) · Clinical Rheumatology · doi:10.1007/s10067-022-06254-4 · Cited by 22 · see citing works
Chromatin lysine acylation: On the path to chromatin homeostasis and genome integrity
Chen, F., He, X., Xu, W., Zhou, L., Liu, Q., Chen, W., Zhu, W., & Zhang, J. (2024) · Cancer Science · doi:10.1111/cas.16321 · Cited by 20 · see citing works
Chao, C., Kuo, F.-C., & Lin, S. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.09.012 · Cited by 21 · see citing works
Wang, M., Mu, G., Qiu, B., Wang, S., Tao, C., Mao, Y., Zhao, X., Liu, J., Chen, K., Li, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57546-7 · Cited by 20 · see citing works
Kovalenko, M. V., Erdin, S., Andrew, M. A., Claire, J. S., Shaughnessey, M., Hubert, L., Neto, J. L., Stortchevoi, A., Fass, D. M., Pinto, R. M., et al. (2020) · eLife · doi:10.7554/elife.55911 · Cited by 21 · see citing works
Lai, T.-H., Özer, H. G., Gasparini, P., Nigita, G., Distefano, R., Yu, L., Ravikrishnan, J., Yilmaz, A. S., Gallegos, J. J., Shukla, S. A., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022007998 · Cited by 20 · see citing works
Histone Deacetylase Inhibitors as Cognitive Enhancers and Modifiers of Mood and Behavior
Pal, D., Sahu, P., Mishra, A. K., Hagelgans, A., & Sukocheva, O. A. (2022) · Current Drug Targets · doi:10.2174/1389450124666221207090108 · Cited by 19 · see citing works
Lao, Y., Jin, Y., Wu, S., Fang, T., Wang, Q., Sun, L., & Sun, B. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02199-1 · Cited by 19 · see citing works
Lysine Crotonylation: An Emerging Player in DNA Damage Response
Zhao, Y., Hao, S., Wu, W., Li, Y., Hou, K., Liu, Y., Cui, W., Xu, X., & Wang, H. (2022) · Biomolecules · doi:10.3390/biom12101428 · Cited by 21 · see citing works
Lysine crotonylation in disease: mechanisms, biological functions and therapeutic targets
Ji, Y., Liu, S., Zhang, Y., Min, Y., Wei, L., Guan, C., Yu, H., & Zhang, Z. (2025) · Epigenetics & Chromatin · doi:10.1186/s13072-025-00577-7 · Cited by 18 · see citing works
Lysine crotonylation: A challenging new player in the epigenetic regulation of plants
la Rosa, P. A. C.-D., Aragón-Rodríguez, C., Ceja-López, J. A., García-Arteaga, K. F., & De‐la‐Peña, C. (2022) · Journal of Proteomics · doi:10.1016/j.jprot.2022.104488 · Cited by 18 · see citing works
Protein lysine crotonylation in cellular processions and disease associations
Zhao, H., Han, Y., Zhou, P., Guan, H., & Gao, S. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.06.029 · Cited by 17 · see citing works
Alipour, N. J., Meshkani, R., Toolabi, K., Azadi, S. M., Zand, S., & Emamgholipour, S. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05431-5 · Cited by 17 · see citing works
Kelly, R. D., Stengel, K. R., Chandru, A., Johnson, L. C., Hiebert, S. W., & Cowley, S. M. (2024) · Genome Research · doi:10.1101/gr.278050.123 · Cited by 17 · see citing works
Self-citationHua, H.-S., Wen, H.-C., Lee, H.-S., Weng, C.-M., Yuliani, F. S., Kuo, H.-P., Chen, B.-C., & Lin, C.-H. (2023) · Journal of Biomedical Sciences · doi:10.1186/s12929-023-00931-5 · Cited by 17 · see citing works
Bhattacharya, S., & Tu, B. P. (2024) · Journal of Cell Science · doi:10.1242/jcs.261250 · Cited by 15 · see citing works
ARHGEF3 regulates the stability of ACLY to promote the proliferation of lung cancer
Zhou, F., Ai, W., Zhang, Y., Hu, Q., Gan, M., Wang, J., & Han, T. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05297-4 · Cited by 16 · see citing works
Liao, X., Guo, Y., He, Y., Xiao, Y., Li, J., & Liu, R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105834 · Cited by 14 · see citing works
Liu, Y., Liang, J., Liu, Z., Tian, X., & Sun, C. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.130816 · Cited by 15 · see citing works
Fan, S., Kong, C., Zhou, R., Zheng, X., Ren, D., & Yin, Z. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c08332 · Cited by 15 · see citing works
Salt stress downregulates 2-hydroxybutyrylation in Arabidopsis siliques
Hong, G., Su, X., Xu, K., Liu, B., Wang, G., Li, J., Wang, R., Zhu, M., & Li, G. (2021) · Journal of Proteomics · doi:10.1016/j.jprot.2021.104383 · Cited by 15 · see citing works
Crotonylation modification and its role in diseases
Guo, Y., Li, J., & Zhang, K. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1492212 · Cited by 14 · see citing works
Xu, Y., Zhang, H., & Nie, D. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1521550 · Cited by 14 · see citing works
Mechanism and application of feedback loops formed by mechanotransduction and histone modifications
Sun, H., Gao, Y., Ma, X., Deng, Y., Bi, L., & Li, L. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.06.030 · Cited by 14 · see citing works
Wu, J. T., Meng, X., Jiang, W., Wang, Z., Zhang, J., Meng, F., Yao, X., Ye, M., Yao, L., Wang, L., et al. (2022) · Frontiers in Plant Science · doi:10.3389/fpls.2022.822374 · Cited by 14 · see citing works
Lam‐ubol, A., & Phattarataratip, E. (2022) · Scientific Reports · doi:10.1038/s41598-022-19174-9 · Cited by 14 · see citing works
Histone deacetylases and their inhibitors in kidney diseases
Zheng, Y., Zhang, T., Hao, P.-H., Yang, N., & Du, Y. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.026 · Cited by 13 · see citing works
Mahindra, A., Millard, C. J., Black, I., Archibald, L. J., Schwabe, J. W. R., & Jamieson, A. G. (2019) · Organic Letters · doi:10.1021/acs.orglett.9b00885 · Cited by 13 · see citing works
Self-citationGuo, H., Han, Y., Yao, S., Chen, B., Zhao, H., Jin, J., Chen, S., Liu, Y., Gao, S., Guan, H., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107554 · Cited by 13 · see citing works
Histone acetylation regulated by histone deacetylases during spermatogenesis
Ou, X., Yang, J., Yang, L., Zeng, H., & Shao, L. (2024) · Andrology · doi:10.1111/andr.13723 · Cited by 12 · see citing works
Function and mechanism of lysine crotonylation in health and disease
Hou, L., Chen, Y. J., Zhong, Q., Pei, J., Liu, L., Pi, H., Xie, M., & Zhao, G. (2024) · QJM · doi:10.1093/qjmed/hcae034 · Cited by 11 · see citing works
HDAC-driven mechanisms in anticancer resistance: epigenetics and beyond
Minisini, M., Mascaro, M., & Brancolini, C. (2024) · Cancer Drug Resistance · doi:10.20517/cdr.2024.103 · Cited by 11 · see citing works
Dong, J., Li, Y., Zheng, F., Chen, W., Huang, S., Zhou, X., Wang, K., Cai, W., Liu, H., Yin, L., et al. (2021) · ACS Omega · doi:10.1021/acsomega.1c01161 · Cited by 11 · see citing works
Transcription suppression is mediated by the HDAC1–Sin3 complex in Xenopus nucleoplasmic extract
Quaas, C. E., Lin, B., & Long, D. T. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102578 · Cited by 10 · see citing works
Protein crotonylation: An emerging regulator in DNA damage response
Ji, P., Zhang, G., Guo, Y., Song, H., Yuan, X., Hu, X., Guo, Z., Xia, P., Shen, R., & Wang, D. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122059 · Cited by 11 · see citing works
Short chain fatty acids as epigenetic and metabolic regulators of neurocognitive health and disease
Mihaylova, M. M., & Stratton, M. S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816843-1.00023-0 · Cited by 11 · see citing works
Chen, Z., Chi, G., Balo, T., Chen, X., Montes, B. R., Clifford, S. C., D’Angiolella, V., Szabo, T., Kiss, A., Novak, T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58350-z · Cited by 10 · see citing works
Xu, G., Liang, S., Hu, G., Zhao, W., Li, Y., Zheng, M., Wu, Z., Xie, T., Fang, S., Peng, S., et al. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03610-5 · Cited by 10 · see citing works
Application of crotonylation modification in pan-vascular diseases
Yan, W., Zhang, Y., Dai, Y., & Ge, J. (2024) · Journal of drug targeting · doi:10.1080/1061186x.2024.2372316 · Cited by 10 · see citing works
Gupta, R. V., & Kumar, P. (2021) · ACS Omega · doi:10.1021/acsomega.1c05827 · Cited by 10 · see citing works
Jiang, C., Liao, J., Yang, F., Jiang, T., Zhang, D., & Xin, Y. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/5049116 · Cited by 10 · see citing works
RetractedCrotonylation versus acetylation in petunia corollas with reduced acetyl‐CoA due to PaACL silencing
Yang, W., Li, X., Jiang, G., Yu, L., Li, H., Yu, S., Zhao, H., & Liu, J. (2022) · Physiologia Plantarum · doi:10.1111/ppl.13794 · Cited by 10 · see citing works
Protein lysine four‐carbon acylations in health and disease
Fang, Y., & Li, X. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.30981 · Cited by 10 · see citing works
Huang, C., Wu, X., & Wang, X. (2019) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2019.105565 · Cited by 10 · see citing works
Kollenstart, L., van der Horst, S. C., Vreeken, K., Janssen, G. M. C., Martino, F., Vlaming, H., van Veelen, P. A., van Leeuwen, F., & van Attikum, H. (2021) · Scientific Reports · doi:10.1038/s41598-021-91359-0 · Cited by 10 · see citing works
Histone crotonylation in tumors (Review)
Wang, X., Qu, Y., Li, Z., & Xia, Q. (2025) · Molecular and Clinical Oncology · doi:10.3892/mco.2025.2834 · Cited by 9 · see citing works
Sodium butyrate attenuates liver fibrogenesis via promoting H4K8 crotonylation
Tang, R., Zha, H., Liu, R., Lv, J., Cao, D., & Li, . (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05274-3 · Cited by 9 · see citing works
Chen, L.-J., Tu, Z.-Y., Wang, Y., He, Y., Wang, X., Tao, S.-Z., Xu, Y., Li, C., Wang, R., Yang, Z., et al. (2022) · Research · doi:10.34133/2022/9834963 · Cited by 9 · see citing works
Protein crotonylation: Basic research and clinical diseases
Li, D., Lin, L., Xu, F., Feng, T., Tao, Y., Miao, H., & Yang, F. (2024) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2024.101694 · Cited by 8 · see citing works
Subba, P., & Prasad, T. S. K. (2021) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2021.0132 · Cited by 8 · see citing works
Emerging posttranslational modifications and their roles in DNA damage response
Wu, Z., Liu, Y., Zhang, M., & Wang, D. (2023) · Genome Instability & Disease · doi:10.1007/s42764-023-00115-3 · Cited by 8 · see citing works
- Authors
- Kelly, R. D. W., Chandru, A., Watson, P. J., Song, Y., Blades, M., Robertson, N. S., Jamieson, A. G., Schwabe, J. W. R., & Cowley, S. M.
- Affiliations
- University of Leicester (GB)
- University of Cambridge (GB)
- University of Glasgow (GB)
- Corresponding author
- Cowley, S. M.
- Venue
- Scientific Reports
- Published
- 2018-10-02
- Volume
- 8
- Issue
- 1
- Pages
- 14690-14690
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6168483
- OpenAlex
- W2892763111
- Semantic Scholar
- 5dcbd5abb94c07fb1ae9c0b7b1a6842367d603a5
- Cited by
- 138
- References
- 49
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 25 · 2023: 17 · 2022: 19 · 2021: 21 · 2020: 12 · 2019: 11
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Engineering and Physical Sciences Research Council (EP/N034260/1)
- Wellcome Trust (100237)
- Biotechnology and Biological Sciences Research Council (BB/N002954/1, BB/P021689/1)
- Medical Research Council (MR/J009202/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- HDAC1, HDAC2, histone crotonylation, histone acetylation, LSD1, H3K18, histone acylation, corepressor complex, epigenetic regulation, embryonic stem cells
- MeSH terms
- Cell Line, Histones, Humans, Multienzyme Complexes, Protein Processing, Post-Translational, Histone Deacetylase 1, Histone Deacetylase 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
