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Intragenic DNA methylation prevents spurious transcription initiation
Open accessAbstract
In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer.
Overview
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Written from the paper’s full text.
TL;DR
Dnmt3b-mediated DNA methylation within gene bodies, recruited via H3K36me3, suppresses spurious intragenic RNA polymerase II entry and cryptic transcription initiation in mouse embryonic stem cells. The resulting aberrant transcripts can be degraded by the RNA exosome or capped, polyadenylated, exported, and ribosome-associated, with possible relevance to intragenic hypomethylation in cancer.
Key findings
- Dnmt3b knockout reduced gene-body 5-methylcytosine, especially on exons and introns, and increased intragenic transcription: 1,445 genes (18% of genes with RPKM > 1) showed an intermediate-exon/first-exon log2 ratio above 1.
- DECAP-seq identified 2,627 high-expression intragenic transcription start sites (RPM > 6) specific to Dnmt3b−/− cells, versus 780 shared and 936 WT-specific sites; Dnmt3b−/−-specific sites accounted for 2.76% of mapped reads, while shared sites accounted for 5.22%.
- SetD2 silencing reduced H3K36me3 and Dnmt3b gene-body binding and produced 3,560 high-confidence intragenic TSSs, of which 2,759 were specific to the knockdown and more than 2,000 overlapped with Dnmt3b−/− sites.
- Rescue experiments showed that wild-type Dnmt3b, but not the catalytically inactive V725G mutant or H3K36me3-binding mutants S277P and VW-RR, reduced the intermediate/first-exon ratio; cryptic RNAs were partly degraded by the RNA exosome, partly polyadenylated, and showed increased ribosome occupancy in intronic regions.
Methods
- Mouse E14 embryonic stem cells were used, with two independent Dnmt3b knockout lines generated by TALEN targeting of exon 17; SetD2, Dis3, and Rrp6 were silenced by shRNA, and Dnmt3b rescue used wild-type or mutant constructs.
- Genome-wide assays included ChIP-seq for Dnmt3b, RNA Pol II, H3K36me3, and other marks; whole-genome bisulfite sequencing; total, polyA+, and cytoplasmic RNA-seq; CAPIP-seq; DECAP-seq for single-base TSS mapping; and ART-seq ribosome profiling.
- Analyses mapped reads to an E14-specific mm9 variant and used TopHat/Cuffdiff, Bowtie, BSMAP, MACS, and custom scripts, with significance assessed by Wilcoxon rank-sum, chi-square, hypergeometric, and correlation tests.
Limitations
- The paper has no dedicated limitations section; it notes that alternative splicing and repetitive-element activation events in Dnmt3b−/− cells were sporadic, with only 4 of 2,563 genes showing intragenic alternative-promoter reactivation.
- The cancer relevance is discussed as an implication rather than tested directly, and the production of aberrant proteins from cryptic transcripts is suggested by ribosome profiling rather than demonstrated.
- Evident from the text: the work is restricted to mouse ESCs and relies heavily on knockout/knockdown and overexpression systems, so the findings may not generalize to other cell types or in vivo tumor settings.
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43 Own result · 19 Own interpretation · 10 Own method · 6 Not checked yet
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In the paper
“In contrast, we observed a significant increase of RNA Pol II binding on intragenic regions when comparing Dnmt3b -/-to WT cells treated with DRB.This was especially true on introns and exons of q3-q4 genes using both antibodies (Fig. 2c, d and Extended Data Fig. 4f)”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“Dnmt3b -/- cells displayed a significantly higher ratio starting from the second exon (Fig. 2a).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“We did not observe any significant changes in H3K36me3 and RNA Pol II genomic profiles when comparing untreated WT to Dnmt3b -/-cells (Fig. 2c, d and Extended Data Fig. 4d-f).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“1445 genes (18% of total genes having RPKM > 1) had a log2 ratio of intermediate exons versus first exon > 1 (Fig. 2b).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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In the paper
“Even though some alternative promoters' reactivation events take place in Dnmt3b -/-cells, the Dnmt3b loss did not show evidence of a general reactivation of these events at genome-wide level (Extended Data Fig. 3).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“Application of this technique to total RNA, showed a significant enrichment of CAP signal in intermediate intronic and exonic regions of Dnmt3b -/-transcripts (Extended Data Fig. 5f-g).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“DECAP-seq analysis in WT and Dnmt3b -/-cells revealed a significant increase of the transcription start sites (TSSs) in Dnmt3b -/-cells with respect to WT cells on the gene bodies of the q3 and q4 genes (Fig. 3a, b and Extended Data Fig. 6f, g).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“Introns half-life is generally lower with respect to the mRNAs half-life,”
§ Intragenic DNA methylation prevents spurious transcription initiation > References
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“Interestingly, within a region of 50 bp centred at the Dnmt3bdependent intragenic TSSs, we found a statistically significant enrichment of the CpG dinucleotide and several transcription factor binding motifs containing CpG sequence, including SP1 and members of the ETS family (Fig. 3g, h and Extended data Fig. 7a).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“The intronic RNA inclusion in Dnmt3b -/-cells remained always higher than in WT cells along the time course (Fig. 5f)”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of spurious transcripts
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“This analysis identified 2627 highly expressed TSSs (RPM > 6) specific of the Dnmt3b -/-cells, 780 TSSs common in both the cell lines and 936 specific of WT cells (Fig. 3c).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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“ChIP-seq analysis revealed the intragenic binding of the endogenous Dnmt3b especially on the genes belonging to the third and fourth quartiles (q3-q4) of gene expression and correlated with H3K36me3 histone modification (Fig. 1a-c and Extended Data Fig 1g-q).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Dnmt3b loss reduces gene body DNA methylation
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“Whole genome bisulfite sequencing (WGBS) in WT or Dnmt3b -/-ESCs revealed a global reduction of genomic DNA methylation, with a significant decrease of the level of 5methylcytosine (5mC) on exons and introns (Fig. 1d and Extended Data Fig. 1r).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Dnmt3b loss reduces gene body DNA methylation
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“Genome splitting in deciles of H3K36me3 occupancy showed that both Dnmt3b binding and DNA methylation loss in Dnmt3b -/-cells markedly correlate with the abundance of H3K36me3 (Fig. 1e).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Dnmt3b loss reduces gene body DNA methylation
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“Our data confirm this observation on canonical TSSs, while on intragenic TSSs we observed the loss of the pyrimidine enrichment at position -1 and a reduced enrichment of the purine at position +1 (Fig. 3f).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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In the paper
“The intragenic TSSs identified in Dnmt3b -/-cells were within genomic regions with significantly higher H3K36me3 and Dnmt3b binding, showed loss of methylation upon Dnmt3b depletion, and lower nucleosome occupancy with respect to randomly chosen intragenic regions (Fig. 3e).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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In the paper
“Interestingly, almost all the highly expressed TSSs identified in Dnmt3b -/-cells can be found in the PolyA+ and cytosolic DECAP-seq fractions (Fig. 5c), even though, with a significantly lower level of expression with consequent reduction of the percentage of the total mapped reads (Fig. 5d, e)”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of spurious transcripts
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“The analysis revealed that fast decay mRNAs are mainly involved in cell cycle and transcription biological processes, while slow decay mRNAs are more related to metabolism and translation.”
§ Intragenic DNA methylation prevents spurious transcription initiation > References
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In the paper
“Both the Dnmt3b proteins showed similar intragenic binding profiles (Fig. 4g, h and Extended Data Fig. 9b, c), although only the cells expressing the WT protein showed an increase of DNA methylation levels (Extended Data Fig. 9d, e).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Crosstalk between H3K36me3 and DNA methylation
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In the paper
“We tested these hypotheses and, in agreement with the literature, we found few events of alternative splicing and activation of repetitive elements actually occurring in Dnmt3b -/-cells (data not shown). However, these regulations were sporadic in our model.”
§ Intragenic DNA methylation prevents spurious transcription initiation > DNA methylation takes place both at the promoters and within the gene body.
What the sources say
- Not checked yetcites [32] Maunakea, A. K., Chepelev, I., Cui, K. & Zhao, K. Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res. 23, 1256–1269 (2013) source
- Not checked yetcites [33] Yearim, A. et al. HP1 is involved in regulating the global impact of DNA methylation on alternative splicing. Cell Reports 10, 1122–1134 (2015) source
- Not checked yetcites [34] Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012) source
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In the paper
“This analysis revealed 3560 high confident (RPM > 6) intragenic TSSs in SetD2 silenced cells, of which 2759 were specific of the SetD2 knockdown and more than 2000 were in common with the TSSs identified in Dnmt3b -/-cells (Extended Data Fig. 8l-o and 9a).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Crosstalk between H3K36me3 and DNA methylation
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In the paper
“The percentage of the total mapped reads specific for Dnmt3b -/-TSSs was 2.76%, while the percentage of common TSSs was 5.22%”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
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In the paper
“SetD2 knockdown resulted in a drastic reduction of H3K36me3 both in WT and Dnmt3b -/-cells and loss of Dnmt3b intragenic binding in WT cells (Fig. 4a-c and Extended Data Fig. 8a-f).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Crosstalk between H3K36me3 and DNA methylation
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In the paper
“Specific impairment of Dnmt3b binding and DNA methylation is observed in both the mutants compared to the rescue by using WT Dnmt3b enzyme.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Additional information
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In the paper
“Dot intensity quantification from three biological replicates revealed that Dnmt3b WT (but not the V725G mutant) significantly (p=0.003)increases global DNA 5mC.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Additional information
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In the paper
“Total RNA-seq (Extended Data Fig. 9f, g) revealed a significant reduction of the intermediates/first exon ratio in the cells expressing the WT Dnmt3b enzyme, but not in those expressing Dnmt3bV725G mutant (Fig. 4i, j).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Crosstalk between H3K36me3 and DNA methylation
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In the paper
“These Dnmt3b mutants showed lower intragenic binding with reduced DNA methylation activity (Extended Data Fig. 9i, j) and were unable to reduce the intermediates/first exon ratio (Extended Data Fig. 10a-d).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Crosstalk between H3K36me3 and DNA methylation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Silencing of the Dis3 and Rrp6 component of the RNA exosome complex did not show changes in the total number of intragenic TSSs (Extended Data Fig. 10e-g), but a significant increase of their expression level (Extended Data Fig. 10h-k).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of spurious transcripts
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Here, we show that the Dnmt3b-dependent intragenic DNA methylation protects the gene body from RNA Polymerase II spurious entry and cryptic transcription initiation.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Abstract
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In the paper
“Furthermore, the spurious transcripts can be either degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment on the gene body by H3K36me3.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent studies have reported that Dnmt3b binds preferentially to the gene bodies by interacting with the histone modification H3K36me3 10,11 .”
§ Intragenic DNA methylation prevents spurious transcription initiation > Abstract
What the sources say
- Not checked yetcites [10] Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243–247 (2015) source
- Not checked yetcites [11] Morselli, M. et al. In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. eLife 4, e06205 (2015) source
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Probably not a substantial claim.
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In the paper
“Indeed, the global DNA hypomethylation, especially occurring on intragenic regions, is a general feature of most tumours [35][36][37] .”
§ Intragenic DNA methylation prevents spurious transcription initiation > DNA methylation takes place both at the promoters and within the gene body.
What the sources say
- Not checked yetcites [35] Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002) source
- Not checked yetcites [36] Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003) source
- Not checked yetcites [37] Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“confirming that a fraction of the spurious transcripts is actually degraded and indicating that not all cryptic transcripts undergo polyadenylation and nuclear export.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of spurious transcripts
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Partial internal RNAs generated by the loss of transcription initiation fidelity, could impact on multiple biological processes impairing molecular mechanisms such as regulation of the gene expression, miRNA targeting, truncated proteins generation and others, thus favouring (stochastic) tumour cell heterogeneity and neoplastic predisposition.”
§ Intragenic DNA methylation prevents spurious transcription initiation > DNA methylation takes place both at the promoters and within the gene body.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Analysis performed on technical and biological replicates, and validation by RT-qPCR on a subset of genes confirmed this result (Extended Data Fig. 2c-e).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Methylation calling was performed using the methratio.pyscript provided with the BSMAP tool and comparative analyses were performed by using only CpG covered at least 5x in both wt and Dnmt3b -/-cells.”
§ Intragenic DNA methylation prevents spurious transcription initiation > CAPIP-seq analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“RppH treated and untreated samples showed a double peak around 130bp corresponding to the dimers of adapter, but only the RppH treated sample showed a higher enrichment (in the red box) corresponding to the decapped RNA fragments.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Additional information
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, several recent studies reported the loss/mutation of SETD2 and the consequent loss of H3K36me3 histone mark as a key event in promoting cancer growth and malignancy [38][39][40] .”
§ Intragenic DNA methylation prevents spurious transcription initiation > DNA methylation takes place both at the promoters and within the gene body.
What the sources say
- Not checked yetcites [38] Kanu, N. et al. SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene 34, 5699–5708 (2015) source
- Not checked yetcites [39] Fontebasso, A. M. et al. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 125, 659–669 (2013) source
- Not checked yetcites [40] Duns, G. et al. Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma. Cancer Res. 70, 4287–4291 (2010) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, only the reexpression of the WT Dnmt3b was able to rescue the loss of spurious intragenic transcription initiation in Dnmt3b -/-cells demonstrating that Dnmt3bdependent DNA methylation is responsible for preventing the occurrence of cryptic intragenic transcription.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Crosstalk between H3K36me3 and DNA methylation
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“we generated two independent Dnmt3b knockout cell lines from mouse embryonic stem cell (ESC) line E14 to exclude experimental artefacts due to different genetic backgrounds, or prolonged cell culturing (Extended Data Fig. 1a-f).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Dnmt3b loss reduces gene body DNA methylation
plainn = 2- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“This result is in agreement with that previously observed in mESCs 54,55 , thus suggesting the bona fide of the experiment.”
§ Intragenic DNA methylation prevents spurious transcription initiation > References
What the sources say
- Not checked yetcites [54] Sharova, L. V. et al. Database for mRNA half-life of 19 977 genes obtained by DNA microarray analysis of pluripotent and differentiating mouse embryonic stem cells. DNA Res. 16, 45–58 (2009) source
- Not checked yetcites [55] Schwanhäusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011) source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The cells were mycoplasma free.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Cell culture
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The ChIP-seq data were validated by ChIP-qPCR, using several biological replicates, on target genomic regions and by not cross-linked co-immunoprecipitation experiments between Dnmt3b and H3K36me3 in WT or Dnmt3b -/-ESCs (Extended Data Fig.1o, p).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Extended Data Figure 3: Dnmt3b loss does not extensively affect alternative promoter activation.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We now demonstrate that Dnmt3b-dependent DNA methylation on the gene body is responsible for the prevention of aberrant transcription initiation events necessary to guarantee the mRNA transcription initiation fidelity (Extended Data Fig. 12a).”
§ Intragenic DNA methylation prevents spurious transcription initiation > DNA methylation takes place both at the promoters and within the gene body.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of note, Mock ESCs showed higher correlation with Dnmt3b mutant transfected ESCs (r = 0.99) with respect that Dnmt3b WT transfected ESCs (r = 0.95), thus suggesting that DNA methylation enzymatic activity is the major driver of the Dnmt3b-dependent transcriptome alterations.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Additional information
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of intragenic TSSs and the reads distribution was similar in both the DECAP-seq replicates showing high overlap (Extended Data Fig. 6k-m)”
§ Intragenic DNA methylation prevents spurious transcription initiation > Analysis of intragenic spurious transcription
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To investigate the distribution of the endogenous Dnmt3b we tested different antibodies and found one that was able to immunoprecipitate the endogenous Dnmt3b cross-linked to chromatin, which showed no background signal in Dnmt3b -/-(Extended Data Fig. 1g-i”
§ Intragenic DNA methylation prevents spurious transcription initiation > Chromatin Immunoprecipitation assay
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A pronounced sharp peak (red arrow) is present on the TSS only on the respective gene strand, thus reflecting both the cap-and strandnessspecificity of the method.”
§ Intragenic DNA methylation prevents spurious transcription initiation > Additional information
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“in Thermopol buffer is able to mediate decapping and pyrophosphate removal from the 5´ end of RNA to leave a 5´ monophosphate RNA (5'-P).”
§ Intragenic DNA methylation prevents spurious transcription initiation > Additional information
What the sources say
- Not checked yetcites S1
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The function of gene body DNA methylation in highly expressed genes has not yet been clarified.
“while the functional role of gene body DNA methylation in highly expressed genes has yet to be clarified.”
“the function of gene body DNA methylation has not yet been clarified.”
The paper relies on this without support.
Silencing SetD2 in mammalian cells causes cryptic transcription initiation in a large fraction of active genes.
“Silencing of SetD2 in mammalian cells leads to cryptic transcription initiation of a large fraction of active genes.”
The paper relies on this without support.
Silencing Dis3 and Rrp6 impairs RNA exosome degradation of cryptic transcripts.
“Silencing of the Dis3 and Rrp6 component of the RNA exosome complex did not show changes in the total number of intragenic TSSs (Extended Data Fig. 10e-g), but a significant increase of their expression level (Extended Data Fig. 10h-k).”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“loss of DNA methyltransferase 3B (DNMT3B) in mouse embryonic stem (ES) cells was shown to result in spurious initiation of alternative promoters21.”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [21]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The methyltransferase SETD2 deposits H3K36me355 after Pol2 passage56, which in turn recruits DNMT3B21 to maintain a repressive chromatin state57.”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“As H3K36me3 recruits DNMT3B21, the gene body coverage of H3K36me3 (Supplementary Fig. 6b) coincides with the DNMT3B coverage”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [21]
In the citing paper
“Although discoveries regarding 5mC function and regulation have been made with genome-wide perturbation strategies, these methods are associated with pleiotropic phenotypes and inevitably confound the interpretation of results (35).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [35]
In the citing paper
“We observed that genes in the A compartment had lower methylation at transcription starting site (TSS) but higher methylation at gene bodies than genes in the B compartment (Extended Data Fig. 11b), consistent with the distinct roles of DNA methylations at different regions47.”
From Subtype-specific 3D genome alteration in acute myeloid leukaemia (2022) · cites this paper as [47]
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Metadata
- Authors
- Neri, F., Rapelli, S., Krepelova, A., Incarnato, D., Parlato, C., Basile, G., Maldotti, M., Anselmi, F., & Oliviero, S.
- Affiliations
- Italian institute for Genomic Medicine (IT)
- University of Turin (IT)
- Corresponding author
- Neri, Francesco
- Oliviero, Salvatore
- Venue
- Nature
- Published
- 2017-02-22
- Volume
- 543
- Issue
- 7643
- Pages
- 72-77
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2589386142
- Semantic Scholar
- 1e92f02718723d76aae589d66f60a1d9a01188d5
- Cited by
- 739
- References
- 55
- Citations by year
- 2026: 54 · 2025: 53 · 2024: 79 · 2023: 92 · 2022: 97 · 2021: 92 · 2020: 75 · 2019: 89 · 2018: 63 · 2017: 43
- FWCI
- 30.15
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro (IG-2014)
- Institute of Molecular and Cell Biology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- gene body methylation, DNMT3B, RNA polymerase II, H3K36me3, SETD2, RNA exosome, epigenetic crosstalk, mouse embryonic stem cells, CpG methylation
- MeSH terms
- Mouse Embryonic Stem Cells, DNA Methyltransferase 3B, Animals, Cell Line, DNA, DNA (Cytosine-5-)-Methyltransferases, Genes, Histones, Lysine, Neoplasms, Histone-Lysine N-Methyltransferase, Ribosomes, RNA Caps, RNA Polymerase II, RNA, Messenger, DNA Methylation, RNA Stability, Transcription Initiation Site, Polyadenylation, Epigenesis, Genetic, Mice, Transcription Initiation, Genetic
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