The DOI matches its Crossref record; 68 of the 69 references it cites were found in a registry or an index, and 1 are not checked yet; 2 of the 125 sources its claims cite were checked for support.
Dynamic DNA methylation: In the right place at the right time
Open accessAbstract
The classical model of cytosine DNA methylation (the presence of 5-methylcytosine, 5mC) regulation depicts this covalent modification as a stable repressive regulator of promoter activity. However, whole-genome analysis of 5mC reveals widespread tissue- and cell type–specific patterns and pervasive dynamics during mammalian development. Here we review recent findings that delineate 5mC functions in developmental stages and diverse genomic compartments as well as discuss the molecular mechanisms that connect transcriptional regulation and 5mC. Beyond the newly appreciated dynamics, regulatory roles for 5mC have been suggested in new biological contexts, such as learning and memory or aging. The use of new single-cell measurement techniques and precise editing tools will enable functional analyses of 5mC in gene expression, clarifying its role in various biological processes.
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In the paper
“These findings are supported by the identification of both methyltransferase and demethylase for deposition and removal of 6mA, respectively (60, 61).”
§ Dynamic DNA methylation: in the right place at the right time > Beyond cytosine base modifications: 6mA -the new kid on the block
What the sources say
- Supportedcites [60] Xiao C-L, N6-Methyladenine DNA Modification in the Human Genome. Mol. Cell 71, 306– 318.e7 (2018). 30017583 source
The Discussion states that the authors identified N6AMT1 and ALKBH1 as responsible for the addition and removal of 6mA in human genomic DNA, respectively. This directly supports the part of the citing sentence attributed to this paper. (LLM, conf=0.94)
- Supportedcites [61] Wu TP, DNA methylation on N(6)-adenine in mammalian embryonic stem cells. Nature. 532, 329– 333 (2016). 27027282 PMC4977844 source
The sentence cites two sources for two enzymes; this paper supports the demethylase portion. In the section “Alkbh1 encodes a demethylase for N6-mA in ES cells” (page unavailable), the authors report that recombinant ALKBH1 reduces N6-mA and that wild-type Alkbh1 rescues elevated N6-mA in knockout cells. (LLM, conf=0.92)
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In the paper
“These tissue-type specific DMRs are defined by both lineage specific gain and loss of 5mC during embryogenesis.”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [4] Schultz MD, Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 523, 212– 216 (2015). 26030523 PMC4499021 source
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In the paper
“In addition, studies suggest that numerous transcription factors (TFs) can also directly sense the state of cytosine methylation through the modulation of their binding affinity and specificity (26).”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors read DNA methylation
What the sources say
- Not checked yetcites [26] Zhu H, Wang G, Qian J, Transcription factors as readers and effectors of DNA methylation. Nat. Rev. Genet 17, 551– 565 (2016). 27479905 PMC5559737 source
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In the paper
“These dynamically methylated CpGs cluster into over 1 million tissue specific differentially methylated regions (DMRs).”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [4] Schultz MD, Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 523, 212– 216 (2015). 26030523 PMC4499021 source
- Not checked yetcites [5] Ziller MJ, Charting a dynamic DNA methylation landscape of the human genome. Nature. 500, 477– 481 (2013). 23925113 PMC3821869 source
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In the paper
“The deletion of REST led to increased 5mC at lowly methylated regions normally bound by REST.”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors direct local 5mC remodelling
What the sources say
- Not checked yetcites [6] Stadler MB, DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 480, 490– 495 (2011). 22170606 source
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In the paper
“Notably, such gain of 5mC can be reversed by re-introducing REST.”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors direct local 5mC remodelling
What the sources say
- Not checked yetcites [6] Stadler MB, DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 480, 490– 495 (2011). 22170606 source
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In the paper
“and numerous genes are expressed during spermatogenesis despite high level methylation at their promoters (18).”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [18] Hammoud SS, Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis. Cell Stem Cell. 15, 239– 253 (2014). 24835570 source
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In the paper
“Promoter H3K4me3, in turn, inhibits the activity of the de novo DNA methyltransferase DNMT3a thus preventing methylation at CGIs (20).”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors direct local 5mC remodelling
What the sources say
- Not checked yetcites [20] Guo X, Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature. 517, 640– 644 (2015). 25383530 source
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In the paper
“These proteins include components of the H3K4 methyltransferase complex (19).”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors direct local 5mC remodelling
What the sources say
- Not checked yetcites [19] Smith ZD, Meissner A, DNA methylation: roles in mammalian development. Nat. Rev. Genet 14, 204– 220 (2013). 23400093 source
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In the paper
“For example, global erasure of DNA methylation in primordial germ cells (PGCs) does not lead to widespread transcriptional activation (16, 17)”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [16] Seisenberger S, The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849– 862 (2012). 23219530 PMC3533687 source
- Not checked yetcites [17] Hill PWS, Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature. 555, 392– 396 (2018). 29513657 PMC5856367 source
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 41
- Probably not a substantial claim. 2
In the paper
“The presence of an intact CTCF motif is sufficient and necessary for local methylation depletion.”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors direct local 5mC remodelling
What the sources say
- Not checked yetcites [6] Stadler MB, DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 480, 490– 495 (2011). 22170606
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In fact, local 5mC depletion is a reliable signature of promoters and enhancers: CpG sites in promoter associated CGIs are often less than 10% methylated, while distal regulatory sequences such as enhancers are commonly marked by levels of 5mC ranging from 10% to 50% (6).”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [6] Stadler MB, DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 480, 490– 495 (2011). 22170606
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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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
“In summary, 5mC patterns in differentiated tissues are highly specific and established primarily by site specific remodeling at regulatory sequences.”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A study profiling 5mC dynamics during mouse late fetal development with daily sampling (12) revealed a temporal uncoupling of the loss and gain of 5mC during the development of all tissues analyzed: enhancers predominantly lose 5mC during fetal development whereas most de novo 5mC occurs after birth (Fig. 1) (12).”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [12] He Y, Hariharan M, Gorkin DU, Dickel DE, Luo C, Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus. bioRxiv (2017) (available at http://www.biorxiv.org/content/early/2017/07/21/166744.abstract). PMC7398276 32728242
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“One example is ASCL1 whose forced expression directly converts fibroblasts to post-mitotic neurons and leads to reduced 5mC at most of its binding sites (22, 23).”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors direct local 5mC remodelling
What the sources say
- Not checked yetcites [22] Wapinski OL, Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell. 155, 621– 635 (2013). 24243019 PMC3871197
- Not checked yetcites [23] Luo C, Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons. bioRxiv (2018), p. 371427. PMC6333439 30644360
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In the paper
“Tissue or cell type-specific regulatory sequences can be effectively identified by DMRs and are enriched in recognition sites for TFs with tissue specific functions (4, 5, 21).”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors direct local 5mC remodelling
What the sources say
- Not checked yetcites [4] Schultz MD, Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 523, 212– 216 (2015). 26030523 PMC4499021
- Not checked yetcites [5] Ziller MJ, Charting a dynamic DNA methylation landscape of the human genome. Nature. 500, 477– 481 (2013). 23925113 PMC3821869
- Not checked yetcites [21] Hon GC, Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues. Nat. Genet 45, 1198– 1206 (2013). 23995138 PMC4095776
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“DMRs are predominantly distal to transcriptional start sites and overlap with enhancers.”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [4] Schultz MD, Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 523, 212– 216 (2015). 26030523 PMC4499021
- Not checked yetcites [5] Ziller MJ, Charting a dynamic DNA methylation landscape of the human genome. Nature. 500, 477– 481 (2013). 23925113 PMC3821869
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Contrary to what is observed in somatic cells, genome-wide changes of DNA methylation patterns occur during preimplantation mammalian development and in the early embryonic germ line (Fig. 1) (14–17).”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [14] Smith ZD, A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 484, 339– 344 (2012). 22456710 PMC3331945
- Not checked yetcites [15] Smith ZD, DNA methylation dynamics of the human preimplantation embryo. Nature. 511, 611– 615 (2014). 25079558 PMC4178976
- Not checked yetcites [16] Seisenberger S, The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849– 862 (2012). 23219530 PMC3533687
- Not checked yetcites [17] Hill PWS, Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature. 555, 392– 396 (2018). 29513657 PMC5856367
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In mouse brain cortex, synchronized de novo 5mC is observed during the second postnatal week, primarily targeting enhancers that are embryonically active (12).”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
What the sources say
- Not checked yetcites [12] He Y, Hariharan M, Gorkin DU, Dickel DE, Luo C, Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus. bioRxiv (2017) (available at http://www.biorxiv.org/content/early/2017/07/21/166744.abstract). PMC7398276 32728242
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“However, these global methylation changes are coordinated with genome-wide changes in histone modifications and reflect a global reprogramming of epigenetic information rather than locus specific transcriptional regulation.”
§ Dynamic DNA methylation: in the right place at the right time > Dynamic DNA methylation in development
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Intragenic 5mCH is positively correlated with gene expression in hESC, but is negatively correlated with gene expression in the brain (13).”
§ Dynamic DNA methylation: in the right place at the right time > Intragenic DNA methylation and transcription
What the sources say
- Not checked yetcites [13] Lister R, Global epigenomic reconfiguration during mammalian brain development. Science. 341, 1237905 (2013). 23828890 PMC3785061
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In the paper
“Pull down experiments of methylated and unmethylated random sequences using a recombinant TF protein followed by sequencing (methyl-SELEX) concluded that the binding of approximately 60% of TFs was influenced by 5mC, with the binding of comparable numbers of TFs enhanced or inhibited by 5mC (28).”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors read DNA methylation
What the sources say
- Not checked yetcites [28] Yin Y, Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 356 (2017), doi: 10.1126/science.aaj2239. PMC8009048 28473536
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“MECP2 is a methyl-CpG binding protein and mutations in MECP2 have been linked to Rett syndrome - an autism spectrum disorder (41).”
§ Dynamic DNA methylation: in the right place at the right time > Intragenic DNA methylation and transcription
What the sources say
- Not checked yetcites [41] Guy J, Cheval H, Selfridge J, Bird A, The role of MeCP2 in the brain. Annu. Rev. Cell Dev. Biol 27, 631– 652 (2011). 21721946
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Specifically, DNMT3B preferentially binds to H3K36me and deposits 5mC within gene bodies.”
§ Dynamic DNA methylation: in the right place at the right time > Intragenic DNA methylation and transcription
What the sources say
- Not checked yetcites [32] Baubec T, Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature. 520, 243– 247 (2015). 25607372
- Not checked yetcites [33] Morselli M, In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. Elife. 4, e06205 (2015). 25848745 PMC4412109
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“5hmC is generated by the Ten Eleven Translocation methylcytosine dioxygenase (TET) family of proteins and is an intermediate product of 5mC demethylation mediated by TET in combination with thymine DNA glycosylase (TDG)-mediated base excision repair (24).”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [24] Wu H, Zhang Y, Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell. 156, 45– 68 (2014). 24439369 PMC3938284
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In both cases, hypermethylation of the binding site prevents CTCF binding and results in the disruption of chromatin topological domains leading to ectopic enhancer-promoter interactions.”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors read DNA methylation
What the sources say
- Not checked yetcites [8] Bell AC, Felsenfeld G, Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 405, 482– 485 (2000). 10839546 source
- Not checked yetcites [9] Flavahan WA, Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 529, 110– 114 (2016). 26700815 PMC4831574 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In one well characterized example, aberrant gain of 5mC at the binding site of insulator protein CCCTC-binding factor (CTCF) is observed in the Igf2/H19 locus in Beckwith-Wiedemann (fetal overgrowth) syndrome, and in the PDGFRA locus of IDH mutant gliomas (8, 9).”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors read DNA methylation
What the sources say
- Not checked yetcites [8] Bell AC, Felsenfeld G, Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 405, 482– 485 (2000). 10839546 source
- Not checked yetcites [9] Flavahan WA, Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 529, 110– 114 (2016). 26700815 PMC4831574 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Many signature genes of human tissues overlap with intragenic large-DMRs, suggesting that intragenic 5mC may regulate tissue specific gene expression (4).”
§ Dynamic DNA methylation: in the right place at the right time > Intragenic DNA methylation and transcription
What the sources say
- Not checked yetcites [4] Schultz MD, Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 523, 212– 216 (2015). 26030523 PMC4499021
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, DNA affinity purification sequencing (DAP-seq) of over 500 Arabidopsis (plant) TFs determined that >75% of TFs are sensitive to 5mC (29), suggesting the regulation of TF binding by 5mC is conserved across animal and plant kingdoms.”
§ Dynamic DNA methylation: in the right place at the right time > Transcription factors read DNA methylation
What the sources say
- Not checked yetcites [29] O’Malley RC, Cistrome and Epicistrome Features Shape the Regulatory DNA Landscape. Cell. 165, 1280– 1292 (2016). 27203113 PMC4907330
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In the paper
“At many developmental genes enriched in H3K27me3, intragenic 5mC antagonize polycomb repression and thus is positively correlated with transcription (34).”
§ Dynamic DNA methylation: in the right place at the right time > Intragenic DNA methylation and transcription
What the sources say
- Not checked yetcites [34] Wu H, Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science. 329, 444– 448 (2010). 20651149 PMC3539760
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In summary, intragenic 5mC (including 5mCH) performs fine-tuning and supportive roles in transcription regulation but is nevertheless functionally important as suggested by the disease links to intragenic 5mCA and MECP2 repression (39).”
§ Dynamic DNA methylation: in the right place at the right time > Intragenic DNA methylation and transcription
What the sources say
- Not checked yetcites [39] Gabel HW, Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. 522, 89– 93 (2015). 25762136 PMC4480648
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This loss in DNA methylation observed during aging may be due to the insufficient maintenance of DNA methylation across an increasing number of cell divisions (44), which ties similar methylation changes to both cancer and in aging (44, 45).”
§ Dynamic DNA methylation: in the right place at the right time > Aberrant methylation patterns in diseases and aged tissues
What the sources say
- Not checked yetcites [44] Zhou W, DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat. Genet 50, 591– 602 (2018). 29610480 PMC5893360
- Not checked yetcites [45] Horvath S, Raj K, DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet 19, 371– 384 (2018). 29643443 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the 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).”
§ Dynamic DNA methylation: in the right place at the right time > Towards site-specific manipulation of DNA methylation
What the sources say
- Not checked yetcites [35] Neri F, Intragenic DNA methylation prevents spurious transcription initiation. Nature. 543, 72– 77 (2017). 28225755 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Both 5mCA and 5hmCA can be bound by MECP2 (39, 40), whereas the oxidation of 5mCG to 5hmCG abolishes the MECP2 interaction and disrupts the function of 5mCG as a repressive mark (Fig. 2B).”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [39] Gabel HW, Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. 522, 89– 93 (2015). 25762136 PMC4480648
- Not checked yetcites [40] Mellén M, Ayata P, Heintz N, 5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes. Proc. Natl. Acad. Sci. U. S. A 114, E7812– E7821 (2017). 28847947 PMC5604027
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“Improvements in single cell methylome approaches now provide the power to distinguish cellular heterogeneity within a tissues/ cell population and identify epigenome fluctuations in a given cell type over time.”
§ Dynamic DNA methylation: in the right place at the right time > Single-cell techniques uncover the diversity of DNA methylation patterns
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Studies also suggest that the majority of 5hmC can be relatively stable arguing against 5hmC solely as a short lived demethylation intermediate and potentially pointing towards epigenetic/regulatory role for this modification (43).”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [43] Bachman M, 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat. Chem 6, 1049– 1055 (2014). 25411882 PMC4382525
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Tumor methylomes are characterized by global hypomethylation and localized hypermethylation at specific CGIs, many of them associated with tumor suppressor genes (2).”
§ Dynamic DNA methylation: in the right place at the right time > Aberrant methylation patterns in diseases and aged tissues
What the sources say
- Not checked yetcites [2] Jones PA, Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet 13, 484– 492 (2012). 22641018 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Studies using these techniques have identified cell-to-cell epigenetic variation in early mouse and human embryos (51, 52), demonstrating the enhancement of resolution enabled by multi-omic single-cell methods.”
§ Dynamic DNA methylation: in the right place at the right time > Single-cell techniques uncover the diversity of DNA methylation patterns
What the sources say
- Not checked yetcites [51] Li L, Single-cell multi-omics sequencing of human early embryos. Nat. Cell Biol. (2018), doi: 10.1038/s41556-018-0123-2. 29915357
- Not checked yetcites [52] Rulands S, Genome-Scale Oscillations in DNA Methylation during Exit from Pluripotency. Cell Syst. 7, 63– 76.e12 (2018). 30031774 PMC6066359
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although sequencing-based approaches have only found 5hmC in CG dinucleotides in mESC and brain cortical tissue (24), 5hmCH accounted for 38% of 5mCH+5hmCH in cerebellar granule cells, suggesting that 5mCH is also targeted for TET mediated methylation turnover (40).”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [40] Mellén M, Ayata P, Heintz N, 5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes. Proc. Natl. Acad. Sci. U. S. A 114, E7812– E7821 (2017). 28847947 PMC5604027
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Intriguingly, limited PMD hypomethylation can be detected in healthy tissue and increases with age (44).”
§ Dynamic DNA methylation: in the right place at the right time > Aberrant methylation patterns in diseases and aged tissues
What the sources say
- Not checked yetcites [44] Zhou W, DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat. Genet 50, 591– 602 (2018). 29610480 PMC5893360
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, 5hmCG and 5hmCA (the main context of non-CG methylation) interact with MECP2 differently and lead to opposite gene regulatory outputs.”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [39] Gabel HW, Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. 522, 89– 93 (2015). 25762136 PMC4480648
- Not checked yetcites [40] Mellén M, Ayata P, Heintz N, 5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes. Proc. Natl. Acad. Sci. U. S. A 114, E7812– E7821 (2017). 28847947 PMC5604027
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar gains of methylation at distinct polycomb repressed sequences has also been observed, although to a lesser degree, during placental development (46), suggesting an interesting and mechanistically important interplay between DNA methylation and polycomb regulated epigenetic systems.”
§ Dynamic DNA methylation: in the right place at the right time > Aberrant methylation patterns in diseases and aged tissues
What the sources say
- Not checked yetcites [46] Smith ZD, Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature. 549, 543– 547 (2017). 28959968 PMC5789792
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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
“In instances where DNA methylation is globally reduced as a part of normal developmental program, no aberrant transcriptional activation is observed, suggesting an alternative or compensatory gene expression regulatory mechanism.”
§ Dynamic DNA methylation: in the right place at the right time > Aberrant methylation patterns in diseases and aged tissues
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“An increase in PMD abundance is also found during the early development of placenta, along with comparable CGI hypermethylation as also observed in cancers (46).”
§ Dynamic DNA methylation: in the right place at the right time > Aberrant methylation patterns in diseases and aged tissues
What the sources say
- Not checked yetcites [46] Smith ZD, Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature. 549, 543– 547 (2017). 28959968 PMC5789792
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, off-target de novo methylation activity can be widespread across the entire genome (57), and not easily detected with steady-state 5mC measurements.”
§ Dynamic DNA methylation: in the right place at the right time > Towards site-specific manipulation of DNA methylation
What the sources say
- Not checked yetcites [57] Galonska C, Genome-wide tracking of dCas9-methyltransferase footprints. Nat. Commun 9, 597 (2018). 29426832 PMC5807365
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, TETs are likely to play important roles in local 5mC dynamics at the regulatory sequences as TET binding is enriched in promoters and enhancers and found in complexes with transcription factors suggesting involvement in 5mC dynamics following TF binding (24).”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [24] Wu H, Zhang Y, Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell. 156, 45– 68 (2014). 24439369 PMC3938284
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Both 5mCA and 5hmCA can be bound by MECP2 (39, 40), whereas the oxidation of 5mCG to 5hmCG abolishes the MECP2 interaction and disrupts the function of 5mCG as a repressive mark (Fig. 2B).”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [39] Gabel HW, Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. 522, 89– 93 (2015). 25762136 PMC4480648
- Not checked yetcites [40] Mellén M, Ayata P, Heintz N, 5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes. Proc. Natl. Acad. Sci. U. S. A 114, E7812– E7821 (2017). 28847947 PMC5604027
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Interestingly, these are sequences that are transcriptionally repressed by the polycomb system (and lack DNA methylation) under normal physiological conditions (47).”
§ Dynamic DNA methylation: in the right place at the right time > Aberrant methylation patterns in diseases and aged tissues
What the sources say
- Not checked yetcites [47] Schlesinger Y, Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet 39, 232– 236 (2007). 17200670
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although TET enzymes are highly expressed during the developmental periods of global DNA demethylation, their role in the observed methylation dynamics seems auxiliary and primarily antagonizes the activity of de novo methylation (17, 42).”
§ Dynamic DNA methylation: in the right place at the right time > Functions of cytosine hydroxymethylation
What the sources say
- Not checked yetcites [17] Hill PWS, Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature. 555, 392– 396 (2018). 29513657 PMC5856367
- Not checked yetcites [42] Amouroux R, De novo DNA methylation drives 5hmC accumulation in mouse zygotes. Nat. Cell Biol. 18, 225– 233 (2016). 26751286 PMC4765106
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In addition, meta-analysis of 5mC microarray data has identified a small number (~300–400) of CpG sites that are associated with age across multiple tissues and the existence of an methylome-based clock (45).”
§ Dynamic DNA methylation: in the right place at the right time > Outlook
What the sources say
- Not checked yetcites [45] Horvath S, Raj K, DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet 19, 371– 384 (2018). 29643443 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Epigenome-wide association studies have associated 5mC signatures with many diseases (63).”
§ Dynamic DNA methylation: in the right place at the right time > Outlook
What the sources say
- Not checked yetcites [63] Paul DS, Beck S, Advances in epigenome-wide association studies for common diseases. Trends Mol. Med 20, 541– 543 (2014). 25092140 PMC4186777
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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, many studies use correlative analysis and report only moderate 5mC differences detected from complex tissues.”
§ Dynamic DNA methylation: in the right place at the right time > Outlook
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
The paper relies on this without support.
The classical model of 5mC regulation as a stable repressive regulator of promoter activity is the prevailing baseline that the review's new findings revise.
“The classical model of cytosine DNA methylation (5mC) regulation depicts this covalent modification as a stable repressive regulator of promoter activity.”
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?
In the citing paper
“The importance of the various methylation pathways is highlighted by the fact that their dysregulation is linked to many diseases 1-5 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [3]
Citations
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Metadata
- Authors
- Luo, C., Hajkova, P., & Ecker, J. R.
- Affiliations
- Salk Institute for Biological Studies (US)
- MRC London Institute of Medical Sciences (LMS), Du Cane Road, W12 0NN London, UK.
- Corresponding author
- Luo, Chongyuan
- Ecker, Joseph R.
- Venue
- Science
- Published
- 2018-09-28
- Volume
- 361
- Issue
- 6409
- Pages
- 1336-1340
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6197482
- OpenAlex
- W2894083868
- Cited by
- 668
- References
- 68
- Citations by year
- 2026: 46 · 2025: 85 · 2024: 96 · 2023: 88 · 2022: 105 · 2021: 96 · 2020: 86 · 2019: 57 · 2018: 8
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (5R21MH112161, 5R01MH112763, 1U19MH114831)
- National Human Genome Research Institute (5R21HG009274)
- National Institute of Diabetes and Digestive and Kidney Diseases (5U24DK112348)
- National Institute of Environmental Health Sciences (5R01ES025585)
- Medical Research Council (MC_US_A652_5PY70)
- European Research Council (ERC-CoG- 648879 – dynamic modifications)
- 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 › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, 5-methylcytosine, epigenetics, transcriptional regulation, developmental dynamics, tissue-specific methylation, cell type-specific methylation, promoter repression, learning and memory, aging, single-cell epigenomics, epigenome editing
- MeSH terms
- Gene Editing, Aging, Animals, Disease, Humans, Memory, Neoplasms, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Developmental, DNA Methylation, 5-Methylcytosine, Single-Cell Analysis
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