Dynamic DNA methylation: In the right place at the right time

In the paper

“The presence of an intact CTCF motif is sufficient and necessary for local methylation depletion.”

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

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).”

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

In the paper

“In summary, 5mC patterns in differentiated tissues are highly specific and established primarily by site specific remodeling at regulatory sequences.”

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).”

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

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).”

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

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).”

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

In the paper

“DMRs are predominantly distal to transcriptional start sites and overlap with enhancers.”

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

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).”

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

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).”

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

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.”

In the paper

“Intragenic 5mCH is positively correlated with gene expression in hESC, but is negatively correlated with gene expression in the brain (13).”

What the sources say

• Not checked yetcites [13] Lister R, Global epigenomic reconfiguration during mammalian brain development. Science. 341, 1237905 (2013). 23828890 PMC3785061

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).”

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

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).”

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

In the paper

“Specifically, DNMT3B preferentially binds to H3K36me and deposits 5mC within gene bodies.”

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

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).”

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

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.”

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

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).”

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

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).”

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

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.”

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

In the paper

“At many developmental genes enriched in H3K27me3, intragenic 5mC antagonize polycomb repression and thus is positively correlated with transcription (34).”

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

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).”

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

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).”

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

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).”

What the sources say

• Not checked yetcites [35] Neri F, Intragenic DNA methylation prevents spurious transcription initiation. Nature. 543, 72– 77 (2017). 28225755 source

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).”

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

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.”

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).”

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

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).”

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

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.”

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

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).”

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

In the paper

“Intriguingly, limited PMD hypomethylation can be detected in healthy tissue and increases with age (44).”

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

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.”

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

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.”

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

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.”

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).”

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

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.”

What the sources say

• Not checked yetcites [57] Galonska C, Genome-wide tracking of dCas9-methyltransferase footprints. Nat. Commun 9, 597 (2018). 29426832 PMC5807365

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).”

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

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).”

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

In the paper

“Interestingly, these are sequences that are transcriptionally repressed by the polycomb system (and lack DNA methylation) under normal physiological conditions (47).”

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

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).”

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

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).”

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

In the paper

“Epigenome-wide association studies have associated 5mC signatures with many diseases (63).”

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

In the paper

“However, many studies use correlative analysis and report only moderate 5mC differences detected from complex tissues.”