Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

Noh, Kyung‐Min; Wang, Haibo; Kim, Hyunjae R.; Wenderski, Wendy; Fang, Fang; Li, Charles; Dewell, Scott; Hughes, Stephen H.; Melnick, Ari; Patel, Dinshaw J.; Li, Haitao; Allis, C. David

doi:10.1016/j.molcel.2018.01.014

Cited by 8 publications

(8 citation statements)

References 30 publications

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“…Similarly, these regions are prone to spurious DNA methylation in aging (Figure 6C). Overall, H3K4me1-marked nucleosomal DNA at CpG islands borders carry low levels of cytosine methylation in PrECs and (legend continued on next page) display a greater shift toward higher methylation levels in LNCaP cells in comparison with H3K27me3-bound DNA (Figure 6D), whereas H3K4me3-marked nucleosomal DNA at CpG islands is mutually exclusive with CpG methylation, in agreement with other studies (Noh et al, 2015;Ooi et al, 2007;Weber et al, 2007).…”

Section: Cpg ''Seeding'' Methylation At H3k4me1-marked Island Borders That Become Hypermethylated In Cancersupporting

confidence: 90%

“…H3K4me3 marked nucleosomes are reported to be important for the establishment and maintenance of unmethylated CpG islands at the promoters of active genes as this modification is agnostic to DNA methylation (Weber et al, 2007). Indeed the DNA methyltransferase DNMT3A/L shows no detectable binding to H3K4me2/3 but displays the highest binding affinity to nucleosomes marked with H3K4me0, and interestingly only a $2-fold reduction in binding affinity to H3K4me1 (Noh et al, 2015;Ooi et al, 2007). This raises the possibility that H3K4 monomethylation may play a role in shaping DNA methylation patterns at regulatory elements.…”

Section: Introductionmentioning

confidence: 99%

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DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns

et al. 2019

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Section: Cpg ''Seeding'' Methylation At H3k4me1-marked Island Borders That Become Hypermethylated In Cancersupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns

et al. 2019

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“…The ADD domain acts as a molecular module that recognizes unmodified histone H3 lysine 4 [136]. The crystal structure of the ADD domain of DNMT3A in complex with the amino-terminal tail of histone H3 showed the specific interaction of the ADD domain with H3K4me0, not with H3K4me2 and H3K4me3 [137][138][139]. These results are consistent with the fact that H3K4me3 and DNA methylation distribution are mutually exclusive [138][139][140][141][142].…”

Section: Genome-wide Change Of Dna Methylation Landscape In Cancersupporting

confidence: 80%

“…The crystal structure of the ADD domain of DNMT3A in complex with the amino-terminal tail of histone H3 showed the specific interaction of the ADD domain with H3K4me0, not with H3K4me2 and H3K4me3 [137][138][139]. These results are consistent with the fact that H3K4me3 and DNA methylation distribution are mutually exclusive [138][139][140][141][142]. Moreover, the histone H3 tail stimulates the enzymatic activity of DNMT3A in vitro [138,140,141].…”

Section: Genome-wide Change Of Dna Methylation Landscape In Cancersupporting

confidence: 76%

Navigating the DNA methylation landscape of cancer

2021

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DNA methylation is a chemical modification that defines cell type and lineage through the control of gene expression and genome stability. Disruption of DNA methylation control mechanisms causes a variety of diseases, including cancer. Cancer cells are characterized by aberrant DNA methylation (i.e., genome-wide hypomethylation and site-specific hypermethylation), mainly targeting CpG islands in gene expression regulatory elements. In particular, the early findings that a variety of tumor suppressor genes (TSGs) are targets of DNA hypermethylation in cancer led to the proposal of a model in which aberrant DNA methylation promotes cellular oncogenesis through TSGs silencing. However, recent genome-wide analyses have revealed that this classical model needs to be reconsidered. In this review, we will discuss the molecular mechanisms of DNA methylation abnormalities in cancer as well as their therapeutic potential. DNA methylationDNA methylation is a chemical modification that plays an important role in the regulation of epigenetic gene expression [1-3], genomic imprinting [4-6], X chromosome inactivation [7,8], transposon (see Glossary) silencing [9], and genome stability [10,11]. DNA methylation is mainly catalyzed by three enzymes, DNMT1, DNMT3A, and DNMT3B (Figure 1). De novo DNA methylation is mainly catalyzed by the DNA methyltransferases (DNMTs) DNMT3A and 3B (Box 1), while established DNA methylation patterns are maintained by the daughter DNA through a maintenance DNA methylation mechanism during cell proliferation (Box 2). Both de novo DNA methylation and maintenance DNA methylation are important for normal development. DNMT1 inactivation and DNMT3A/3B double knockout (KO) mouse embryos show significant growth inhibition and are lethal before mid-gestation [12,13]. In contrast, DNA methylation is not necessarily required in embryonic stem (ES) cells; even when CpG methylation is completely lost by combined KO of three DNMTs Dnmt1, Dnmt3a, and Dnmt3b, there is a minimal change in phenotype in undifferentiated ES cells [14]. Although DNA methylation is a stable modification, there are also several pathways of demethylation and these pathways play an important role in the regulation of DNA methylation in various biological contexts (Box 3). In normal cells, most CpG sequences in the genome are methylated, but CpG islands and the nearby CpG island shores (the region within 2 kb of the islands) are exceptionally hypomethylated [15,16]. Many of these hypomethylated regions of DNA function as elements that regulate gene expression, such as promoters and enhancers. In addition, systematic analysis of unmethylated DNA and methylated CpG as ligands has revealed that DNA methylation promotes the binding of many transcription factors [17]. Recently, broad unmethylated regions were also reported as DNA methylation canyons [18] or DNA methylation valleys [19] that are associated with either the active histone mark H3K4me3 or the inhibitory mark H3K27me3.Accumulating evidence demonstrate that cancer cells show largely di...

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“…Indeed, we observe a striking correlation between degree of H3K4me3 loss and DNAme gain in Dppa2/4 mutants. Consistently, a Dnmt3a engineered to tolerate H3K4me3 enables aberrant de novo methylation at developmental genes 45 , supporting a model whereby Dppa2-dependent H3K4me3 protects against DNAme. Such a system is likely necessary due to widespread de novo methylation activity throughout developmental (re)programming phases 15 , which presumably maintains epigenetic repression at specific genomic compartments such as TE, but could also aberrantly target developmental genes if not restrained 46 .…”

Section: Discussionsupporting

confidence: 53%

Dppa2 and Dppa4 counteract de novo methylation to establish a permissive epigenome for development

Gretarsson

Hackett

2020

Nat Struct Mol Biol

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Early mammalian development entails genome-wide epigenome remodeling, including DNA methylation erasure and reacquisition, which facilitates developmental competence. To uncover the mechanisms that orchestrate DNA methylation (DNAme) dynamics, we coupled a single-cell ratiometric DNAme reporter with unbiased CRISPR screening in ESC. We identify key genes and regulatory pathways that drive global DNA hypomethylation, and characterise roles for Cop1 and Dusp6. We also identify Dppa2 and Dppa4 as essential safeguards of focal epigenetic states. In their absence, developmental genes and evolutionary-young LINE1 elements, which DPPA2 specifically binds, lose H3K4me3 and gain ectopic de novo DNA methylation in pluripotent cells. Consequently, lineage-associated genes (and LINE1) acquire a repressive epigenetic memory, which renders them incompetent for activation during future lineage-specification. Dppa2/4 thereby sculpt the pluripotent epigenome by facilitating H3K4me3 and bivalency to counteract de novo methylation; a function coopted by evolutionary young LINE1 to evade epigenetic decommissioning. 2.

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Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

Cited by 8 publications

References 30 publications

DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns

DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns

Navigating the DNA methylation landscape of cancer

Dppa2 and Dppa4 counteract de novo methylation to establish a permissive epigenome for development

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