DNMT3A reads and connects histone H3K36me2 to DNA methylation

Xu, Wenqi; Li, Jiahui; Rong, Bowen; Zhao, Bin; Wang, Mei; Dai, Ruofei; Chen, Qilong; Liu, Huan; Gu, Zhongkai; Liu, Shuxian; Guo, Rui; Shen, Hongjie; Wu, Feizhen; Lan, Fei

doi:10.1007/s13238-019-00672-y

Cited by 35 publications

(31 citation statements)

References 15 publications

(20 reference statements)

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“…In fact, we found the greatest overlap of HypoMe probes between patients with mutations in NSD1 or in one of the two de novo DNMTs, consistent with the known link between H3K36 methylation and recruitment of DNMT3 enzymes at methylation sites (1636 and 1085 unique probes shared between NSD1 and DNMT3B or DNMT3A mutants, respectively) ( Supplementary Figure S9A ). However, the intersection of methylomes of patients with mutations in NSD1, DNMT3A or DNMT3B showed very poor overlap (63 shared HypoMPs) consistent with the distinct preferences of DNMT3A or B for di- or tri-methylation of H3K36, respectively [ 10 , 54 , 55 ]. Of note, the few HypoMPs in patients with SETD2 mutations also showed poor overlap with HypoMPs found in ICF1 (15 unique probes) or TBRS (9 unique probes) patients.…”

Section: Resultsmentioning

confidence: 95%

“…This result may reflect the existence of the afore mentioned crosstalk between H3K36 and CpG methylation, which involve the PWWP domain of DNMT3 enzymes. Several recent studies have reported that the distribution of DNMT3 activity at euchromatin regions of the genome is orchestrated by the presence of H3K36me2 and H3K36me3 catalyzed by the NSD1 and SETD2 enzymes, respectively [ 10 , 54 , 55 , 87 ]. In addition, experimental evidence highlighted the preference of DNMT3B for H3K36me3 mark at active gene bodies, whereas DNMT3A preferred intergenic regions enriched in H3K36me2 [ 10 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

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Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

Velasco

Ulveling

Rondeau

et al. 2021

IJMS

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DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

Velasco

Ulveling

Rondeau

et al. 2021

IJMS

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“…Increasing evidence suggests that DNMT3A and DNMT3B closely interact with H3K36 methylation through their PWWP domain to maintain the proper level of intergenic and intragenic DNA methylation, which plays critical roles in mammalian development and has been implicated in human developmental disorders and cancers. Two promising studies simultaneously revealed that DNMT3A was recruited to the H3K36me2-marked domain to regulate the establishment of intergenic DNA methylation (Xu et al 2020 ; Weinberg et al 2019 ). Aberrant levels of histone H3K36me2 lead to significant alterations in global 5-mC levels, which result from abnormal DNA hypermethylation by DNMT3A in the intergenic region (Xu et al 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…Two promising studies simultaneously revealed that DNMT3A was recruited to the H3K36me2-marked domain to regulate the establishment of intergenic DNA methylation (Xu et al 2020 ; Weinberg et al 2019 ). Aberrant levels of histone H3K36me2 lead to significant alterations in global 5-mC levels, which result from abnormal DNA hypermethylation by DNMT3A in the intergenic region (Xu et al 2020 ). In contrast, missense-mutant (Y365C, I310N or W297del) DNMT3A in the PWWP domain, which causes Tatton–Brown–Rahman syndrome (TBRS), a childhood overgrowth disorder, abolishes its binding affinity towards H3K36me2 resulting in aberrant intergenic CpG methylation (Weinberg et al 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Proteins in DNA methylation and their role in neural stem cell proliferation and differentiation

et al. 2021

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Background Epigenetic modifications, namely non-coding RNAs, DNA methylation, and histone modifications such as methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation play a significant role in brain development. DNA methyltransferases, methyl-CpG binding proteins, and ten-eleven translocation proteins facilitate the maintenance, interpretation, and removal of DNA methylation, respectively. Different forms of methylation, including 5-methylcytosine, 5-hydroxymethylcytosine, and other oxidized forms, have been detected by recently developed sequencing technologies. Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development, plasticity, and disorders of the mammalian central nervous system. Neural stem cells (NSCs), originating from the neuroepithelium, generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain. Main body Here, we summarized recent research in proteins responsible for the establishment, maintenance, interpretation, and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs. In addition, we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases. Conclusion Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding.

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“…H3K6me2 was associated with both activation and repression of the gene expression [ 24 ]. It was recently reported that Nsd1/Nsd2-mediated intergenic H3K36me2 recruited Dnmt3a for DNA methylation [ 25 , 26 ]. In yeast cells, H3K36me1/2/3 was also shown to repress cryptic transcription [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Nsd2 Represses Endogenous Retrovirus MERVL in Embryonic Stem Cells

Gao

Chen

Zhang

et al. 2021

Stem Cells International

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The facilitates chromatin transcription (FACT) complex is a histone H2A/H2B chaperone, which represses endogenous retroviruses (ERVs) and transcription of ERV-chimeric transcripts. It binds to both transcription start site and gene body region. Here, we investigated the downstream targets of FACT complex to identify the potential regulators of MERVL, which is a key 2-cell marker gene. H3K36me2 profile was positively correlated with that of FACT component Ssrp1. Among H3K36me2 deposition enzymes, Nsd2 was downregulated after the loss of Ssrp1. Furthermore, we demonstrated that Nsd2 repressed the expression of ERVs without affecting the expression of pluripotency genes. The expression of MERVL and 2-cell genes was partially rescued by Nsd2 overexpression. The enrichment of H3K36me2 decreased on MERVL-chimeric gene in ESCs without Ssrp1. Our study discovers that Nsd2 is a repressor of MERVL, and FACT partially represses MERVL expression by regulating the expression of Nsd2 and its downstream H3K36me2.

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DNMT3A reads and connects histone H3K36me2 to DNA methylation

Cited by 35 publications

References 15 publications

Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

Proteins in DNA methylation and their role in neural stem cell proliferation and differentiation

Nsd2 Represses Endogenous Retrovirus MERVL in Embryonic Stem Cells

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