Gestational Choline Supply Regulates Methylation of Histone H3, Expression of Histone Methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA Methylation of Their Genes in Rat Fetal Liver and Brain

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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DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

Nature Communications ◽

10.1038/s41467-021-22665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Wendan Ren ◽

Huitao Fan ◽

Sara A. Grimm ◽

Jae Jin Kim ◽

Linhui Li ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Histone H3 ◽

Genomic Stability ◽

Mammalian Genome ◽

Dna Methyltransferase 1 ◽

Chromatin Modifications ◽

Direct Link ◽

Histone H4 ◽

Radiation Induced

AbstractDNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

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Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase

Nature ◽

10.1038/nature731 ◽

2002 ◽

Vol 416 (6880) ◽

pp. 556-560 ◽

Cited By ~ 788

Author(s):

James P. Jackson ◽

Anders M. Lindroth ◽

Xiaofeng Cao ◽

Steven E. Jacobsen

Keyword(s):

Dna Methylation ◽

Histone H3

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Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4-20h2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats

Carcinogenesis ◽

10.1093/carcin/bgi364 ◽

2006 ◽

Vol 27 (6) ◽

pp. 1180-1186 ◽

Cited By ~ 105

Author(s):

Igor P. Pogribny ◽

Sharon A. Ross ◽

Volodymyr P. Tryndyak ◽

Marta Pogribna ◽

Lionel A. Poirier ◽

...

Keyword(s):

Histone H3 ◽

Histone Methyltransferases

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Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes

Nucleic Acids Research ◽

10.1093/nar/gkab107 ◽

2021 ◽

Author(s):

Qian-Qian Sha ◽

Ye-Zhang Zhu ◽

Yunlong Xiang ◽

Jia-Li Yu ◽

Xiao-Ying Fan ◽

...

Keyword(s):

Dna Methylation ◽

Histone H3 ◽

Finger Protein ◽

Maternal Genome ◽

Wide Range ◽

Transcriptional Changes ◽

Nuclear Events ◽

Genomic Regions ◽

Cxxc Finger Protein 1

Abstract During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

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Histone H3 and H4 acetylation patterns are more dynamic than those of DNA methylation in Brachypodium distachyon embryos during seed maturation and germination

PROTOPLASMA ◽

10.1007/s00709-017-1088-x ◽

2017 ◽

Vol 254 (5) ◽

pp. 2045-2052 ◽

Cited By ~ 3

Author(s):

Elzbieta Wolny ◽

Agnieszka Braszewska-Zalewska ◽

Daria Kroczek ◽

Robert Hasterok

Keyword(s):

Dna Methylation ◽

Brachypodium Distachyon ◽

Histone H3 ◽

Seed Maturation

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Dynamic Methylation Changes of DNA and H3K4 by RG108 Improve Epigenetic Reprogramming of Somatic Cell Nuclear Transfer Embryos in Pigs

Cellular Physiology and Biochemistry ◽

10.1159/000494598 ◽

2018 ◽

Vol 50 (4) ◽

pp. 1376-1397 ◽

Cited By ~ 5

Author(s):

Yanhui Zhai ◽

Zhiren Zhang ◽

Hao Yu ◽

Li Su ◽

Gang Yao ◽

...

Keyword(s):

Dna Methylation ◽

Somatic Cell ◽

Histone Modifications ◽

Somatic Cell Nuclear Transfer ◽

Nuclear Transfer ◽

Histone H3 ◽

Dna Demethylation ◽

Epigenetic Reprogramming ◽

Expression Levels ◽

Fetal Fibroblasts

Background/Aims: DNA methylation and histone modifications are essential epigenetic marks that can significantly affect the mammalian somatic cell nuclear transfer (SCNT) embryo development. However, the mechanisms by which the DNA methylation affects the epigenetic reprogramming have not been fully elucidated. Methods: In our study, we used quantitative polymerase chain reaction (qPCR), Western blotting, immunofluorescence staining (IF) and sodium bisulfite genomic sequencing to examine the effects of RG108, a DNA methyltransferase inhibitor (DNMTi), on the dynamic pattern of DNA methylation and histone modifications in porcine SCNT embryos and investigate the mechanism by which the epigenome status of donor cells’ affects SCNT embryos development and the crosstalk between epigenetic signals. Results: Our results showed that active DNA demethylation was enhanced by the significantly improving expression levels of TET1, TET2, TET3 and 5hmC, and passive DNA demethylation was promoted by the remarkably inhibitory expression levels of DNMT1, DNMT3A and 5mC in embryos constructed from the fetal fibroblasts (FFs) treated with RG108 (RG-SCNT embryos) compared to the levels in embryos from control FFs (FF-SCNT embryos). The signal intensity of histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 9 acetylation (H3K9Ac) was significantly increased and the expression levels of H3K4 methyltransferases were more than 2-fold higher expression in RG-SCNT embryos. RG-SCNT embryos had significantly higher cleavage and blastocyst rates (69.3±1.4%, and 24.72±2.3%, respectively) than FF-SCNT embryos (60.1±2.4% and 18.38±1.9%, respectively). Conclusion: Dynamic changes in DNA methylation caused by RG108 result in dynamic alterations in the patterns of H3K4me3, H3K9Ac and histone H3 lysine 9 trimethylation (H3K9me3), which leads to the activation of embryonic genome and epigenetic modification enzymes associated with H3K4 methylation, and contributes to reconstructing normal epigenetic modifications and improving the developmental efficiency of porcine SCNT embryos.

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