SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development

Xu, Qianhua; Xiang, Yunlong; Wang, Qiujun; Wang, Leyun; Brind’Amour, Julie; Bogutz, Aaron B.; Zhang, Yu; Zhang, Bingjie; Yu, Guang; Xia, Weikun; Du, Zhenhai; Ci, Huang; Ma, Jing; Zheng, Hui; Li, Yuanyuan; Liu, Chao; Walker, Cheryl L.; Jonasch, Eric; Lefebvre, Louis; Wu, Min; Lorincz, Matthew C.; Wei, Li; Li, Li; Xie, Wei

doi:10.1038/s41588-019-0398-7

Cited by 216 publications

(287 citation statements)

References 64 publications

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“…Interestingly, we also found higher expression level of H3K36me3 in GOF/GFP + L-ESCs (Figure 4D). This result is consistent with H3K36me3 remarked by the guard of DNA methylation process (Xu et al , 2019).…”

Section: Resultssupporting

confidence: 92%

“…We also show that DNMT3A and H3K36me3 expression was higher in L-ESCs compare to 2i/L-ESCs. Recently multiple studies suggested that H3K36me3 participates in cross-talk with other chromatin marks, and promotes de novo DNA methylation by interacting with DNMTs and SETD2 (Xu et al , 2019). H3K36me3 are responsible for establishing and safeguarding the maternal epigenome (Xu et al , 2019).…”

Section: Discussionmentioning

confidence: 99%

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DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming

et al. 2020

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24 25 26 27 Highlights and novelty 1  LIF alone supports ESCs self-renew and pluripotency in chemically defined media. 2  L-ESCs re-establish the epigenetic memory in reprogramming. 3  DNA methylation is indispensable for L-ESCs reprogramming. 4  L-ESCs contribute to somatic tissues and germ cells in chimaeras. Abstract 7 Naï ve pluripotency can be maintained by the 2i/LIF supplements (CHIR99021, 8 PD0325901 and LIF), which primarily affect canonical WNT, FGF/ERK, and 9 JAK/STAT3 signaling. However, whether one of these tripartite supplements alone is 10 sufficient to maintain naï ve self-renewal remain unclear. Here we show that LIF alone is 11 sufficient to induce reprogramming of 2i/LIF cultured ESCs (2i/L-ESCs) to ESCs with 12 hypermethylated state (L-ESCs). In vitro, upon withdrawal of 2i, 2i/L-ESCs overcome 13 the epigenetic barrier and DNA hypermethylated, which accompanies transcriptional 14 changes and subsequent establishment of epigenetic memory. Global transcriptome 15 features also show that L-ESCs are close to 2i/L-ESCs and in a stable state between 16 naï ve and primed pluripotency. Notably, our results demonstrate that DNA methylation 17 is indispensable for LIF-dependent mouse ESCs reprogramming and self-renew. 18 LIF-dependent ESCs reprogramming efficiency is significantly increased in serum 19 treatment and reduced in Dnmt3a or Dnmt3l knockout ESCs. Importantly, unlike 20 epiblast and EpiSCs, L-ESCs contribute to somatic tissues and germ cells in chimaeras. 21 Such simple culture system of ESCs is more conducive to clarify the molecular 22 mechanism of ESCs in vitro culture.23 24 Key Words 25Embryonic stem cells; Leukemia inhibitory factor; Reprogramming; Epigenetic; Genomic 26 imprinting; DNA methylation 2 pre-implantation embryos (Evans & Kaufman, 1981; Martin, 1981). Since pluripotent mouse 3 embryonic stem cells were first established four decades ago, various culture systems of ESCs 4 have been developed including the initial feeder/serum/cytokines, then the 5 feeder/serum/Leukemia inhibitory factor (LIF) or Bone morphogenetic protein 4 (BMP4) 6 (Smith et al, 1988; Williams et al, 1988; Ying et al, 2003), and the recent 2i/LIF (two 7 inhibitors CHIR99021, PD0325901 and LIF) (Ying et al, 2008). It is generally believed that 8 the optimal culture condition for ground sate ESCs comprises three additive 2i/LIF 9 supplements which affect canonical WNT, FGF/ERK, and JAK/STAT3 signals. It has been 10 reported that combination of any two of these tripartite supplements was sufficient to maintain 11 naï ve self-renewal of ESCs (Hackett et al, 2017). However, whether any one of the tripartite 12 supplements plays a critical role with unique critical targets and signaling for ESCs 13 pluripotency and self-renew remain elusive. 14 15 LIF is the most pleiotropic member of the interleukin-6 family of cytokines, and utilizes a 16 receptor that consists of the LIF receptor B and gp130 (Ohtsuka et al, 2015). LIF is able to 17 activate three intracellular signaling pathway: the JAK/STAT pathway, the PI3...

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming

et al. 2020

Preprint

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“…Although the extent of histone post-translational modification (PTM) maintenance following fertilization is controversial 34,36,37 , the retention and/or rapid deposition of H3K4 methylation at CGI promoters may protect these regions against de novo DNAme 38 in the developing male germline as well as the early embryo. Indeed, most CGI promoters are enriched for H3K4me3 and remain hypomethylated on both parental genomes throughout early embryonic development and in adult tissues 16,39 .…”

Section: Introductionmentioning

confidence: 99%

“…As in sperm, CGIs in oocytes are generally hypomethylated and harbor nucleosomes enriched for H3K4me3 36 and/or H3K27me3 40,41 . However, a subset of CGIs, are de novo methylated in growing oocytes by DNMT3A, which is highly expressed in oocytes [42][43][44] . Paradoxically, despite widespread DNAme loss from the paternal genome in mouse zygotes, maternal DNMT3A is also clearly detected in the paternal pronucleus at this stage 14,27 and ongoing de novo DNAme is required for maintaining paternal allele DNAme of the paternally imprinted H19 locus in early embryos 45 .…”

Section: Introductionmentioning

confidence: 99%

Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

Albert

Yeung

Toriyama

et al. 2020

Preprint

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De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. Following fertilization, the paternal genome undergoes widespread DNAme loss before the first S-phase. Paradoxically, recent mass spectrometry analysis revealed that a low level of de novo DNAme occurs exclusively on the zygotic paternal genome. However, the loci involved and impact on genic transcription was not addressed. Here, we employ allele-specific analysis of wholegenome bisulphite sequencing (WGBS) data and show that a number of genomic regions, including several dozen CGI promoters, are de novo methylated on the paternal genome in 2-cell embryos. A subset of these promoters maintains DNAme through development to the blastocyst stage. Consistent with zygotic paternal DNAme acquisition (PDA), many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Strikingly, PDA is lost following maternal deletion of Dnmt3a. Furthermore, a subset of promoters showing PDA which are normally transcribed from the paternal allele in blastocysts show premature transcription at the 4-cell stage in maternal Dnmt3a knockout embryos. These observations uncover an unexpected role for maternal DNMT3A activity in postfertilization epigenetic reprogramming and transcriptional silencing of the paternal genome.

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“…[7][8][9] SETD2 was shown to determine chromatin integrity during transcription. 18 In addition, reductions of H3K36me3 due to SETD2 depletion could cause embryonic death around E10.5-E11.5 in mice. 11-14 SETD2 functions in multiple biological events by interacting with many effector proteins bind trimethylated H3K36.…”

Section: Introductionmentioning

confidence: 99%

SETD2 reduction adversely affects the development of mouse early embryos

Huang

2019

J of Cellular Biochemistry

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SET domain‐containing protein 2 (SETD2), the protein of regulating trimethylation status of histone H3 at lysine 36 (H3K36), participates in the maintenance of chromatin architecture, transcription elongation, genome stability, and other biological events. However, its function in preimplantation embryos is still obscure. In this study, specific small interfering RNA was employed to investigate the functions of SETD2. We find that deletion of SETD2 results in the developmental delay of mouse early embryos, indicative of the compromised developmental potential. Remarkably, SETD2 knockdown induces the accumulation of the DNA lesions and apoptotic blastomeres in early embryos. In addition, the methylation level of H3K36 is significantly reduced in two‐cell embryos depleted of SETD2. In summary, our data indicate that SETD2 maintains genome stability perhaps via regulating trimethylation status of H3K36, consequently controlling the embryo quality. These findings pave the avenue for understanding the cross‐talk between epigenome and SETD2 during early embryo development.

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SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development

Cited by 216 publications

References 64 publications

DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming

DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming

Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

SETD2 reduction adversely affects the development of mouse early embryos

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