The push and pull of DNA methylation

doi:10.1126/science.abh3187

GSTDTAP > 气候变化

DOI	10.1126/science.abh3187
	The push and pull of DNA methylation
	Tianpeng Gu; Margaret A. Goodell
	2021-04-09
发表期刊	Science
出版年	2021
英文摘要	DNA methylation is an important covalent modification of mammalian genomic DNA that represses transcription. Genomic DNA is mostly maintained with high amounts of methylation, but some regions such as CpG islands are nearly perpetually unmethylated. Recently, large valleys or canyons of unmethylated DNA were discovered throughout the mammalian genome ([ 1 ][1], [ 2 ][2]). Most are associated with conserved developmental regulators, such as homeobox genes, and are thought to be actively regulated. The size of these canyons is maintained by a push and pull interplay between DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) dioxygenases that oxidize 5-methylcytosine, which leads to demethylation ([ 2 ][2]). On page 146 of this issue, Dixon et al. ([ 3 ][3]) identify QSER1 (glutamine and serine–rich protein 1) as part of the “push” protection mechanism that restricts DNA methylation. They show that QSER1 cooperates with TET1 by antagonizing chromatin binding of DNMT3A and DNMT3B, thus helping to retain the developmental potential of stem cells. Chromatin binding of DNMT3A and DNMT3B, and hence their activity in establishing de novo DNA methylation, is directed by multiple factors, including nucleosomes ([ 4 ][4]), histone modifications ([ 5 ][5], [ 6 ][6]), and specific interacting partners. For example, DNMT3A is recruited to intergenic regions through dimethylated lysine 36 of histone 3 (H3K36me2), whereas DNMT3B shows enhanced binding to gene bodies of actively transcribed genes in a trimethylated H3K36 (H3K36me3)–dependent manner. Although the mechanism is still unclear, the long DNMT3A1 isoform is enriched at regions flanking CpG islands (“shores”) at bivalent promoters bearing both the transcription-activating H3K4me3 and the transcription-repressive H3K27me3 histone modifications ([ 7 ][7], [ 8 ][8]). ![Figure][9] Regulating DNA methylation canyons QSER1 (glutamine and serine–rich protein 1) and TET1 (ten-eleven translocation 1) protect DNA methylation canyons from hypermethylation by antagonizing DNA methyltransferase 3A (DNMT3A) and DNMT3B binding and safeguard the developmental potential of stem cells. GRAPHIC: KELLIE HOLOSKI/ SCIENCE Although such histone modifications appear to guide the activity of DNMTs, additional features are used to actively oppose DNA methylation at CpG islands and canyons. TET proteins in particular have been shown to safeguard bivalent promoters against hypermethylation in human and mouse embryonic stem cells ([ 8 ][8], [ 9 ][10]). The finding of QSER1 through a clever CRISPR screen to identify unknown regulators of DNA methylation by Dixon et al. was consistent with previous data indicating that it is a TET1 binding partner ([ 10 ][11]). They demonstrated that the two proteins are mutually dependent on each other for chromatin binding and that they compete for DNA binding with DNMT3A and DNMT3B at canyons (see the figure). Notably, in human embryonic stem cells lacking QSER1 and TET1 , many promoter regions became hypermethylated and showed decreased transcription; the stem cells were less able to differentiate into pancreatic progenitors, underscoring the in vivo biological importance of QSER1-TET1–regulated DNA methylation for stem cell function. Growing evidence, including the work by Dixon et al. , suggests that tightly regulated regional DNA methylation around bivalent promoters is critical for cell-fate decisions. Enrichment of 5-hydroxymethylcytosine, a key intermediate of TET-mediated DNA demethylation at the shores of canyons, signals the greatest methylation turnover at these regions during stem cell self-renewal and differentiation ([ 2 ][2]). Any gene mutations that disrupt the balance of DNA methylation and demethylation at such regulatory regions could be pathogenic. Gain-of-function DNMT3A mutations in the PWWP (Pro-Trp-Trp-Pro) domain cause human growth failure and DNA hypermethylation at canyons associated with the histone modifying Polycomb-repressive complexes in corresponding mouse models ([ 11 ][12], [ 12 ][13]). Mutations of DNA methylation regulators, including loss-of-function mutations of DNMT3A and TET2 and gain-of-function mutations of isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 , are frequently found in hematological malignancies, highlighting an essential role for stable DNA methylation status at focal regions in maintaining hematopoietic homeostasis. Moreover, in different cancer types, DNA hypermethylation within the promoters of tumor-suppressor genes occurs concomitantly with global DNA hypomethylation; both are thought to contribute to cancer cell transformation, underscoring the importance of maintaining balance in DNA methylation. The study of Dixon et al. validates QSER1 as a regulator for DNA methylation; nevertheless, some important questions remain unanswered. There are three TET proteins with distinct expression patterns across various cell types. It is unknown whether QSER1 interacts with TET2 and TET3, if any such interactions even exist in somatic tissues, or whether there are distinct mechanisms that serve with (or instead of) QSER1 to keep canyons hypomethylated in different contexts. Animal models in which QSER1 is ablated will reveal the extent to which QSER1 is essential and will further illustrate the regulatory function of QSER1 during embryogenesis and development. Given the involvement of TET proteins in DNA demethylation, future research should focus on the coordinated function of QSER1 and TETs in epigenetic reprogramming in early embryos and establishing genomic imprinting in primordial germ cells. The maintenance of DNA methylation at canyons in somatic stem cells is also involved in three-dimensional chromatin architecture ([ 13 ][14]); it will be interesting to establish whether QSER1 has a role. There are limited data available on genetic alterations of QSER1 in patients. Considering the dysregulation of DNA methylation in multiple diseases, it is likely that mutations in QSER1 will be identified. Future investigation should integrate QSER1 in the regulatory network to achieve a better understanding for bivalent genes associated with cell differentiation and developmental transitions. DNA methylation and demethylation are balanced through DNMT3 and TET proteins both competing and cooperating in synchrony with histone modifications; the mechanisms through which expression of developmental genes are regulated remain poorly understood ([ 14 ][15], [ 15 ][16]). The discovery of QSER1 offers a new facet to the push and pull regulation of DNA methylation. 1. [↵][17]1. W. Xie et al ., Cell 153, 1134 (2013). [OpenUrl][18][CrossRef][19][PubMed][20][Web of Science][21] 2. [↵][22]1. M. Jeong et al ., Nat. Genet. 46, 17 (2014). [OpenUrl][23][CrossRef][24][PubMed][25] 3. [↵][26]1. G. Dixon et al ., Science 372, eabd0875 (2021). [OpenUrl][27][Abstract/FREE Full Text][28] 4. [↵][29]1. T. H. Xu et al ., Nature 586, 151 (2020). [OpenUrl][30][CrossRef][31] 5. [↵][32]1. T. Baubec et al ., Nature 520, 243 (2015). [OpenUrl][33][CrossRef][34][PubMed][35] 6. [↵][36]1. D. N. Weinberg et al ., Nature 573, 281 (2019). [OpenUrl][37][CrossRef][38][PubMed][39] 7. [↵][40]1. M. 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[OpenUrl][70][CrossRef][71][PubMed][72] Acknowledgments: The Goodell lab is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, the National Institute on Aging, and the Edward P. Evans Foundation. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/322073
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Tianpeng Gu,Margaret A. Goodell. The push and pull of DNA methylation[J]. Science,2021.
APA	Tianpeng Gu,&Margaret A. Goodell.(2021).The push and pull of DNA methylation.Science.
MLA	Tianpeng Gu,et al."The push and pull of DNA methylation".Science (2021).