TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

被引：83

作者：

Charlton, Jocelyn ^{[1
,2
,3
]}

Jung, Eunmi J. ^{[1
]}

Mattei, Alexandra L. ^{[1
,3
,4
]}

Bailly, Nina ^{[3
,5
]}

Liao, Jing ^{[1
]}

Martin, Eric J. ^{[6
,7
]}

Giesselmann, Pay ^{[3
]}

Braendl, Bjoern ^{[3
]}

Stamenova, Elena K. ^{[2
]}

Mueller, Franz-Josef ^{[3
,8
]}

Kiskinis, Evangelos ^{[6
,7
]}

Gnirke, Andreas ^{[2
]}

Smith, Zachary D. ^{[1
,2
]}

Meissner, Alexander ^{[1
,2
,3
,5
]}

机构：

[1] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] Max Planck Inst Mol Genet, Dept Genome Regulat, Berlin, Germany

[4] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA

[5] Free Univ Berlin, Inst Chem & Biochem, Berlin, Germany

[6] Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, Chicago, IL 60611 USA

[7] Northwestern Univ, Dept Physiol, Feinberg Sch Med, Chicago, IL 60611 USA

[8] Zentrum Integrat Psychiat gGmbH, Univ Klinikum Schleswig Holstein, Kiel, Germany

来源：

NATURE GENETICS | 2020年 / 52卷 / 08期

关键词：

DE-NOVO METHYLATION; DNA METHYLATION; SELF-RENEWAL; MOUSE; PROTEINS; BINDING; 5-METHYLCYTOSINE; EXPRESSION; ROLES; 5MC;

D O I：

10.1038/s41588-020-0639-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Mammalian cells stably maintain high levels of DNA methylation despite expressing both positive (DNMT3A/B) and negative (TET1-3) regulators. Here, we analyzed the independent and combined effects of these regulators on the DNA methylation landscape using a panel of knockout human embryonic stem cell (ESC) lines. The greatest impact on global methylation levels was observed in DNMT3-deficient cells, including reproducible focal demethylation at thousands of normally methylated loci. Demethylation depends on TET expression and occurs only when both DNMT3s are absent. Dynamic loci are enriched for hydroxymethylcytosine and overlap with subsets of putative somatic enhancers that are methylated in ESCs and can be activated upon differentiation. We observe similar dynamics in mouse ESCs that were less frequent in epiblast stem cells (EpiSCs) and scarce in somatic tissues, suggesting a conserved pluripotency-linked mechanism. Taken together, our data reveal tightly regulated competition between DNMT3s and TETs at thousands of somatic regulatory sequences within pluripotent cells. Whole-genome bisulfite sequencing analysis of human embryonic stem cells shows that DNMT3 deficiency leads to global and local demethylation, which depends on TET activity. Dynamic loci overlap with putative somatic enhancers that are highly methylated in ESCs.

引用

页码：819 / +

页数：29

共 64 条

[1] Circadian Entrainment Triggers Maturation of Human In Vitro Islets [J].

Alvarez-Dominguez, Juan R. ;

Donaghey, Julie ;

Rasouli, Niloofar ;

Kenty, Jennifer H. R. ;

Helman, Aharon ;

Charlton, Jocelyn ;

Straubhaar, Juerg R. ;

Meissner, Alexander ;

Melton, Douglas A. .

CELL STEM CELL, 2020, 26 (01) :108-+

[2] Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation [J].

Baubec, Tuncay ;

Colombo, Daniele F. ;

Wirbelauer, Christiane ;

Schmidt, Juliane ;

Burger, Lukas ;

Krebs, Arnaud R. ;

Akalin, Altuna ;

Schuebeler, Dirk .

NATURE, 2015, 520 (7546) :243-U278

[3] Principles of regulatory information conservation between mouse and human [J].

Cheng, Yong ;

Ma, Zhihai ;

Kim, Bong-Hyun ;

Wu, Weisheng ;

Cayting, Philip ;

Boyle, Alan P. ;

Sundaram, Vasavi ;

Xing, Xiaoyun ;

Dogan, Nergiz ;

Li, Jingjing ;

Euskirchen, Ghia ;

Lin, Shin ;

Lin, Yiing ;

Visel, Axel ;

Kawli, Trupti ;

Yang, Xinqiong ;

Patacsil, Dorrelyn ;

Keller, Cheryl A. ;

Giardine, Belinda ;

Kundaje, Anshul ;

Wang, Ting ;

Pennacchio, Len A. ;

Weng, Zhiping ;

Hardison, Ross C. ;

Snyder, Michael P. .

NATURE, 2014, 515 (7527) :371-+

[4] Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways [J].

Cirulli, Elizabeth T. ;

Lasseigne, Brittany N. ;

Petrovski, Slave ;

Sapp, Peter C. ;

Dion, Patrick A. ;

Leblond, Claire S. ;

Couthouis, Julien ;

Lu, Yi-Fan ;

Wang, Quanli ;

Krueger, Brian J. ;

Ren, Zhong ;

Keebler, Jonathan ;

Han, Yujun ;

Levy, Shawn E. ;

Boone, Braden E. ;

Wimbish, Jack R. ;

Waite, Lindsay L. ;

Jones, Angela L. ;

Carulli, John P. ;

Day-Williams, Aaron G. ;

Staropoli, John F. ;

Xin, Winnie W. ;

Chesi, Alessandra ;

Raphael, Alya R. ;

McKenna-Yasek, Diane ;

Cady, Janet ;

de Jong, J. M. B. Vianney ;

Kenna, Kevin P. ;

Smith, Bradley N. ;

Topp, Simon ;

Miller, Jack ;

Gkazi, Athina ;

Al-Chalabi, Ammar ;

van den Berg, Leonard H. ;

Veldink, Jan ;

Silani, Vincenzo ;

Ticozzi, Nicola ;

Shaw, Christopher E. ;

Baloh, Robert H. ;

Appel, Stanley ;

Simpson, Ericka ;

lagier-Tourenne, ClotilDe ;

Pulst, Stefan M. ;

Gibson, Summer ;

Trojanowski, John Q. ;

Elman, Lauren ;

McCluskey, Leo ;

Grossman, Murray ;

Shneider, Neil A. ;

Chung, Wendy K. .

SCIENCE, 2015, 347 (6229) :1436-1441

[5] Histone H3K27ac separates active from poised enhancers and predicts developmental state [J].

Creyghton, Menno P. ;

Cheng, Albert W. ;

Welstead, G. Grant ;

Kooistra, Tristan ;

Carey, Bryce W. ;

Steine, Eveline J. ;

Hanna, Jacob ;

Lodato, Michael A. ;

Frampton, Garrett M. ;

Sharp, Phillip A. ;

Boyer, Laurie A. ;

Young, Richard A. ;

Jaenisch, Rudolf .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (50) :21931-21936

[6] Combined Deficiency of Tet1 and Tet2 Causes Epigenetic Abnormalities but Is Compatible with Postnatal Development [J].

Dawlaty, Meelad M. ;

Breiling, Achim ;

Le, Thuc ;

Raddatz, Guenter ;

Barrasa, M. Inmaculada ;

Cheng, Albert W. ;

Gao, Qing ;

Powell, Benjamin E. ;

Li, Zhe ;

Xu, Mingjiang ;

Faull, Kym F. ;

Lyko, Frank ;

Jaenisch, Rudolf .

DEVELOPMENTAL CELL, 2013, 24 (03) :310-323

[7] TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells [J].

de la Rica, Lorenzo ;

Deniz, Ozgen ;

Cheng, Kevin C. L. ;

Todd, Christopher D. ;

Cruz, Cristina ;

Houseley, Jonathan ;

Branco, Miguel R. .

GENOME BIOLOGY, 2016, 17

[8] Genome-wide tracking of dCas9-methyltransferase footprints [J].

Galonska, Christina ;

Charlton, Jocelyn ;

Mattei, Alexandra L. ;

Donaghey, Julie ;

Clement, Kendell ;

Gu, Hongcang ;

Mohammad, Arman W. ;

Stamenova, Elena K. ;

Cacchiarelli, Davide ;

Klages, Sven ;

Timmermann, Bernd ;

Cantz, Tobias ;

Schoeler, Hans R. ;

Gnirke, Andreas ;

Ziller, Michael J. ;

Meissner, Alexander .

NATURE COMMUNICATIONS, 2018, 9

[9] Impact of epigenetics in aging and age related neurodegenerative diseases [J].

Gangisetty, Omkaram ;

Cabrera, Miguel A. ;

Murugan, Sengottuvelan .

FRONTIERS IN BIOSCIENCE-LANDMARK, 2018, 23 :1445-1464

[10] Nanopype: a modular and scalable nanopore data processing pipeline (vol 35, 4770, 2019) [J].

Giesselmann, Pay ;

Hetzel, Sara ;

Mueller, Franz-Josef ;

Meissner, Alexander ;

Kretzmer, Helene .

BIOINFORMATICS, 2019, 35 (21) :4536-4536

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