DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells

被引：190

作者：

Zhang, Xiaotian ^{[1
,2
,3
]}

Su, Jianzhong ^{[4
]}

Jeong, Mira ^{[1
,2
]}

Ko, Myunggon ^{[5
,6
]}

Huang, Yun ^{[7
]}

Park, Hyun Jung ^{[4
]}

Guzman, Anna ^{[1
,2
]}

Lei, Yong ^{[1
,2
]}

Huang, Yung-Hsin ^{[1
,2
]}

Rao, Anjana ^{[5
]}

Li, Wei ^{[4
]}

Goodall, Margaret A. ^{[1
,2
,3
]}

机构：

[1] Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA

[2] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[4] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA

[5] La Jolla Inst Allergy & Immunol, La Jolla, CA USA

[6] Ulsan Natl Inst Sci & Technol, Sch Life Sci, Ulsan, South Korea

[7] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 09期

基金：

英国惠康基金;

关键词：

EPIGENETIC REGULATORS; CLONAL HEMATOPOIESIS; B-CELL; MUTATIONS; DNA; 5-HYDROXYMETHYLCYTOSINE; LEADS; MOUSE; 5-METHYLCYTOSINE; HYPERMETHYLATION;

D O I：

10.1038/ng.3610

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Mutations in the epigenetic modifiers DNMT3A and TET2 non-randomly co-occur in lymphoma and leukemia despite their epistasis in the methylation-hydroxymethylation pathway. Using Dnmt3a and Tet2 double-knockout mice in which the development of malignancy is accelerated, we show that the double-knockout methylome reflects regions of independent, competitive and cooperative activity. Expression of lineage-specific transcription factors, including the erythroid regulators Klf1 and Epor, is upregulated in double-knockout hematopoietic stem cells (HSCs). DNMT3A and TET2 both repress Klf1, suggesting a model of cooperative inhibition by epigenetic modifiers. These data demonstrate a dual role for TET2 in promoting and inhibiting HSC differentiation, the loss of which, along with DNMT3A, obstructs differentiation, leading to transformation.

引用

页码：1014 / +

页数：12

共 67 条

[1] Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies [J].

Abdel-Wahab, Omar ;

Mullally, Ann ;

Hedvat, Cyrus ;

Garcia-Manero, Guillermo ;

Patel, Jay ;

Wadleigh, Martha ;

Malinge, Sebastien ;

Yao, JinJuan ;

Kilpivaara, Outi ;

Bhat, Rukhmi ;

Huberman, Kety ;

Thomas, Sabrena ;

Dolgalev, Igor ;

Heguy, Adriana ;

Paietta, Elisabeth ;

Le Beau, Michelle M. ;

Beran, Miloslav ;

Tallman, Martin S. ;

Ebert, Benjamin L. ;

Kantarjian, Hagop M. ;

Stone, Richard M. ;

Gilliland, D. Gary ;

Crispino, John D. ;

Levine, Ross L. .

BLOOD, 2009, 114 (01) :144-147

[2] Acute loss of TET function results in aggressive myeloid cancer in mice [J].

An, Jungeun ;

Gonzalez-Avalos, Edahi ;

Chawla, Ashu ;

Jeong, Mira ;

Lopez-Moyado, Isaac F. ;

Li, Wei ;

Goodell, Margaret A. ;

Chavez, Lukas ;

Ko, Myunggon ;

Rao, Anjana .

NATURE COMMUNICATIONS, 2015, 6

[3] Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation [J].

Celik, Hamza ;

Mallaney, Cates ;

Kothari, Alok ;

Ostrander, Elizabeth L. ;

Eultgen, Elizabeth ;

Martens, Andrew ;

Miller, Christopher A. ;

Hundal, Jasreet ;

Klco, Jeffery M. ;

Challen, Grant A. .

BLOOD, 2015, 125 (04) :619-628

[4] Dnmt3a and Dnmt3b Have Overlapping and Distinct Functions in Hematopoietic Stem Cells [J].

Challen, Grant A. ;

Sun, Deqiang ;

Mayle, Allison ;

Jeong, Mira ;

Luo, Min ;

Rodriguez, Benjamin ;

Mallaney, Cates ;

Celik, Hamza ;

Yang, Liubin ;

Xia, Zheng ;

Cullen, Sean ;

Berg, Jonathan ;

Zheng, Yayun ;

Darlington, Gretchen J. ;

Li, Wei ;

Goodell, Margaret A. .

CELL STEM CELL, 2014, 15 (03) :350-364

[5] Dnmt3a is essential for hematopoietic stem cell differentiation [J].

Challen, Grant A. ;

Sun, Deqiang ;

Jeong, Mira ;

Luo, Min ;

Jelinek, Jaroslav ;

Berg, Jonathan S. ;

Bock, Christoph ;

Vasanthakumar, Aparna ;

Gu, Hongcang ;

Xi, Yuanxin ;

Liang, Shoudan ;

Lu, Yue ;

Darlington, Gretchen J. ;

Meissner, Alexander ;

Issa, Jean-Pierre J. ;

Godley, Lucy A. ;

Li, Wei ;

Goodell, Margaret A. .

NATURE GENETICS, 2012, 44 (01) :23-U43

[6]

Chambers Stuart M, 2007, Cell Stem Cell, V1, P578, DOI 10.1016/j.stem.2007.10.003

[7] DANPOS: Dynamic analysis of nucleosome position and occupancy by sequencing [J].

Chen, Kaifu ;

Xi, Yuanxin ;

Pan, Xuewen ;

Li, Zhaoyu ;

Kaestner, Klaus ;

Tyler, Jessica ;

Dent, Sharon ;

He, Xiangwei ;

Li, Wei .

GENOME RESEARCH, 2013, 23 (02) :341-351

[8] TET1 is a tumor suppressor of hematopoietic malignancy [J].

Cimmino, Luisa ;

Dawlaty, Meelad M. ;

Ndiaye-Lobry, Delphine ;

Yap, Yoon Sing ;

Bakogianni, Sofia ;

Yu, Yiting ;

Bhattacharyya, Sanchari ;

Shaknovich, Rita ;

Geng, Huimin ;

Lobry, Camille ;

Mullenders, Jasper ;

King, Bryan ;

Trimarchi, Thomas ;

Aranda-Orgilles, Beatriz ;

Liu, Cynthia ;

Shen, Steven ;

Verma, Amit K. ;

Jaenisch, Rudolf ;

Aifantis, Iannis .

NATURE IMMUNOLOGY, 2015, 16 (06) :653-+

[9] Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission [J].

Corces-Zimmerman, M. Ryan ;

Hong, Wan-Jen ;

Weissman, Irving L. ;

Medeiros, Bruno C. ;

Majeti, Ravindra .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (07) :2548-2553

[10] TET2 and DNMT3A Mutations in Human T-Cell Lymphoma [J].

Couronne, Lucile ;

Bastard, Christian ;

Bernard, Olivier A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (01) :95-96

← 1 2 3 4 5 6 7 →