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

被引：200

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

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