Dnmt3a is essential for hematopoietic stem cell differentiation

被引：829

作者：

Challen, Grant A. ^{[1
,2
,3
]}

Sun, Deqiang ^{[4
,5
]}

Jeong, Mira ^{[1
,2
]}

Luo, Min ^{[6
]}

Jelinek, Jaroslav ^{[7
]}

Berg, Jonathan S. ^{[8
,9
]}

Bock, Christoph ^{[10
,11
]}

Vasanthakumar, Aparna ^{[12
]}

Gu, Hongcang ^{[7
]}

Xi, Yuanxin ^{[4
,5
]}

Liang, Shoudan ^{[13
]}

Lu, Yue

Darlington, Gretchen J. ^{[6
]}

Meissner, Alexander ^{[10
,11
]}

Issa, Jean-Pierre J. ^{[7
]}

Godley, Lucy A. ^{[12
]}

Li, Wei ^{[4
,5
]}

Goodell, Margaret A. ^{[1
,2
,14
]}

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 Pathol, Houston, TX 77030 USA

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

[5] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[6] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

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

[9] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[10] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA

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

[12] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[14] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NOVO DNA METHYLTRANSFERASE; MAMMALIAN DNA; SELF-RENEWAL; METHYLATION; GENE; HYPERMETHYLATION; TRANSCRIPTION; HYPOMETHYLATION; MUTATIONS; EXPRESSION;

D O I：

10.1038/ng.1009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Loss of the de novo DNA methyltransferases Dnmt3a and Dnmt3b in embryonic stem cells obstructs differentiation; however, the role of these enzymes in somatic stem cells is largely unknown. Using conditional ablation, we show that Dnmt3a loss progressively impairs hematopoietic stem cell (HSC) differentiation over serial transplantation, while simultaneously expanding HSC numbers in the bone marrow. Dnmt3a-null HSCs show both increased and decreased methylation at distinct loci, including substantial CpG island hypermethylation. Dnmt3a-null HSCs upregulate HSC multipotency genes and downregulate differentiation factors, and their progeny exhibit global hypomethylation and incomplete repression of HSC-specific genes. These data establish Dnmt3a as a critical participant in the epigenetic silencing of HSC regulatory genes, thereby enabling efficient differentiation.

引用

页码：23 / U43

页数：11

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