Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites.
Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites.
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DOI：
10.1101/gr.132878.111
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发表时间：
2012-08
期刊：
影响因子：
7
通讯作者：
Bodine DM
中科院分区：
文献类型：
--
作者：
Hogart A;Lichtenberg J;Ajay SS;Anderson S;NIH Intramural Sequencing Center;Margulies EH;Bodine DM
DNA甲基化是正常发育所需的重要表观遗传标记。敲除小鼠造血区室中的DNA甲基转移酶揭示了甲基化对于造血分化至关重要。为了更好地理解DNA甲基化在造血中的作用，我们表征了原代小鼠造血干细胞（HSC）、普通髓系祖细胞（CMP）和成红细胞（ERY）中的全基因组DNA甲基化。使用甲基结合结构域蛋白2（MBD）富集DNA，然后进行大规模平行测序（MBD-seq）来绘制全基因组DNA甲基化。在全球范围内，DNA甲基化在HSC中最丰富，CMP减少40%，ERY减少67%。只有3%的峰值出现在分化过程中，表明在红细胞发育过程中DNA甲基化的全基因组下降。基因组特征分析显示，98%的启动子CpG岛是低甲基化的，而20%-25%的非启动子CpG岛是甲基化的。在所有细胞类型中，表达基因的近端启动子序列都是低甲基化的，而基因体甲基化与HSC和CMP中的基因表达呈正相关。在HSC中升高的全基因组DNA甲基化以及甲基化与基因表达之间的正相关表明DNA甲基化是HSC中细胞可塑性的标志。使用从头基序发现，我们确定了甲基化序列中过度表达的转录因子共有结合基序。包括GABPA和ELF 1在内的几种ETS转录因子的基序在甲基化区域中过度表达。我们的全基因组调查表明，DNA甲基化显着改变骨髓分化过程中，并确定关键区域的基因组和转录因子程序，有助于造血。
DNA methylation is an essential epigenetic mark that is required for normal development. Knockout of the DNA methyltransferase enzymes in the mouse hematopoietic compartment reveals that methylation is critical for hematopoietic differentiation. To better understand the role of DNA methylation in hematopoiesis, we characterized genome-wide DNA methylation in primary mouse hematopoietic stem cells (HSCs), common myeloid progenitors (CMPs), and erythroblasts (ERYs). Methyl binding domain protein 2 (MBD) enrichment of DNA followed by massively parallel sequencing (MBD-seq) was used to map genome-wide DNA methylation. Globally, DNA methylation was most abundant in HSCs, with a 40% reduction in CMPs, and a 67% reduction in ERYs. Only 3% of peaks arise during differentiation, demonstrating a genome-wide decline in DNA methylation during erythroid development. Analysis of genomic features revealed that 98% of promoter CpG islands are hypomethylated, while 20%–25% of non-promoter CpG islands are methylated. Proximal promoter sequences of expressed genes are hypomethylated in all cell types, while gene body methylation positively correlates with gene expression in HSCs and CMPs. Elevated genome-wide DNA methylation in HSCs and the positive association between methylation and gene expression demonstrates that DNA methylation is a mark of cellular plasticity in HSCs. Using de novo motif discovery, we identified overrepresented transcription factor consensus binding motifs in methylated sequences. Motifs for several ETS transcription factors, including GABPA and ELF1, are overrepresented in methylated regions. Our genome-wide survey demonstrates that DNA methylation is markedly altered during myeloid differentiation and identifies critical regions of the genome and transcription factor programs that contribute to hematopoiesis.
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影响因子：
4.4
作者：
Lee, Choong-Gu;Kwon, Ho-Keun;Im, Sin-Hyeog
通讯作者：
Im, Sin-Hyeog
影响因子：
32.4
作者：
Mansson, Robert;Hultquist, Anne;Jacobsen, Sten Eirik W.
通讯作者：
Jacobsen, Sten Eirik W.
TransFac及其模块移植：真核生物中的转录基因调节。
影响因子：
14.9
作者：
Matys V;Kel-Margoulis OV;Fricke E;Liebich I;Land S;Barre-Dirrie A;Reuter I;Chekmenev D;Krull M;Hornischer K;Voss N;Stegmaier P;Lewicki-Potapov B;Saxel H;Kel AE;Wingender E
通讯作者：
Wingender E
影响因子：
30.8
作者：
Broeske, Ann-Marie;Vockentanz, Lena;Rosenbauer, Frank
通讯作者：
Rosenbauer, Frank
影响因子：
10.5
作者：
Hollenhorst, Peter C.;Shah, Atul A.;Graves, Barbara J.
通讯作者：
Graves, Barbara J.