Genomic prevalence of heterochromatic H3K9me2 and transcription do not discriminate pluripotent from terminally differentiated cells.
Genomic prevalence of heterochromatic H3K9me2 and transcription do not discriminate pluripotent from terminally differentiated cells.
复制标题
DOI：
10.1371/journal.pgen.1002090
复制
发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
Schübeler D
中科院分区：
文献类型：
--
作者：
Lienert F;Mohn F;Tiwari VK;Baubec T;Roloff TC;Gaidatzis D;Stadler MB;Schübeler D
细胞分化需要转录组从多能性命运重新编程为单能性命运。这一过程被认为与抑制性异染色质的整体增加相一致，这导致转录可塑性和潜力的降低。在这里，我们报告的动态转录组和丰富的异染色质组蛋白的修改，二甲基化组蛋白H3在赖氨酸9（H3K9me2），在胚胎干细胞的神经元分化。与流行的模型相反，我们发现H3K9me2占据了干细胞中超过50%的染色体区域。标记的是缺乏转录的大多数基因组区域和组蛋白修饰的亚组。重要的是，在分化过程中没有发生整体增加，但可以检测到H3K9me2的离散局部变化，特别是在基因区域。与细胞命运变化相对应，许多基因在分化时表现出改变的表达。然而，转录本的定量测序表明，干细胞和几种测试的分化细胞类型之间的活性基因的总数是相等的。总之，这些发现揭示了干细胞中异染色质标记的高流行率，并挑战了干细胞中表观遗传抑制的低丰度和由此产生的全局基础水平转录的模型。这表明细胞分化需要表观遗传抑制和转录活性的局部而不是全局变化。DNA和结合组蛋白的表观遗传修饰是细胞类型特异性基因表达模式的主要决定因素。干细胞生物学中的一个流行模型表明，多能性的丧失需要异染色质的整体增加和谱系无关基因的同时关闭。我们在晚期鼠神经元分化模型中进行了H3K9二甲基化模式和全局转录组的分析。在这个范例中，我们没有发现异染色质H3K9二甲基化的整体增加或转录组复杂性降低的证据，因为干细胞成为终末分化的有丝分裂后神经元。这表明多能胚胎干细胞与体细胞相比，在异染色质丰度和转录可塑性方面本身并不独特。相反，染色质的局部变化可能有助于稳定任何发育阶段的细胞状态。
Cellular differentiation entails reprogramming of the transcriptome from a pluripotent to a unipotent fate. This process was suggested to coincide with a global increase of repressive heterochromatin, which results in a reduction of transcriptional plasticity and potential. Here we report the dynamics of the transcriptome and an abundant heterochromatic histone modification, dimethylation of histone H3 at lysine 9 (H3K9me2), during neuronal differentiation of embryonic stem cells. In contrast to the prevailing model, we find H3K9me2 to occupy over 50% of chromosomal regions already in stem cells. Marked are most genomic regions that are devoid of transcription and a subgroup of histone modifications. Importantly, no global increase occurs during differentiation, but discrete local changes of H3K9me2 particularly at genic regions can be detected. Mirroring the cell fate change, many genes show altered expression upon differentiation. Quantitative sequencing of transcripts demonstrates however that the total number of active genes is equal between stem cells and several tested differentiated cell types. Together, these findings reveal high prevalence of a heterochromatic mark in stem cells and challenge the model of low abundance of epigenetic repression and resulting global basal level transcription in stem cells. This suggests that cellular differentiation entails local rather than global changes in epigenetic repression and transcriptional activity. Epigenetic modifications of DNA and bound histones are major determinants of cell type–specific gene expression patterns. A prevalent model in stem cell biology suggests that the loss of pluripotency entails global increase in heterochromatin and coinciding shutdown of lineage unrelated genes. We performed analysis of both H3K9 dimethylation pattern and the global transcriptome in an advanced murine neuronal differentiation model. In this paradigm, we do not find evidence for a global increase in heterochromatic H3K9 dimethylation or reduction of transcriptome complexity as stem cells become terminally differentiated post-mitotic neurons. This suggests that pluripotent embryonic stem cells are not per se unique in regards to heterochromatin abundance and transcriptional plasticity as compared to somatic cells. Instead, focal changes in chromatin might help to stabilize cellular states at any developmental stage.
登录
查看更多内容
影响因子：
64.5
作者：
Hanna JH;Saha K;Jaenisch R
通讯作者：
Jaenisch R
影响因子：
64.8
作者：
Gaspar-Maia A;Alajem A;Polesso F;Sridharan R;Mason MJ;Heidersbach A;Ramalho-Santos J;McManus MT;Plath K;Meshorer E;Ramalho-Santos M
通讯作者：
Ramalho-Santos M
影响因子：
25
作者：
Bibel, M;Richter, J;Barde, YA
通讯作者：
Barde, YA
KAP1结合的全基因组分析表明KRAB-ZNF的自动调节。
影响因子：
4.5
作者：
O'Geen, Henriette;Squazzo, Sharon L.;Iyengar, Sushma;Blahnik, Kim;Rinn, John L.;Chang, Howard Y.;Green, Roland;Farnham, Peggy J.
通讯作者：
Farnham, Peggy J.
影响因子：
7
作者：
Koch, Christoph M.;Andrews, Robert M.;Dunham, Ian
通讯作者：
Dunham, Ian