DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility.
DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility.
复制标题
DOI：
10.1038/s41467-020-19001-7
复制
发表时间：
2020-10-15
影响因子：
16.6
通讯作者：
Manke T
中科院分区：
文献类型：
--
作者：
Ferrari F;Arrigoni L;Franz H;Izzo A;Butenko L;Trompouki E;Vogel T;Manke T
在神经元分化过程中，神经定向细胞的转录谱和表观遗传背景发生了显著的重排，但仍然缺少对全局组蛋白修饰变化的系统定量。在这里，我们表明，H3K79me2增加和H3K27ac减少在体外神经元分化的小鼠胚胎干细胞的全球。DOT1L介导H3K79的所有三种甲基化程度，其酶活性对于调节细胞分化和重编程至关重要。在这种情况下，我们发现，DOT1L在神经祖细胞中的抑制偏向神经元分化的转录状态，导致在转录上调的基因标记的H3K27me3的启动子区域。我们进一步表明，DOT1L抑制影响SOX 2结合增强子的可及性，并损害神经祖细胞中的SOX 2结合。我们的工作提供的证据表明，DOT1L活性门分化的祖细胞允许SOX 2依赖性转录的干性程序。神经元分化需要神经细胞的转录和染色质景观的重排。在这里，作者研究了小鼠胚胎干细胞（ESC）的体外神经元分化，以表明这一过程受到DOT1L活性的调节，DOT1L活性调节H3K79me2的积累，并保留了SOX 2结合增强子的可及性。
During neuronal differentiation, the transcriptional profile and the epigenetic context of neural committed cells is subject to significant rearrangements, but a systematic quantification of global histone modification changes is still missing. Here, we show that H3K79me2 increases and H3K27ac decreases globally during in-vitro neuronal differentiation of murine embryonic stem cells. DOT1L mediates all three degrees of methylation of H3K79 and its enzymatic activity is critical to modulate cellular differentiation and reprogramming. In this context, we find that inhibition of DOT1L in neural progenitor cells biases the transcriptional state towards neuronal differentiation, resulting in transcriptional upregulation of genes marked with H3K27me3 on the promoter region. We further show that DOT1L inhibition affects accessibility of SOX2-bound enhancers and impairs SOX2 binding in neural progenitors. Our work provides evidence that DOT1L activity gates differentiation of progenitors by allowing SOX2-dependent transcription of stemness programs. Neuronal differentiation requires rearrangement of the transcriptional and chromatin landscapes of neural cells. Here, the authors study in-vitro neuronal differentiation of murine embryonic stem cells (ESCs) to show that this process is modulated by DOT1L activity, which regulates H3K79me2 accumulation, and preserves accessibility of SOX2-bound enhancers.
登录
查看更多内容
影响因子：
5.1
作者：
Bovio, Patrick Piero;Franz, Henriette;Vogel, Tanja
通讯作者：
Vogel, Tanja
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
5.8
作者：
Bhardwaj, Vivek;Heyne, Steffen;Manke, Thomas
通讯作者：
Manke, Thomas
影响因子：
82.9
作者：
Chen, Chun-Wei;Koche, Richard P.;Sinha, Amit U.;Deshpande, Aniruddha J.;Zhu, Nan;Eng, Rowena;Doench, John G.;Xu, Haiming;Chu, Scott H.;Qi, Jun;Wang, Xi;Delaney, Christopher;Bernt, Kathrin M.;Root, David E.;Hahn, William C.;Bradner, James E.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
影响因子：
14.9
作者：
Cheng C;Gerstein M
通讯作者：
Gerstein M