Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal.
Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal.
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DOI：
10.1101/gr.173435.114
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发表时间：
2015-01
期刊：
影响因子：
7
通讯作者：
Martynoga B
中科院分区：
文献类型：
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作者：
Mateo JL;van den Berg DL;Haeussler M;Drechsel D;Gaber ZB;Castro DS;Robson P;Lu QR;Crawford GE;Flicek P;Ettwiller L;Wittbrodt J;Guillemot F;Martynoga B
到目前为止，支持神经干细胞(NS细胞)自我更新的基因调控网络(GRN)的特征还不是很充分。了解中央转录因子(TF)、它们结合的非编码基因调节区以及它们调节其表达的基因对于释放这些细胞的全部治疗潜力至关重要。在这里，我们使用DNase-seq结合组蛋白修饰的分析来识别多种表观遗传和功能不同的顺式调节元件(CRE)。通过基序分析和芯片序列分析，我们确定了NS细胞中几个关键的Tf调节因子。该网络的核心是基本螺旋-环-螺旋(BHLH)、核因子I(NFI)、SOX和Fox家族的转录因子，其中CRE通常被这些不同的转录因子中的几个紧密结合。我们使用机器学习来强调网络的几个关键的调节功能，这些功能支持NS细胞的自我更新和多能性。我们通过对bHLHTFOLIG2的泛函分析验证了我们的预测。这种转录因子通过同时激活促增殖基因和防止促进神经元分化和干细胞静止的基因的过早激活，对NS细胞的自我更新做出了重要贡献。
The gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
44.1
作者：
Hawkins, R. David;Hon, Gary C.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
Bonaguidi MA;Wheeler MA;Shapiro JS;Stadel RP;Sun GJ;Ming GL;Song H
通讯作者：
Song H
影响因子：
14.9
作者：
Flicek P;Ahmed I;Amode MR;Barrell D;Beal K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fairley S;Fitzgerald S;Gil L;García-Girón C;Gordon L;Hourlier T;Hunt S;Juettemann T;Kähäri AK;Keenan S;Komorowska M;Kulesha E;Longden I;Maurel T;McLaren WM;Muffato M;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ritchie GR;Ruffier M;Schuster M;Sheppard D;Sobral D;Taylor K;Thormann A;Trevanion S;White S;Wilder SP;Aken BL;Birney E;Cunningham F;Dunham I;Harrow J;Herrero J;Hubbard TJ;Johnson N;Kinsella R;Parker A;Spudich G;Yates A;Zadissa A;Searle SM
通讯作者：
Searle SM
影响因子：
9.8
作者：
通讯作者：
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