The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation.
The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation.
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DOI：
10.1038/s41588-021-00947-3
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发表时间：
2021-11
期刊：
影响因子：
30.8
通讯作者：
Khavari PA
中科院分区：
文献类型：
--
作者：
Kim DS;Risca VI;Reynolds DL;Chappell J;Rubin AJ;Jung N;Donohue LKH;Lopez-Pajares V;Kathiria A;Shi M;Zhao Z;Deep H;Sharmin M;Rao D;Lin S;Chang HY;Snyder MP;Greenleaf WJ;Kundaje A;Khavari PA
转录因子结合顺式调节元件(CRE)中的DNA序列基序词汇，在细胞状态转换过程中调节染色质状态和基因表达。由于顺式调节代码的组合性质，对模体词典如何影响动态调节活动的定量理解一直难以捉摸。为了解决这个问题，我们进行了染色质的多组数据分析和跨表皮分化的表达动态，以识别与3,609个动态表达基因相关的40,103个动态CRE，然后应用一个可解释的深度学习框架来模拟染色质可及性的顺式调节逻辑。这个分析框架确定了动态Cres调节同步基因模块中的协同DNA序列规则，这些基因模块在皮肤分化中扮演着不同的角色。大规模平行报告分析验证了时间动力学和协作性顺式调控逻辑。与人类多基因皮肤病相关的变异在这些依赖时间的组合基序规则中得到了丰富。这种综合的方法显示了表皮分化的顺式调节组合词典，并代表了破译动态基因调节顺式调节密码的组织原则的一般框架。
Transcription factors bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory activity has been elusive due to the combinatorial nature of the cis-regulatory code. To address this, we undertook multiomic data profiling of chromatin and expression dynamics across epidermal differentiation to identify 40,103 dynamic CREs associated with 3,609 dynamically expressed genes, then applied an interpretable deep-learning framework to model the cis-regulatory logic of chromatin accessibility. This analysis framework identified cooperative DNA sequence rules in dynamic CREs regulating synchronous gene modules with diverse roles in skin differentiation. Massively parallel reporter assay analysis validated temporal dynamics and cooperative cis-regulatory logic. Variants linked to human polygenic skin disease were enriched in these time-dependent combinatorial motif rules. This integrative approach shows the combinatorial cis-regulatory lexicon of epidermal differentiation and represents a general framework for deciphering the organizational principles of the cis-regulatory code of dynamic gene regulation.
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影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
ZnF750与KLF4和RCOR1，KDM1A和CTBP1/2染色质调节剂相互作用，以抑制表皮祖细胞基因并诱导分化基因。
影响因子：
10.5
作者：
Boxer LD;Barajas B;Tao S;Zhang J;Khavari PA
通讯作者：
Khavari PA
影响因子：
64.5
作者：
BANERJI, J;RUSCONI, S;SCHAFFNER, W
通讯作者：
SCHAFFNER, W
DOI：
10.1073/pnas.1605085113
发表时间：
2016-06-07
影响因子：
11.1
作者：
Farley, Emma K.;Olson, Katrina M.;Levine, Michael S.
通讯作者：
Levine, Michael S.