Conserved and species-specific transcription factor co-binding patterns drive divergent gene regulation in human and mouse.
Conserved and species-specific transcription factor co-binding patterns drive divergent gene regulation in human and mouse.
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DOI：
10.1093/nar/gky018
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发表时间：
2018-02-28
影响因子：
14.9
通讯作者：
Boyle AP
中科院分区：
文献类型：
--
作者：
Diehl AG;Boyle AP
小鼠被广泛用作研究人类遗传机制的系统。然而，转录调控网络的广泛重新布线经常混淆人类和小鼠之间的翻译结果。个体转录因子结合位点（TFBS）的位点特异性获得和丧失导致了正向调控位点的功能分化，因此我们必须超越这种位置保守性来理解调控控制的共同主题。幸运的是，跨物种共享的转录因子共结合模式通常执行保守的调控功能。这些可以被比作“监管句子”，无论序列和物种背景如何，它们都保持相同的含义。通过分析在四种人类和小鼠细胞类型中观察到的TFBS共同占用模式，我们学到了一种调节语法：TFBS组合成有意义的调节句子的规则。这种语法的不同部分与特定的功能注释集相关联，而不管序列保守性如何，并且比位置保守性更准确地预测功能签名。我们进一步表明，这一语法的物种特异性和保守的部分参与基因表达的分歧和人类疾病的风险。这些发现扩展了我们对转录调控机制的理解，表明表型差异和疾病风险是由高度保守和物种特异性转录调控途径之间复杂的相互作用驱动的。
The mouse is widely used as system to study human genetic mechanisms. However, extensive rewiring of transcriptional regulatory networks often confounds translation of findings between human and mouse. Site-specific gain and loss of individual transcription factor binding sites (TFBS) has caused functional divergence of orthologous regulatory loci, and so we must look beyond this positional conservation to understand common themes of regulatory control. Fortunately, transcription factor co-binding patterns shared across species often perform conserved regulatory functions. These can be compared to ‘regulatory sentences’ that retain the same meanings regardless of sequence and species context. By analyzing TFBS co-occupancy patterns observed in four human and mouse cell types, we learned a regulatory grammar: the rules by which TFBS are combined into meaningful regulatory sentences. Different parts of this grammar associate with specific sets of functional annotations regardless of sequence conservation and predict functional signatures more accurately than positional conservation. We further show that both species-specific and conserved portions of this grammar are involved in gene expression divergence and human disease risk. These findings expand our understanding of transcriptional regulatory mechanisms, suggesting that phenotypic divergence and disease risk are driven by a complex interplay between deeply conserved and species-specific transcriptional regulatory pathways.
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影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
64.8
作者：
Jones, Felicity C.;Grabherr, Manfred G.;Chan, Yingguang Frank;Russell, Pamela;Mauceli, Evan;Johnson, Jeremy;Swofford, Ross;Pirun, Mono;Zody, Michael C.;White, Simon;Birney, Ewan;Searle, Stephen;Schmutz, Jeremy;Grimwood, Jane;Dickson, Mark C.;Myers, Richard M.;Miller, Craig T.;Summers, Brian R.;Knecht, Anne K.;Brady, Shannon D.;Zhang, Haili;Pollen, Alex A.;Howes, Timothy;Amemiya, Chris;Lander, Eric S.;Di Palma, Federica;Lindblad-Toh, Kerstin;Kingsley, David M.
通讯作者：
Kingsley, David M.
影响因子：
9.5
作者：
Hubisz, Melissa J.;Pollard, Katherine S.;Siepel, Adam
通讯作者：
Siepel, Adam
DOI：
10.1126/science.aad5497
发表时间：
2016-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chuong EB;Elde NC;Feschotte C
通讯作者：
Feschotte C
影响因子：
64.8
作者：
Gibbs, RA;Belmont, JW;Tanaka, T
通讯作者：
Tanaka, T