Rethinking gene regulatory networks in light of alternative splicing, intrinsically disordered protein domains, and post-translational modifications.
Rethinking gene regulatory networks in light of alternative splicing, intrinsically disordered protein domains, and post-translational modifications.
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DOI：
10.3389/fcell.2015.00008
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发表时间：
2015
影响因子：
5.5
通讯作者：
Newman SA
中科院分区：
文献类型：
--
作者：
Niklas KJ;Bondos SE;Dunker AK;Newman SA
遗传调控和细胞命运规范模型的特点是假设基因调控网络（grn）本质上是确定性的，并表现出多种稳定状态，指定可选择的，但预先确定的细胞命运。然而，越来越多的证据表明，大多数真核前体rna经历选择性剪接（AS），大多数转录因子含有内在无序蛋白（IDP）结构域，其功能依赖于上下文，并受到翻译后修饰（PTM）的影响。因此，许多转录因子没有固定的顺式调控靶点，仅靠grn来决定发育是站不住脚的。对这些现象进行建模需要多尺度方法来解释grn如何与细胞内和细胞间环境相互作用。有证据表明，AS、IDP和PTM使基因表达复杂化，并协同作用，促进和促进涉及细胞信号传导和细胞命运规范的时间和细胞特异性蛋白修饰，从而破坏严格的确定性grn表型定位。AS、IDP和PTM的联合作用使蛋白质组具有生理可塑性、适应性反应性和发育多功能性，而不会无效地扩大基因组大小。它们还帮助我们了解蛋白质功能如何通过缓冲突变后果来经历重大的进化变化。
Models for genetic regulation and cell fate specification characteristically assume that gene regulatory networks (GRNs) are essentially deterministic and exhibit multiple stable states specifying alternative, but pre-figured cell fates. Mounting evidence shows, however, that most eukaryotic precursor RNAs undergo alternative splicing (AS) and that the majority of transcription factors contain intrinsically disordered protein (IDP) domains whose functionalities are context dependent as well as subject to post-translational modification (PTM). Consequently, many transcription factors do not have fixed cis-acting regulatory targets, and developmental determination by GRNs alone is untenable. Modeling these phenomena requires a multi-scale approach to explain how GRNs operationally interact with the intra- and intercellular environments. Evidence shows that AS, IDP, and PTM complicate gene expression and act synergistically to facilitate and promote time- and cell-specific protein modifications involved in cell signaling and cell fate specification and thereby disrupt a strict deterministic GRN-phenotype mapping. The combined effects of AS, IDP, and PTM give proteomes physiological plasticity, adaptive responsiveness, and developmental versatility without inefficiently expanding genome size. They also help us understand how protein functionalities can undergo major evolutionary changes by buffering mutational consequences.
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DOI：
10.1126/science.1251033
发表时间：
2014-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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通讯作者：
Rendon A
影响因子：
7
作者：
Bondos, SE;Tan, XX;Matthews, KS
通讯作者：
Matthews, KS
影响因子：
64.5
作者：
Braunschweig U;Gueroussov S;Plocik AM;Graveley BR;Blencowe BJ
通讯作者：
Blencowe BJ
DOI：
10.1073/pnas.1100990108
发表时间：
2011-08-09
影响因子：
11.1
作者：
Brayer, Kathryn J.;Lynch, Vincent J.;Wagner, Guenter P.
通讯作者：
Wagner, Guenter P.
DOI：
10.1016/j.jsbmb.2013.12.008
发表时间：
2014-03
影响因子：
4.1
作者：
Abdel-Hafiz, Hany A.;Horwitz, Kathryn B.
通讯作者：
Horwitz, Kathryn B.