Locally acting transcription factors regulate p53-dependent cis-regulatory element activity
Locally acting transcription factors regulate p53-dependent cis-regulatory element activity
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DOI：
10.1093/nar/gkaa147
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发表时间：
2020-05-07
影响因子：
14.9
通讯作者：
Sammons, Morgan A.
中科院分区：
文献类型：
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作者：
Catizone, Allison N.;Uzunbas, Gizem Karsli;Sammons, Morgan A.
主要的肿瘤抑制因子P53控制一个广泛的基因网络的转录，该基因网络涉及细胞凋亡、细胞周期停滞、DNA损伤修复和衰老。最近的研究表明，p53与顺式调控元件(Cres)的结合普遍存在，Cres是DNA的非编码片段，通过结合局部转录因子在空间和时间上控制转录。虽然P53作为基因表达的强大反式激活因子的作用是众所周知的，但作用于P53结合的Cres的协同调节因子和局部序列相对较少。我们设计并执行了大规模平行报告实验(MPRA)来研究转录因子结合基序和局部序列背景对P53结合的Cre活性的影响。我们的数据表明，p53结合的CRE既受到局部序列背景变化的影响，也受到协同调控TF基序变化的影响。我们的数据表明，P53具有与多种转录因子协同作用的灵活性，以调节Cre活性。通过利用Cres中不同的辅助因子集，我们假设全球P53活性可防止失去任何一个调节伙伴，从而允许动态和冗余地控制P53介导的转录。
The master tumor suppressor p53 controls transcription of a wide-ranging gene network involved in apoptosis, cell cycle arrest, DNA damage repair, and senescence. Recent studies revealed pervasive binding of p53 to cis-regulatory elements (CREs), which are non-coding segments of DNA that spatially and temporally control transcription through the combinatorial binding of local transcription factors. Although the role of p53 as a strong trans-activator of gene expression is well known, the co-regulatory factors and local sequences acting at p53-bound CREs are comparatively understudied. We designed and executed a massively parallel reporter assay (MPRA) to investigate the effect of transcription factor binding motifs and local sequence context on p53-bound CRE activity. Our data indicate that p53-bound CREs are both positively and negatively affected by alterations in local sequence context and changes to co-regulatory TF motifs. Our data suggest p53 has the flexibility to cooperate with a variety of transcription factors in order to regulate CRE activity. By utilizing different sets of co-factors across CREs, we hypothesize that global p53 activity is guarded against loss of any one regulatory partner, allowing for dynamic and redundant control of p53-mediated transcription.