HOX paralogs selectively convert binding of ubiquitous transcription factors into tissue-specific patterns of enhancer activation.
HOX paralogs selectively convert binding of ubiquitous transcription factors into tissue-specific patterns of enhancer activation.
复制标题
DOI：
10.1371/journal.pgen.1009162
复制
发表时间：
2020-12
期刊：
影响因子：
4.5
通讯作者：
Bobola N
中科院分区：
文献类型：
--
作者：
Bridoux L;Zarrineh P;Mallen J;Phuycharoen M;Latorre V;Ladam F;Losa M;Baker SM;Sagerstrom C;Mace KA;Rattray M;Bobola N
基因表达程序决定胚胎发育中的细胞命运及其失调导致疾病。转录因子（TF）通过与增强子结合来控制基因表达，但 TF 如何选择和激活其目标增强子仍不清楚。 HOX TF 共享保守的同源结构域，具有高度相似的序列识别特性，但它们赋予不同动物身体部位的身份。为了了解 HOX TF 如何在体内控制其特定转录程序，我们比较了小鼠胚胎中的 HOXA2 和 HOXA3 结合谱。 HOXA2 和 HOXA3 直接与 TALE TF 合作，并选择性地靶向广泛的 TALE 染色质平台的不同子集。 HOX 和组织特异性 TF 的结合将低亲和力 TALE 结合转化为高置信度的组织特异性结合事件，其带有活性增强子的标记。我们建议 HOX 旁系同源物单独或与组织特异性 TF 组合，通过调节选定增强子处 TALE TF 的活性来产生组织特异性转录输出。沿着动物体轴发育的不同解剖特征是由 HOX 转录因子决定的。 HOX家族的每个成员都出现在发育胚胎的明确区域中，并指导特定的基因表达程序。 HOX 转录因子与体内特异性（发育程序的核心）形成鲜明对比，在体外表现出高度相似的序列识别特性。为了了解 HOX 转录因子如何在体内控制其特定转录程序，我们比较了小鼠胚胎中的 HOXA2 和 HOXA3 结合谱。我们发现 HOXA2 和 HOXA3 占据了大量高置信度、非重叠的基因组区域，这些区域也被三个氨基酸环延伸 (TALE) 转录因子结合。我们确定了 HOX 旁系同源选择性结合的三个主要决定因素：HOX-PBX 基序的独特变体的识别、共享 HOX-PBX 基序的差异亲和力以及组织特异性转录因子的贡献。这些机制导致 HOX-TALE 在不同基因组位置上进行高置信度、协作性结合，这些位置带有活性增强子的标记。我们建议 HOX 旁系同源物单独或与组织特异性转录因子协同作用，在选定的增强子处开启 TALE 功能。
Gene expression programs determine cell fate in embryonic development and their dysregulation results in disease. Transcription factors (TFs) control gene expression by binding to enhancers, but how TFs select and activate their target enhancers is still unclear. HOX TFs share conserved homeodomains with highly similar sequence recognition properties, yet they impart the identity of different animal body parts. To understand how HOX TFs control their specific transcriptional programs in vivo, we compared HOXA2 and HOXA3 binding profiles in the mouse embryo. HOXA2 and HOXA3 directly cooperate with TALE TFs and selectively target different subsets of a broad TALE chromatin platform. Binding of HOX and tissue-specific TFs convert low affinity TALE binding into high confidence, tissue-specific binding events, which bear the mark of active enhancers. We propose that HOX paralogs, alone and in combination with tissue-specific TFs, generate tissue-specific transcriptional outputs by modulating the activity of TALE TFs at selected enhancers. The different anatomical features that develop along the animal body axis are determined by HOX transcription factors. Each member of the HOX family appears in a well-defined territory of the developing embryo, and instruct a specific gene expression program. In stark contrast to their specificity in vivo, which is central to developmental programs, HOX transcription factors display highly similar sequence recognition properties in vitro. To understand how HOX transcription factors control their specific transcriptional programs in vivo, we compared HOXA2 and HOXA3 binding profiles in the mouse embryo. We find that HOXA2 and HOXA3 occupy a large set of high-confidence, non-overlapping genomic regions, that are also bound by three aminoacid loop extension (TALE) transcription factors. We identify three main determinants of HOX paralog-selective binding: recognition of unique variants of the HOX-PBX motif, differential affinity at shared HOX-PBX motifs and, additionally, contribution of tissue-specific transcription factors. These mechanisms result in high-confidence, cooperative HOX-TALE binding at different genomic locations, which bear the mark of active enhancers. We propose that HOX paralogs operate, alone and in concert with tissue-specific transcription factors, to switch on TALE function at selected enhancers.
登录
查看更多内容
影响因子：
7
作者：
Guo Y;Tian K;Zeng H;Guo X;Gifford DK
通讯作者：
Gifford DK
DOI：
10.1016/j.bbagrm.2015.08.006
发表时间：
2015-10-01
影响因子：
4.7
作者：
Bridoux, Laure;Bergiers, Isabelle;Rezsohazy, Rene
通讯作者：
Rezsohazy, Rene
影响因子：
8.8
作者：
Dard, Amelie;Reboulet, Jonathan;Merabet, Samir
通讯作者：
Merabet, Samir
影响因子：
7
作者：
De Kumar B;Parker HJ;Paulson A;Parrish ME;Pushel I;Singh NP;Zhang Y;Slaughter BD;Unruh JR;Florens L;Zeitlinger J;Krumlauf R
通讯作者：
Krumlauf R
影响因子：
64.5
作者：
Boija A;Klein IA;Sabari BR;Dall'Agnese A;Coffey EL;Zamudio AV;Li CH;Shrinivas K;Manteiga JC;Hannett NM;Abraham BJ;Afeyan LK;Guo YE;Rimel JK;Fant CB;Schuijers J;Lee TI;Taatjes DJ;Young RA
通讯作者：
Young RA