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HOXA1 and TALE proteins display cross-regulatory interactions and form a combinatorial binding code on HOXA1 targets
Genome Research ( IF 7 ) Pub Date : 2017-09-01 , DOI: 10.1101/gr.219386.116
Bony De Kumar , Hugo J. Parker , Ariel Paulson , Mark E. Parrish , Irina Pushel , Narendra Pratap Singh , Ying Zhang , Brian D. Slaughter , Jay R. Unruh , Laurence Florens , Julia Zeitlinger , Robb Krumlauf

Hoxa1 has diverse functional roles in differentiation and development. We identify and characterize properties of regions bound by HOXA1 on a genome-wide basis in differentiating mouse ES cells. HOXA1-bound regions are enriched for clusters of consensus binding motifs for HOX, PBX, and MEIS, and many display co-occupancy of PBX and MEIS. PBX and MEIS are members of the TALE family and genome-wide analysis of multiple TALE members (PBX, MEIS, TGIF, PREP1, and PREP2) shows that nearly all HOXA1 targets display occupancy of one or more TALE members. The combinatorial binding patterns of TALE proteins define distinct classes of HOXA1 targets, which may create functional diversity. Transgenic reporter assays in zebrafish confirm enhancer activities for many HOXA1-bound regions and the importance of HOX-PBX and TGIF motifs for their regulation. Proteomic analyses show that HOXA1 physically interacts on chromatin with PBX, MEIS, and PREP family members, but not with TGIF, suggesting that TGIF may have an independent input into HOXA1-bound regions. Therefore, TALE proteins appear to represent a wide repertoire of HOX cofactors, which may coregulate enhancers through distinct mechanisms. We also discover extensive auto- and cross-regulatory interactions among the Hoxa1 and TALE genes, indicating that the specificity of HOXA1 during development may be regulated though a complex cross-regulatory network of HOXA1 and TALE proteins. This study provides new insight into a regulatory network involving combinatorial interactions between HOXA1 and TALE proteins.



中文翻译:

HOXA1和TALE蛋白表现出交叉调节相互作用,并在HOXA1靶标上形成组合结合码

Hoxa1在差异化和发展中具有多种功能。我们确定和表征区域的特性由HOXA1绑定在分化小鼠ES细胞的全基因组范围内。HOXA1绑定区域丰富了HOX,PBX和MEIS的共有结合基序簇,并且许多展示了PBX和MEIS的共同占用。PBX和MEIS是TALE家族的成员,并且对多个TALE成员(PBX,MEIS,TGIF,PREP1和PREP2)进行全基因组分析,结果表明,几乎所有HOXA1靶标均显示一个或多个TALE成员的占有率。TALE蛋白的组合结合模式定义了HOXA1靶标的不同类别,这可能会产生功能多样性。斑马鱼中的转基因报告基因检测证实了许多HOXA1结合区域的增强子活性以及HOX-PBX和TGIF调控基序的重要性。蛋白质组学分析表明,HOXA1在染色质上与PBX,MEIS和PREP家族成员发生物理相互作用,但与TGIF不发生相互作用,这表明TGIF可能对HOXA1结合区域具有独立的输入。因此,TALE蛋白似乎代表了广泛的HOX辅因子,它们可能通过不同的机制整合增强子。我们还发现Hoxa1TALE基因,表明HOXA1在发育过程中的特异性可能通过HOXA1和TALE蛋白质的复杂交叉调控网络进行调控。这项研究为涉及HOXA1和TALE蛋白之间的组合相互作用的调控网络提供了新的见解。

更新日期:2017-09-08
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