Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis.
Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis.
复制标题
DOI：
10.1016/j.cell.2016.01.004
复制
发表时间：
2016-02-25
期刊：
影响因子：
64.5
通讯作者：
Bruneau BG
中科院分区：
文献类型：
--
作者：
Luna-Zurita L;Stirnimann CU;Glatt S;Kaynak BL;Thomas S;Baudin F;Samee MA;He D;Small EM;Mileikovsky M;Nagy A;Holloway AK;Pollard KS;Müller CW;Bruneau BG
转录因子（TF）被认为与伴侣一起发挥作用，以实现特异性和精确的定量输出。在发育中的心脏中，异型TF相互作用，例如T盒TF TBX 5和同源结构域TF NKX 2 -5之间的相互作用，已被提出为人类先天性心脏缺陷的机制。我们报告了TBX 5、NKX 2 -5和锌指TF GATA 4广泛而复杂的相互依赖的基因组占据，协调控制心脏基因表达、分化和形态发生。相互依赖的结合不仅用于共调节基因表达，而且还用于防止TF分布到异位位点并激活谱系不适当的基因。我们定义了TBX 5和NKX 2 -5合作结合位点的优先基序排列，在原子水平上由它们与DNA结合的共晶结构支持，揭示了两个因子之间的直接相互作用，并诱导DNA弯曲。复杂的相互依赖的结合机制揭示了严格调控的TF基因组分布，并定义了异型TF调节分化的组合逻辑。
Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been proposed as a mechanism for human congenital heart defects. We report extensive and complex interdependent genomic occupancy of TBX5, NKX2-5, and the zinc finger TF GATA4, coordinately controlling cardiac gene expression, differentiation, and morphogenesis. Interdependent binding serves not only to co-regulate gene expression, but also to prevent TFs from distributing to ectopic loci and activate lineage-inappropriate genes. We define preferential motif arrangements for TBX5 and NKX2-5 cooperative binding sites, supported at the atomic level by their co-crystal structure bound to DNA, revealing direct interaction between the two factors, and induced DNA bending. Complex interdependent binding mechanisms reveal tightly regulated TF genomic distribution and define a combinatorial logic for heterotypic TF regulation of differentiation.