Mechanisms controlling common and cell type-specific DNA binding of the master regulator PU.1

细胞类型特异性基因调控是由特定的转录因子以及控制染色质中DNA结构和可及性的表观遗传机制的组合控制的。主调节因子（也称为“开拓因子”）如髓样和B细胞特异性转录因子PU. 1在谱系分化和特化中起关键作用，并且具有克服染色质限制和为其他因子打开染色质的独特能力。使它们能够进入染色质中的DNA的主调节因子（或一般的转录因子）的具体特征以及DNA结合的一般规则（通常只有一小部分识别位点被占据）仍有待确定。基于最近自己的和发表的证据，我们假设主调节PU.1基因组DNA的结合是由序列基序亲和力，相邻结合位点之间的合作性和染色质重塑复合物的参与的组合控制。本项目利用计算、分子和生物化学方法，在体外和体内研究PU.1与DNA结合的规律和性质，以揭示其基本原理。这项工作将揭示对主调节器PU.1的生物学的基本见解，这可能适用于其他系统。

Cell type-specific gene regulation is controlled by the combination of specific transcription factors as well as epigenetic mechanisms that control the structure and accessibility of DNA in chromatin. Master regulators (also called "pioneering factors") like the myeloid and B cell-specific transcription factor PU.1 play key roles in lineage differentiation and specification and share a unique ability to overcome chromatin restriction and to open up chromatin for other factors. The specific features of master regulators (or transcription factors in general) that enable them to access DNA in chromatin as well as the general rules for DNA binding (only a minor fraction of recognition sites is usually occupied) remain to be defined. Based on recent own and published evidence, we hypothesize that the binding of the master regulator PU.1 to genomic DNA is controlled by a combination of sequence motif affinity, cooperativeness between neighboring binding sites and the engagement of chromatin remodeling complexes. Using computational, molecular as well as biochemical approaches, this project intends to study the rules and properties for PU.1 binding to DNA in vitro and in vivo to uncover the underlying principles. This work will reveal fundamental insights into the biology of the master regulator PU.1, which are likely applicable to other systems.