Differentiation-associated, macrophage-specific gene expression: Mechanisms of transcription regulation

人单核细胞向成熟效应细胞的分化为研究自然无增殖条件下的转录调控提供了独特的模型。此外，这些细胞表现出显著的表型可塑性，使它们能够成熟为表型多样的细胞，如巨噬细胞、树突状细胞或破骨细胞。该项目旨在了解控制人类单核细胞分化的转录机制。在过去的资助期间，我们已经开始在全球范围内评估与分化相关的转录因子结合、染色质重塑和表观遗传学变化的动态，以推断单核细胞到巨噬细胞分化过程的关键调控因素。我们特别关注增强子的生物学，这是细胞类型特异性基因调控的关键。我们现在希望继续这项工作，并彻底表征转录因子结合、染色质重塑和体外分化过程中的表观遗传学变化之间的相互作用。特别是，我们将继续研究几种转录因子(包括AP1、E-box结合因子等)的作用。在巨噬细胞分化过程中，从功能上分析单个、相关的增强子元件的作用。此外，我们希望将我们的转录启动子和增强子活性分析扩展到不同的巨噬细胞亚型(包括体外产生的和体内产生的亚群)，以在系统生物学水平上研究巨噬细胞的可塑性和局部微环境对巨噬细胞激活的影响。该项目将为巨噬细胞群落产生宝贵的资源，为这种有趣的细胞类型的生物学提供新的和临床相关的见解，并解决增强子生物学的更一般方面。

Differentiation of human monocytes into mature effector cells provides a unique model to study transcription regulation in the natural absence of proliferation. In addition, these cells display remarkable phenotypic plasticity enabling them to mature into phenotypically diverse cells like macrophages, dendritic cells or osteoclasts. This project aims at understanding transcriptional mechanisms controlling the differentiation of human monocytes. During the past funding period we have started to globally assess the dynamics of differentiation-associated transcription factor binding, chromatin remodeling and epigenetic changes to deduce key regulators of the monocyte to macrophage differentiation process. We particularly focused on the biology of enhancers, which are key to cell-type specific gene regulation. We would now like to continue this work and thoroughly characterize the interplay between transcription factor binding, chromatin remodeling and epigenetic changes during in vitro differentiation. In particular, we will continue to study the role of several transcription factors (including AP1, E-box binding factors, etc.) during macrophage differentiation and functionally analyse the role of individual, relevant enhancer elements. In addition, we would like to extend our transcriptional promoter and enhancer activity analyses to various macrophage subtypes (both in vitro generated and in vivo subsets) to address macrophage plasticity and the impact of a local microenvironment on macrophage activation on the systems biology level. The project will generate valuable resources for the macrophage community, provide novel and clinically-relevant insights into the biology of this interesting cell type and address more general aspects of enhancer biology.