Serum Response Factor Utilizes Distinct Promoter- and Enhancer-Based Mechanisms To Regulate Cytoskeletal Gene Expression in Macrophages
Serum Response Factor Utilizes Distinct Promoter- and Enhancer-Based Mechanisms To Regulate Cytoskeletal Gene Expression in Macrophages
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DOI：
10.1128/mcb.00836-10
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发表时间：
2011-02-01
影响因子：
5.3
通讯作者：
Glass, Christopher K.
中科院分区：
文献类型：
--
作者：
Sullivan, Amy L.;Benner, Christopher;Glass, Christopher K.
单核细胞/巨噬细胞谱系的细胞在组织稳态和免疫应答中发挥重要作用，但这些细胞的专门功能所需的细胞骨架基因的协调表达的潜在机制，如定向迁移和吞噬作用，仍然未知。在这里，使用遗传学和基因组学的方法，我们提供的证据表明，血清反应因子（SRF）调节一般和细胞类型的限制组件的细胞骨架基因表达程序在巨噬细胞。巨噬细胞中SRF的全基因组位置分析表明，如预期的那样，SRF结合在遍在表达的靶基因启动子处富集，但也揭示了与细胞类型限制的靶基因相关的大多数SRF结合位点位于远端基因间和基因内位置。这些远端SRF结合位点中的大多数是通过巨噬细胞和B细胞特异性转录因子PU. 1的预先结合而建立的，并表现出增强子的组蛋白修饰特征。与此相一致，与这些元件相关的代表性细胞骨架靶基因需要SRF和PU. 1两者才能完全表达。这些研究结果表明，SRF使用两种不同的分子策略来调节细胞骨架基因表达的程序：一个基于启动子的策略，普遍表达的靶基因和增强子为基础的策略，在靶基因表现出细胞类型限制的表达模式。
Cells of the monocyte/macrophage lineage play essential roles in tissue homeostasis and immune responses, but mechanisms underlying the coordinated expression of cytoskeletal genes required for specialized functions of these cells, such as directed migration and phagocytosis, remain unknown. Here, using genetic and genomic approaches, we provide evidence that serum response factor (SRF) regulates both general and cell type-restricted components of the cytoskeletal gene expression program in macrophages. Genome-wide location analysis of SRF in macrophages demonstrates enrichment of SRF binding at ubiquitously expressed target gene promoters, as expected, but also reveals that the majority of SRF binding sites associated with cell type-restricted target genes are at distal inter-and intragenic locations. Most of these distal SRF binding sites are established by the prior binding of the macrophage-and the B cell-specific transcription factor PU.1 and exhibit histone modifications characteristic of enhancers. Consistent with this, representative cytoskeletal target genes associated with these elements require both SRF and PU.1 for full expression. These findings suggest that SRF uses two distinct molecular strategies to regulate programs of cytoskeletal gene expression: a promoter-based strategy for ubiquitously expressed target genes and an enhancer-based strategy at target genes that exhibit cell type-restricted patterns of expression.