Department of General Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
Department of Clinical and Laboratory Genetics, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland.
Biochim Biophys Acta Gene Regul Mech. 2019 Feb;1862(2):198-208. doi: 10.1016/j.bbagrm.2018.10.019. Epub 2018 Nov 8.
Differentiation of human macrophages predisposes these cells to numerous tasks, i.e. killing invading pathogens, and this entails the need for enhanced intracellular defences against stress, including conditions that may increase DNA damage. Our study shows that expression of DNA repair enzymes, such as PARP1, BRCA1 and XRCC1, are activated during macrophage development by the SWI/SNF chromatin remodelling complex, which serves as a histone acetylation sensor. It recognises and displaces epigenetically marked nucleosomes, thereby enabling transcription. Acetylation is controlled both in monocytes and macrophages by the co-operation of EP300 and HDAC1 activities. Differentiation modulates the activities of individual components of EP300-HDAC1-SWI/SNF functional unit and entails recruitment of PBAF to gene promoters. In monocytes, histone-deacetylated promoters of repressed PARP1, BRCA1 and XRCC1 respond only to HDAC inhibition, with an opening of the chromatin structure by BRM, whereas in macrophages both EP300 and HDAC1 contribute to the fine-tuning of nucleosomal acetylation, with HDAC1 remaining active and the balance of EP300 and HDAC1 activities controlling nucleosome eviction by BRG1-containing SWI/SNF. Since EP300-HDAC1-SWI/SNF operates at the level of gene promoters characterized simultaneously by the presence of E2F binding site(s) and CpG island(s), this allows cells to adjust PARP1, BRCA1 and XRCC1 transcription to the differentiation mode and to restart cell cycle progression. Thus, mutual interdependence between acetylase and deacetylase activities defines the acetylation-dependent code for regulation of histone density and gene transcription by SWI/SNF, notably on gene promoters of DNA repair enzymes.
人巨噬细胞的分化使这些细胞能够完成许多任务，例如杀死入侵的病原体，这需要增强细胞内的应激防御能力，包括可能增加 DNA 损伤的情况。我们的研究表明，DNA 修复酶的表达，如 PARP1、BRCA1 和 XRCC1，在巨噬细胞发育过程中被 SWI/SNF 染色质重塑复合物激活，该复合物作为组蛋白乙酰化传感器。它识别并取代表观遗传标记的核小体，从而实现转录。乙酰化在单核细胞和巨噬细胞中都由 EP300 和 HDAC1 活性的合作控制。分化调节 EP300-HDAC1-SWI/SNF 功能单元的各个组件的活性，并需要将 PBAF 募集到基因启动子。在单核细胞中，受抑制的 PARP1、BRCA1 和 XRCC1 的组蛋白去乙酰化启动子仅对 HDAC 抑制有反应，通过 BRM 打开染色质结构，而在巨噬细胞中，EP300 和 HDAC1 都有助于核小体乙酰化的微调，HDAC1 保持活性，EP300 和 HDAC1 活性的平衡通过含有 BRG1 的 SWI/SNF 控制核小体驱逐。由于 EP300-HDAC1-SWI/SNF 在基因启动子水平上发挥作用，这些启动子同时具有 E2F 结合位点(s)和 CpG 岛(s)，这允许细胞根据分化模式调节 PARP1、BRCA1 和 XRCC1 的转录，并重新启动细胞周期进程。因此，乙酰基转移酶和去乙酰化酶活性之间的相互依存关系定义了 SWI/SNF 调节组蛋白密度和基因转录的依赖于乙酰化的密码，特别是在 DNA 修复酶的基因启动子上。
