Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
PLoS Genet. 2013 May;9(5):e1003503. doi: 10.1371/journal.pgen.1003503. Epub 2013 May 16.
B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes.
B 细胞发生是几个细胞定型、谱系选择和分化过程的结果。每一个分化步骤的特点是激活新的、谱系特异性的遗传程序，并使前一个程序失活。迄今为止，特定转录因子在正向调节这些不同分化过程以获得 B 细胞特异性遗传程序中的核心作用已得到充分证实。然而，负责沉默谱系不适当基因的特定转录抑制因子的存在仍然难以捉摸。在这里，我们研究了 B 细胞中非淋巴细胞基因抑制的分子机制。我们报告说，组蛋白去乙酰化酶 HDAC7 在 pre-B 细胞中高度表达，但在细胞谱系向巨噬细胞转化过程中显著下调。微阵列分析表明，HDAC7 的重新表达干扰了细胞转分化过程中巨噬细胞特征性基因转录程序的获得；HDAC7 的存在阻断了关键基因如免疫、炎症和防御反应、细胞对感染的反应、细胞因子产生的正调节和吞噬作用的诱导。此外，HDAC7 的重新引入抑制了巨噬细胞的关键功能，如吞噬细菌的能力和通过表达主要促炎细胞因子对内毒素的反应能力。为了深入了解介导 pre-B 细胞中 HDAC7 抑制的分子机制，我们进行了共免疫沉淀和染色质免疫沉淀实验方法。我们发现，HDAC7 特异性地与转录因子 MEF2C 在 pre-B 细胞中相互作用，并被募集到位于关键基因的 MEF2 结合位点上，这些基因对巨噬细胞功能至关重要。因此，在 B 细胞中，HDAC7 是不想要的基因的转录抑制剂。我们的研究结果揭示了 HDAC7 在通过沉默谱系不适当基因来维持特定细胞类型身份方面的新作用。
