Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur PO, Bangalore 560064, India.
J Mol Biol. 2010 Mar 19;397(1):1-12. doi: 10.1016/j.jmb.2009.12.058. Epub 2010 Jan 18.
The highly abundant, multifunctional transcriptional positive coactivator 4 (PC4) plays important roles in transcription, replication and DNA repair. Our recent work showed that PC4 is a bona fide non-histone component of chromatin. Here, we report that knockdown of PC4 dramatically alters heterochromatin organization of the genome, accompanied by increased H3K9 (histone H3 at lysine residue 9)/14 acetylation, H3K4 trimethylation and reduction in the level of H3K9 dimethylation. These posttranslational modifications of histone H3 result in overexpression of normally silenced genes (e.g., neural genes) located in heterochromatin. The results of ChIP (chromatin immunoprecipitation) and re-ChIP assays showed that overexpression of a neuronal-specific gene is accompanied by histone hyperacetylation. We further show that PC4 interacts with heterochromatin protein 1alpha, REST/NRSF (RE1-silencing transcription factor/neuron-restrictive silencer factor) and CoREST to establish the repressed state of neural genes in nonneuronal cells. Thus, PC4 plays a crucial role in maintaining a dynamic chromatin state and heterochromatin gene silencing.
高度丰富、多功能的转录正协同因子 4（PC4）在转录、复制和 DNA 修复中发挥重要作用。我们最近的工作表明，PC4 是染色质中真正的非组蛋白成分。在这里，我们报告说，PC4 的敲低显著改变了基因组异染色质的组织，伴随着 H3K9（组蛋白 H3 在赖氨酸残基 9）/14 乙酰化、H3K4 三甲基化和 H3K9 二甲基化水平的降低。这些组蛋白 H3 的翻译后修饰导致通常在异染色质中沉默的基因（例如神经基因）的过度表达。ChIP（染色质免疫沉淀）和再 ChIP 实验的结果表明，神经元特异性基因的过表达伴随着组蛋白的超乙酰化。我们进一步表明，PC4 与异染色质蛋白 1alpha、REST/NRSF（RE1 沉默转录因子/神经元限制沉默因子）和 CoREST 相互作用，以在非神经元细胞中建立神经基因的抑制状态。因此，PC4 在维持动态染色质状态和异染色质基因沉默方面起着至关重要的作用。
