启动子相关的E2F4-RBL2-HDAC1-BRM复合物对PARP1转录的下调有助于抑制人单核细胞中的多能干细胞因子。,Scientific Reports

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启动子相关的E2F4-RBL2-HDAC1-BRM复合物对PARP1转录的下调有助于抑制人单核细胞中的多能干细胞因子。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Aug-25 , DOI: 10.1038/s41598-017-10307-z
Ewelina Wiśnik , Tomasz Płoszaj , Agnieszka Robaszkiewicz

某些细胞类型的分化后是PARP1表达的下调。我们显示，造血祖细胞和单核细胞中PARP1丰度的降低是由细胞周期严格控制的。分化相关的细胞周期出口在PARP1启动子处诱导E2F1替换为E2F4，并且组装了E2F4-RBL2-HDAC1-BRM（SWI / SNF）阻遏物复合物，该复合物使核小体脱乙酰化并压紧染色质。在G1停滞的细胞中，通过募集E2F1-RB1-HDAC1-EZH2（PRC2）-BRM / BRG1（SWI / SNF）来减少PARP1转录，这还会使H3K27发生三甲基化并导致更高的核小体密度增加。通过使用HDAC和EZH2抑制剂的组合用HDAC抑制剂和G1阻滞细胞治疗有丝分裂后单核细胞来重建活性染色质结构，可以完全恢复PARP1表达，但不影响阻遏物复合物与染色质之间的相互作用。这表明RB1和RBL2以及PRC2，SWI / SNF和HDAC1不会干扰转录机制。有趣的是，通过沉默单核细胞中的RBL2或抑制HDAC以及通过在分化的THP-1细胞中用PARP1表达载体转染来恢复PARP1表达，实质上提高了多能干细胞因子（如POU5F1，SOX2和NANOG）的转录。

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Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes.

Differentiation of certain cell types is followed by a downregulation of PARP1 expression. We show that the reduction in the abundance of PARP1 in hematopoietic progenitor cells and monocytes is tightly controlled by the cell cycle. The differentiation-associated cell cycle exit induces E2F1 replacement with E2F4 at the PARP1 promoter and the assembly of an E2F4-RBL2-HDAC1-BRM(SWI/SNF) repressor complex which deacetylates nucleosomes and compacts chromatin. In G1 arrested cells, PARP1 transcription is reduced by the recruitment of E2F1-RB1-HDAC1-EZH2(PRC2)-BRM/BRG1(SWI/SNF), which additionally trimethylates H3K27 and causes an even higher increase in nucleosome density. The re-establishment of an active chromatin structure by treating post-mitotic monocytes with the HDAC inhibitor and G1 arrested cells with a combination of HDAC and EZH2 inhibitors restores PARP1 expression completely but does not affect the interaction between the components of the repressor complex with chromatin. This suggests that RB1 and RBL2, as well as PRC2, SWI/SNF and HDAC1, do not interfere with the transcription machinery. Interestingly, reinstatement of PARP1 expression by the silencing of RBL2 or by the inhibition of HDACs in monocytes and by transfection with the PARP1 expression vector in differentiated THP-1 cells substantially increased transcription of pluripotency stem cell factors such as POU5F1, SOX2 and NANOG.

更新日期：2017-08-25

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