Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes.
Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes.
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通过启动子相关的E2F4-RBL2-HDAC1-BRM复合物对PARP1转录下调有助于抑制人类单核细胞中多能干细胞因子。
DOI：
10.1038/s41598-017-10307-z
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发表时间：
2017-08-25
影响因子：
4.6
通讯作者：
Robaszkiewicz A
中科院分区：
文献类型：
--
作者：
Wiśnik E;Płoszaj T;Robaszkiewicz A
某些细胞类型的分化之后是PARP 1表达的下调。我们表明，在造血祖细胞和单核细胞中的PARP 1丰度的减少受到细胞周期的严格控制。分化相关的细胞周期退出诱导E2 F1在PARP 1启动子处被E2 F4取代，并组装E2 F4-RBL 2-HDAC 1-BRM（SWI/SNF）阻遏物复合物，该复合物使核小体脱乙酰并使染色质致密。在G1期阻滞的细胞中，PARP 1转录通过E2 F1-RB 1-HDAC 1-EZH 2（PRC 2）-BRM/BRG 1（SWI/SNF）的募集而降低，其另外使H3 K27三甲基化并导致核小体密度的甚至更高的增加。通过用HDAC抑制剂处理有丝分裂后的单核细胞和用HDAC和EZH 2抑制剂的组合处理G1停滞的细胞来重建活性染色质结构完全恢复PARP 1表达，但不影响阻遏物复合物的组分与染色质之间的相互作用。这表明RB 1和RBL 2以及PRC 2、SWI/SNF和HDAC 1不干扰转录机制。有趣的是，通过沉默RBL 2或通过抑制单核细胞中的HDAC以及通过在分化的THP-1细胞中用PARP 1表达载体转染来恢复PARP 1表达，显著增加了多能性干细胞因子如POU 5 F1、SOX 2和NANOG的转录。
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.
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影响因子：
23.9
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