From the Department of Internal Medicine, Division of Molecular Medicine, Program in Cancer Genetics, Epigenetics and Genomics, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131, USA.
Nucleic Acids Res. 2019 May 21;47(9):4521-4538. doi: 10.1093/nar/gkz178.
Faithful propagation of transcription programs through cell division underlies cell-identity maintenance. Transcriptional regulators selectively bound on mitotic chromatin are emerging critical elements for mitotic transcriptional memory; however, mechanisms governing their site-selective binding remain elusive. By studying how protein-protein interactions impact mitotic chromatin binding of RBPJ, the major downstream effector of the Notch signaling pathway, we found that histone modifying enzymes HDAC1 and KDM5A play critical, regulatory roles in this process. We found that HDAC1 knockdown or inactivation leads to increased RBPJ occupancy on mitotic chromatin in a site-specific manner, with a concomitant increase of KDM5A occupancy at these sites. Strikingly, the presence of KDM5A is essential for increased RBPJ occupancy. Our results uncover a regulatory mechanism in which HDAC1 negatively regulates RBPJ binding on mitotic chromatin in a KDM5A-dependent manner. We propose that relative chromatin affinity of a minimal regulatory complex, reflecting a specific transcription program, renders selective RBPJ binding on mitotic chromatin.
忠实传播转录程序通过细胞分裂是细胞身份维持的基础。在有丝分裂染色质上选择性结合的转录调节因子是有丝分裂转录记忆的关键因素；然而，调控其位点选择性结合的机制仍不清楚。通过研究蛋白-蛋白相互作用如何影响 Notch 信号通路的主要下游效应因子 RBPJ 在有丝分裂染色质上的结合，我们发现组蛋白修饰酶 HDAC1 和 KDM5A 在这个过程中起着关键的调节作用。我们发现，HDAC1 的敲低或失活导致 RBPJ 在有丝分裂染色质上以特定的方式特异性结合，同时 KDM5A 也在这些部位结合。引人注目的是，KDM5A 的存在对于增加 RBPJ 的占有率是必不可少的。我们的研究结果揭示了一种调节机制，即 HDAC1 以 KDM5A 依赖的方式负调控 RBPJ 在有丝分裂染色质上的结合。我们提出，一个最小的调节复合物的相对染色质亲和力，反映了一个特定的转录程序，使得 RBPJ 能够在有丝分裂染色质上进行选择性结合。
