Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
Biochim Biophys Acta Gene Regul Mech. 2021 Mar;1864(3):194683. doi: 10.1016/j.bbagrm.2020.194683. Epub 2021 Jan 12.
Mitosis is a cellular process that produces two identical progenies. Genome-wide transcription is believed to be silenced during mitosis. However, some transcription factors have been reported to associate with the mitotic chromatin to uphold a role in 'gene-bookmarking'. Here, we investigated the dynamic role of nuclear receptor SHP during cell cycle, and observed intermolecular interactions with PXR and ERα. This was reflected in altered subcellular localization, transcription function and mitotic chromatin behavior of these receptors. Subsequently, by in silico and live cell imaging approaches we identified the minimal domain(s) and crucial amino-acid residues required for such receptor-receptor interactions. It was apparent that both PXR/ERα interact with SHP to translocate cytoplasmic RFP-tagged SHP into the nucleus. In addition, during mitosis SHP interacted with some of the key nuclear receptors, altering partners, as well as, its own relationship with mitotic chromatin. SHP displaced a major fraction of PXR and ERα from the mitotic chromatin while promoted its own weak association reflected in its binding. Since SHP lacks DBD this association is attributed to receptor-receptor interactions rather than SHP-DNA interactions. The abrogation of PXR and ERα from the mitotic chromatin by SHP implies potential implications in regulation of gene bookmarking events in cellular development. Overall, it is concluded that intermolecular interactions between SHP and partner PXR/ERα result in attenuation of target promoter activities. It is proposed that SHP may act as an indirect physiological regulator and functions in a hog-tie manner by displacing the interacting transcription factor from gene regulatory sites.
有丝分裂是一种产生两个相同后代的细胞过程。人们相信，基因组范围的转录在有丝分裂过程中被沉默。然而，已经有报道称一些转录因子与有丝分裂染色质结合，在“基因书签”中发挥作用。在这里，我们研究了核受体 SHP 在细胞周期中的动态作用，并观察到它与 PXR 和 ERα 之间的分子间相互作用。这反映在这些受体的亚细胞定位、转录功能和有丝分裂染色质行为的改变上。随后，通过计算机模拟和活细胞成像方法，我们确定了这些受体之间相互作用所需的最小结构域和关键氨基酸残基。显然，PXR/ERα 都与 SHP 相互作用，将细胞质中的 RFP 标记的 SHP 转运到细胞核中。此外，在有丝分裂过程中，SHP 与一些关键的核受体相互作用，改变了伙伴关系，以及它自身与有丝分裂染色质的关系。SHP 将 PXR 和 ERα 的大部分从有丝分裂染色质中置换出来，同时促进了自身与染色质的弱结合，这反映在其结合上。由于 SHP 缺乏 DBD，这种结合归因于受体-受体相互作用，而不是 SHP-DNA 相互作用。SHP 将 PXR 和 ERα 从有丝分裂染色质中去除，这意味着它可能在细胞发育过程中调节基因书签事件方面具有潜在意义。总的来说，结论是 SHP 与伴侣 PXR/ERα 之间的分子间相互作用导致靶启动子活性的衰减。有人提出，SHP 可能作为一种间接的生理调节剂，通过将相互作用的转录因子从基因调控位点上置换下来，以捆绑的方式发挥作用。
