Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
Exp Cell Res. 2022 Aug 1;417(1):113193. doi: 10.1016/j.yexcr.2022.113193. Epub 2022 May 4.
Mitosis is an essential process for the self-renewal of cells that is accompanied by dynamic changes in nuclear architecture and chromatin organization. Despite all the changes, the cell manages to re-establish all the parental epigenetic marks, post-mitotically. Recent reports suggest that some sequence-specific transcription factors remain attached to mitotic chromatin during cell division to ensure timely reactivation of a subset of transcription factors necessary to maintain cell identity. These mitotically associated factors are suggested to act as 'genome bookmarking factors' and the phenomenon is termed 'genome bookmarking'. Here, we studied this phenomenon with Vitamin D Receptor (VDR), a key regulator of calcium and phosphate homeostasis and a member of the nuclear receptor superfamily. This study, for the first time, has confirmed VDR as a mitotic bookmarking factor that may be playing a crucial role in the maintenance of cell identity and genome bookmarking. Full 'DNA binding domain (DBD)' present in VDR was identified as essential for enrichment of VDR on mitotic chromatin. Furthermore, the study also demonstrates that VDR evokes mitotic chromatin binding behaviour in its heterodimeric partner Retinoid X receptor (RXR). Interestingly, for promoting bookmarking behaviour in RXR, both DBD and/or ligand-binding domain (LBD) in conjunction with hinge region of VDR were required. Additionally, ChIP analysis showed that VDR remains associated with DR3 (direct repeat 3) region of its specific target gene promoter CYP24A1(Cytochrome P450 family 24 subfamily A member1), during mitosis. Altogether, our study illustrates a novel function of VDR in the epigenetic transmission and control of expression of target proteome for maintenance of cell identity and traits in progeny cells.
有丝分裂是细胞自我更新的一个必要过程，伴随着核结构和染色质组织的动态变化。尽管发生了所有的变化，细胞还是设法在后有丝分裂阶段重新建立了所有亲代的表观遗传标记。最近的报告表明，一些序列特异性转录因子在细胞分裂过程中仍然附着在有丝分裂染色质上，以确保及时重新激活一组维持细胞身份所必需的转录因子。这些有丝分裂相关的因子被认为是“基因组书签因子”，这种现象被称为“基因组书签”。在这里，我们研究了维生素 D 受体（VDR）的这种现象，VDR 是钙和磷酸盐稳态的关键调节剂，也是核受体超家族的成员。这项研究首次证实 VDR 是一种有丝分裂书签因子，可能在维持细胞身份和基因组书签方面发挥着关键作用。VDR 中的完整“DNA 结合域（DBD）”被确定为 VDR 在有丝分裂染色质上富集所必需的。此外，该研究还表明，VDR 在其异二聚体伴侣维甲酸 X 受体（RXR）中引起有丝分裂染色质结合行为。有趣的是，为了促进 RXR 的书签行为，需要 VDR 的 DBD 和/或配体结合域（LBD）以及铰链区与结合。此外，ChIP 分析显示，VDR 在有丝分裂期间仍然与 CYP24A1（细胞色素 P450 家族 24 亚家族 A 成员 1）的特定靶基因启动子 DR3（直接重复 3）区域相关联。总的来说，我们的研究说明了 VDR 在维持细胞身份和后代细胞特征的靶蛋白组的表观遗传传递和表达控制中的一个新功能。
