维生素D受体的疾病相关SNP变异表现出受体功能受损和基因组书签特性

Neha Kumari, Jyoti Kashyap, None Rakesh K. Tyagi
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引用次数: 0

摘要

有丝分裂对细胞更新至关重要,涉及动态染色质组织和核结构的改变。不管这些变化,一些表观遗传标记/因子在细胞分裂过程中是可遗传的。多年来,人们发现某些转录因子在转录沉默的有丝分裂阶段仍然与染色质结合,这表明它们在跨代传递调控信息方面具有潜在作用。这种现象被称为“基因组书签”。在最近的研究中,一些核受体(nr)被报道与有丝分裂染色质相关(构成型、配体依赖性或伴侣介导方式)。我们实验室最近的研究表明,NRs的疾病相关多态性变异严重损害了受体所表现出的基因组书签现象。维生素D受体(Vitamin D Receptor, VDR)是NR超家族成员之一,具有钙化和非钙化功能,包括但不限于细胞增殖和分化、免疫调节、生殖和代谢。因此,其功能异常可导致骨关节炎、骨紊乱、癌症、HVDRR、糖尿病等疾病。根据我们实验室的一项研究,VDR通过与有丝分裂染色质的组成性相互作用参与细胞性状向后代细胞的传递。此外,它促进其异二聚体伙伴RXR与有丝分裂染色质的相互作用。此外,在最近的另一项研究中,我们评估了与疾病相关的VDR-SNP变异在多个调控水平上发生故障的机制。这项研究表明,VDR的“基因组书签”特性在几种变体中严重受损,无论是否有其同源配体。此外,研究了VDR-SNP变异的伴侣介导的有丝分裂染色质相互作用,结果表明伴侣RXR不能挽救受损或丢失的有丝分裂染色质相互作用。基于这些发现,被称为“微调配体”的小分子可以将异常的受体构象重新定向到正常的功能输出,可以设计或重新用于疾病管理。
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Disease-Associated SNP Variants of Vitamin D Receptor Exhibit Compromised Receptor Function and Genome Bookmarking Properties
Mitosis is vital for cell renewal and involves dynamic chromatin organization and nuclear architectural alternations. Regardless of these changes, some epigenetic marks/factors are inheritable throughout cell division. Over the years, it has been found that certain transcription factors remain bound to chromatin during the transcriptionally silent mitotic phase suggesting their potential role in transmitting regulatory information trans-generationally. This phenomenon is referred to as ‘genome bookmarking.’ In recent findings, a few Nuclear Receptors (NRs) have been reported to be associated with mitotic chromatin (constitutive, ligand-dependent, or partner-mediated manner). Recent studies from our lab have shown that diseaseassociated polymorphic variants of NRs severely impair the genome bookmarking phenomenon exhibited by the receptor. Vitamin D Receptor (VDR), a member of the NR superfamily, has both calcemic and non-calcemic functions, including but not limited to cell proliferation and differentiation, immune modulation, reproduction, and metabolism. Thus, its abnormal function can lead to diseases like osteoarthritis, bone disorders, cancer, HVDRR, diabetes, etc. According to a study from our laboratory, VDR participates in the transmission of cellular traits to progeny cells by constitutively interacting with mitotic chromatin. Additionally, it promotes the interaction of its heterodimeric partner RXR with mitotic chromatin. Furthermore, in another recent study, we evaluated the mechanism involved in the malfunctioning of disease-associated VDR-SNP variants at multiple regulatory levels. This study revealed that the 'genome bookmarking' property of VDR is severely impaired in several variants, both with and without its cognate ligand. Moreover, partner-mediated mitotic chromatin interaction of VDR-SNP variants was examined, with the results suggesting that partner RXR cannot rescue compromised or lost mitotic chromatin interaction. Based on these findings, small molecules termed ‘tweaker-ligands’ that can reorient aberrant receptor conformation towards the normal functional output could be designed or repurposed for disease management.
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