Disease-Associated SNP Variants of Vitamin D Receptor Exhibit Compromised Receptor Function and Genome Bookmarking Properties

Abstract

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.