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

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  • Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, Delhi ,IN
  • Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, Delhi ,IN
  • Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi – 110067, Delhi ,IN




Genome Bookmarking, Hereditary Vitamin D-Resistant Rickets (HVDRR), Nuclear Receptor, Single Nucleotide Polymorphism (SNP), Tweaker Ligand, Vitamin D Receptor


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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Kumari, N., Kashyap, J., & Rakesh K. Tyagi. (2023). Disease-Associated SNP Variants of Vitamin D Receptor Exhibit Compromised Receptor Function and Genome Bookmarking Properties. Journal of Endocrinology and Reproduction, 27(3), 157–167. https://doi.org/10.18311/jer/2023/34987



Review Article Presented at SRBCE 2023



Kadauke S, Blobel GA. Mitotic bookmarking by transcription factors. Epigenetics Chromatin. 2013; 6(1). https://doi.org/10.1186/1756-8935-6-6 DOI: https://doi.org/10.1186/1756-8935-6-6

Lodhi N, Ji Y, Tulin A. Mitotic bookmarking: Maintaining post-mitotic reprogramming of transcription reactivation. Curr Mol Biol Rep. 2016; 2(1):10-16. https://doi.org/10.1007/s40610-016-0029-3 DOI: https://doi.org/10.1007/s40610-016-0029-3

Egli D, Birkhoff G, Eggan K. Mediators of reprogramming: Transcription factors and transitions through mitosis. Nat Rev Mol Cell Biol. 2008; 9(7):505-16. https://doi.org/10.1038/nrm2439 DOI: https://doi.org/10.1038/nrm2439

Saradhi M, Sengupta A, Mukhopadhyay G, Tyagi RK. Pregnane and Xenobiotic Receptor (PXR/SXR) resides predominantly in the nuclear compartment of the interphase cell and associates with the condensed chromosomes during mitosis. Biochim Biophys Acta Mol Cell Res. 2005; 1746(2):85-94. https://doi.org/10.1016/j.bbamcr.2005.10.004 DOI: https://doi.org/10.1016/j.bbamcr.2005.10.004

Kumar S, Chaturvedi NK, Kumar, S, Tyagi RK. Agonistmediated docking of androgen receptor onto the mitotic chromatin platform discriminates intrinsic mode of action of prostate cancer drugs. Biochim Biophys Acta Mol Cell Res. 2008; 1783(1):59-73. https://doi.org/10.1016/j.bbamcr.2007.11.002 DOI: https://doi.org/10.1016/j.bbamcr.2007.11.002

Kumar S, Tyagi RK. Androgen receptor association with mitotic chromatin - analysis with introduced deletions and disease-inflicting mutations. FEBS J. 2012; 279(24):4598-614. https://doi.org/10.1111/febs.12046 DOI: https://doi.org/10.1111/febs.12046

Lake RJ, Tsai PF, Choi I, Won KJ, Fan HY. RBPJ, the major transcriptional effector of notch signaling, remains associated with chromatin throughout mitosis, suggesting a role in mitotic bookmarking. PLoS Genetics. 2014; 10(3). https://doi.org/10.1371/journal.pgen.1004204 DOI: https://doi.org/10.1371/journal.pgen.1004204

Deluz C, Friman ET, Strebinger D, Benke A, Raccaud M, Callegari A, et al. A role for mitotic bookmarking of SOX2 in pluripotency and differentiation. Genes Dev. 2016; 30(22):2538-50. https://doi.org/10.1101/ gad.289256.116 DOI: https://doi.org/10.1101/gad.289256.116

Raccaud M, Suter DM. Transcription factor retention on mitotic chromosomes: Regulatory mechanisms and impact on cell fate decisions. FEBS Lett. 2018; 592(6):87887. https://doi.org/10.1002/1873-3468.12828 DOI: https://doi.org/10.1002/1873-3468.12828

Shen W, Wang D, Ye B, Shi M, Zhang Y, Zhao Z. A possible role of Drosophila CTCF in mitotic bookmarking and maintaining chromatin domains during the cell cycle. Biol Res. 2015; 48(1). https://doi.org/10.1186/ s40659-015-0019-6 DOI: https://doi.org/10.1186/s40659-015-0019-6

Wang X, Yan J, Shen B, Wei G. Integrated chromatin accessibility and transcriptome landscapes of doxorubicinresistant breast cancer cells. Front Cell Dev Biol. 2021; 9. https://doi.org/10.3389/fcell.2021.708066 12. Zaidi SK, Young DW, Montecino M, van Wijnen AJ, Stein JL, Lian JB, et al. Bookmarking the genome: maintenance of epigenetic information. J Biol Chem. 2011; 286(21):18355-61. https://doi.org/10.1074/jbc.R110.197061 DOI: https://doi.org/10.1074/jbc.R110.197061

Alabert C, Groth A. Chromatin replication and epigenome maintenance. Nat Rev Mol Cell Biol. 2012; 13(3):153-67. https://doi.org/10.1038/nrm3288 DOI: https://doi.org/10.1038/nrm3288

Kashyap J, Tyagi RK. Mitotic genome-bookmarking by nuclear receptor VDR advocates transmission of cellular transcriptional memory to progeny cells. Exp Cell Res. 2022; 417(1). https://doi.org/10.1016/j.yexcr.2022.113193 DOI: https://doi.org/10.1016/j.yexcr.2022.113193

Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995; 83(6):841-50. https://doi.org/10.1016/0092-8674(95)90200-7 DOI: https://doi.org/10.1016/0092-8674(95)90200-7

Christakos S, Raval-Pandya M, Wernyj RP, Yang W. Genomic mechanisms involved in the pleiotropic actions of 1,25-dihydroxyvitamin D3. Biochem J. 1996; 316(2):361-71. https://doi.org/10.1042/bj3160361 DOI: https://doi.org/10.1042/bj3160361

Carlberg C. Genomic signaling of vitamin D. Steroids. 2023; 198. https://doi.org/10.1016/j.steroids. 2023.109271 DOI: https://doi.org/10.1016/j.steroids.2023.109271

Kashyap J, Chhabra A, Rizvi S, Tyagi RK. Vitamin D receptor in human health and disease: An overview. J Endocrinol Reprod. 2022; 26(1):1-23.

Collins FS, Brooks LD, Chakravarti A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 1998; 8(12):1229-31. https://doi.org/10.1101/gr.8.12.1229 DOI: https://doi.org/10.1101/gr.8.12.1229

Peng, Q., Yang, S., Lao, X., Li, R., Chen, Z., Wang, J., Qin, X., & Li, S. (2014). Association of single nucleotide polymorphisms in VDR and DBP genes with HBV-related hepatocellular carcinoma risk in a Chinese population. PloS one, 9(12), e116026. https://doi.org/10.1371/journal.pone.0116026 DOI: https://doi.org/10.1371/journal.pone.0116026

Kashyap J, Kumari N, Ponnusamy K, Tyagi RK. Hereditary vitamin D-Resistant Rickets (HVDRR) associated SNP variants of vitamin D receptor exhibit malfunctioning at multiple levels. Biochim Biophys Acta Gene Regul Mech BBA-Gene Regul Mech. 2023; 1866(1). https://doi.org/10.1016/j.bbagrm.2022.194891 DOI: https://doi.org/10.1016/j.bbagrm.2022.194891

Wang Z, Moult J. SNPs, protein structure, and disease. Hum Mutat. 2001; 17(4):263-70. https://doi.org/10.1002/ humu.22 DOI: https://doi.org/10.1002/humu.22

Kaur, S., Ali, A., Ahmad, U., Siahbalaei, Y., Pandey, A. K., & Singh, B. (2019). Role of single nucleotide polymorphisms (SNPs) in common migraine. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 55(1). https://doi.org/10.1186/s41983-019-0093-8 DOI: https://doi.org/10.1186/s41983-019-0093-8

Frigo DE, Bondesson M, Williams C. Nuclear receptors: From molecular mechanisms to therapeutics. Essays Biochem. 2021; 65(6):847-56. https://doi.org/10.1042/ EBC20210020 DOI: https://doi.org/10.1042/EBC20210020

Hughes MR, Malloy PJ, O’Malley BW, Pike JW, Feldman D. Genetic defects of the 1,25-dihydroxyvitamin D3 receptor. J Recept Res. 1991; 11(1-4):699-716. https://doi.org/10.3109/10799899109066437 DOI: https://doi.org/10.3109/10799899109066437

Mitchell SMS, Weedon MN, Owen KR, Shields B, Wilkins-Wall B, Walker M, et al. Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects. Diabetes. 2003; 52(5):1276-9. https://doi.org/10.2337/ diabetes.52.5.1276 DOI: https://doi.org/10.2337/diabetes.52.5.1276

Wen J, Lv Z, Ding H, Fang X, Sun M. Association between PXR polymorphisms and cancer risk: A systematic review and meta-analysis. Biosci Rep. 2018; 38(3). https://doi.org/10.1042/BSR20171614 DOI: https://doi.org/10.1042/BSR20171614

Abdel-Monem SM, El-Brashy AWSE, Hassan WA, Abdullah OA, Almallah DH. Determination of estrogen receptor alpha gene (ESR1) polymorphism and its relation to systemic lupus erythematosus disease status. Egypt Rheumatol Rehabil. 2002; 49(1). https://doi.org/10.1186/s43166-022-00119-z DOI: https://doi.org/10.1186/s43166-022-00119-z

Goumidi L, Gauthier K, Legry V, Mayi TH, Houzet A, Cottel D, et al. Association between a thyroid hormone receptor-α gene polymorphism and blood pressure but not with coronary heart disease risk. Am J Hypertens. 2011; 24(9):1027-34. https://doi.org/10.1038/ajh.2011.94 DOI: https://doi.org/10.1038/ajh.2011.94

Marcil V, Sinnett D, Seidman E, Boudreau F, Gendron FP, Beaulieu JF, et al. Association between genetic variants in the HNF4A gene and childhood-onset Crohn’s disease. Genes Immun. 2012; 13(7):556-65. https://doi.org/10.1038/gene.2012.37 DOI: https://doi.org/10.1038/gene.2012.37

Gross C, Eccleshall TR, Malloy PJ, Villa ML, Marcus R, Feldman D. The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res. 2010; 11(12):1850-5. https://doi.org/10.1002/ jbmr.5650111204 DOI: https://doi.org/10.1002/jbmr.5650111204

Laplana M, Royo JL, Fibla J. Vitamin D receptor polymorphisms and risk of enveloped virus infection: A meta-analysis. Gene. 2018; 678:384-94. https://doi.org/10.1016/j.gene.2018.08.017 DOI: https://doi.org/10.1016/j.gene.2018.08.017

Robert F, Pelletier J. Exploring the impact of single nucleotide polymorphisms on translation. Front Genet. 2018; 9. https://doi.org/10.3389/fgene.2018.00507 DOI: https://doi.org/10.3389/fgene.2018.00507

Hunt R, Sauna ZE, Ambudkar SV, Gottesman MM, Kimchi-Sarfaty C. Silent (synonymous) SNPs: Should we care about them? Methods Mol Biol. 2009; 578:23-39. https://doi.org/10.1007/978-1-60327-411-1_2 DOI: https://doi.org/10.1007/978-1-60327-411-1_2

Yates CM, Sternberg MJ. The effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on proteinprotein interactions. J Mol Biol. 2013; 425(21):3949-63. https://doi.org/10.1016/j.jmb.2013.07.012 DOI: https://doi.org/10.1016/j.jmb.2013.07.012

Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25- dihydroxyvitamin D-resistant rickets. Endocr Rev. 2015; 20(2):156-88. https://doi.org/10.1210/ er.20.2.156 DOI: https://doi.org/10.1210/edrv.20.2.0359

Malloy PJ, Tiosano D, Feldman D. Hereditary 1,25-dihydroxyvitamin D resistant rickets. Vitamin D. 2018; 4(2):175-99. https://doi.org/10.1016/B978-0-12-8099636.00072-9 DOI: https://doi.org/10.1159/000072776

Malloy PJ, Wang J, Srivastava T, Feldman D. Hereditary 1,25- dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA binding domain of the vitamin D receptor. Mol Genet Metab. 2010; 99(1):72-9. https://doi.org/10.1016/j.ymgme.2009.09.004 DOI: https://doi.org/10.1016/j.ymgme.2009.09.004

Kanakamani J, Tomar N, Kaushal E, Tandon N, Goswami R. Presence of a deletion mutation (c.716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II. Calcif Tissue Int. 2010; 86(1):33-41. https://doi.org/10.1007/s00223-009-9310-2 DOI: https://doi.org/10.1007/s00223-009-9310-2

Manchanda PK, Kibler AJ, Zhang M, Ravi J, Bid HK. Vitamin D receptor as a therapeutic target for benign prostatic hyperplasia. Indian J Urol. 2012; 28(4):377-81. https://doi.org/10.4103/0970-1591.105745 DOI: https://doi.org/10.4103/0970-1591.105745

Nadal M, Prekovic S, Gallastegui N, Helsen C, Abella M, Zielinska K, et al. Structure of the homodimeric androgen receptor ligand-binding domain. Nat Commun. 2017; 8. https://doi.org/10.1038/ncomms14388 DOI: https://doi.org/10.1038/ncomms14388

Gardezi SA, Nguyen C, Malloy PJ, Posner GH, Feldman D, Peleg S. A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,25-dihydroxyvitamin D(3). J Biol Chem. 2001; 276(31):29148-56. https://doi.org/10.1074/jbc.M100898200 DOI: https://doi.org/10.1074/jbc.M100898200

Swann SL, Bergh J, Farach-Carson MC, Ocasio CA, Koh JT. Structure-based design of selective agonists for a rickets-associated mutant of the vitamin d receptor. J Am Chem Soc. 2002; 124(46):13795-805. https://doi.org/10.1021/ja0268377 DOI: https://doi.org/10.1021/ja0268377

Kittaka A, Kurihara M, Peleg S, Suhara Y, Takayama H. 2 alpha-(3-hydroxypropyl)- and 2 alpha-(3-hydroxypropoxy)1 alpha,25-dihydroxyvitamin D3 accessible to vitamin D receptor mutant related to hereditary vitamin D-resistant rickets. Chem Pharm Bull. 2003; 51(3):3578. https://doi.org/10.1248/cpb.51.357 DOI: https://doi.org/10.1248/cpb.51.357

Regueira MA, Samanta S, Malloy PJ, Ordonez-Moran P, Resende D, Sussman F, et al. Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D(3) analogues hydroxymethylated at C-26. J Med Chem. 2011; 54(11):3950-62. https://doi.org/10.1021/jm200276y DOI: https://doi.org/10.1021/jm200276y

Malloy PJ, Xu R, Peng L, Peleg S, Al-Ashwal A, Feldman D. Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. Endocrinology. 2004; 145(11):5106-14. https://doi.org/10.1210/en.2004-0080 DOI: https://doi.org/10.1210/en.2004-0080

Pepe J, Colangelo L, Biamonte F, Sonato C, Danese VC, Cecchetti V, Occhiuto M, et al. Diagnosis and management of hypocalcemia. Endocrine. 2020; 69(3):485-95. https://doi.org/10.1007/s12020-020-02324-2 DOI: https://doi.org/10.1007/s12020-020-02324-2

Kragballe K. Calcipotriol: a new drug for topical psoriasis treatment. Pharmacol Toxicol. 1995; 77(4):241-6. https://doi.org/10.1111/j.1600-0773.1995.tb01020.x DOI: https://doi.org/10.1111/j.1600-0773.1995.tb01020.x

Ding C, Wilding JPH, Bing C. Vitamin D3 analogues ZK159222 and Zk191784 have anti-inflammatory properties in human adipocytes. Oat. 2016:1-8. https://doi.org/10.15761/EMG.1000001 DOI: https://doi.org/10.15761/EMG.1000001

Scharla SH, Schacht E, Lempert UG. Alfacalcidol versus plain vitamin D in inflammation induced bone loss. J Rheumatol Suppl. 2005; 76:26-32.

Coburn JW, Maung HM, Elangovan L, Germain MJ, Lindberg JS, Sprague SM, et al. Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis. 2004; 43(5):877-90. https://doi.org/10.1053/j.ajkd.2004.01.012 DOI: https://doi.org/10.1053/j.ajkd.2004.01.012

Ishizuka S, Kurihara N, Miura D, Takenouchi K, Cornish J, Cundy T, et al. Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 from pagetic bone marrow cells. J Steroid Biochem Mol Biol. 2004; 89-90(1-5):331-4. https://doi.org/10.1016/j.jsbmb.2004.03.025 DOI: https://doi.org/10.1016/j.jsbmb.2004.03.025

Nandhikonda P, Yasgar A, Baranowski AM, Sidhu PS, McCallum MM, Pawlak AJ, et al. Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor. Biochem. 2013; 52(24):4193-203. https://doi.org/10.1021/bi400321p DOI: https://doi.org/10.1021/bi400321p

Coyne DW, Goldberg S, Faber M, Ghossein C, Sprague SM. A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD. Clin J Am Soc Nephrol. 2014; 9(9):1620-26. https://doi.org/10.2215/CJN.10661013 DOI: https://doi.org/10.2215/CJN.10661013

Syuto T, Ishibuchi H, Sogabe Y, Yokoyama Y, Ishikawa O. Efficacy of high-concentration tacalcitol ointment in psoriasis vulgaris after changing from other high-concentration vitamin D3 ointments. Dermatol Online J. 2008; 14(2):2. https://doi.org/10.5070/D39V14X220 DOI: https://doi.org/10.5070/D39V14X220

Miura D, Manabe K, Ozono K, Saito M, Gao Q, Norman AW, et al. Antagonistic action of novel 1alpha,25-dihydroxyvitamin D3-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1alpha,25-dihydroxyvitamin D3. J Biol Chem. 1999; 274(23):16392-9. https://doi.org/10.1074/jbc.274.23.16392 DOI: https://doi.org/10.1074/jbc.274.23.16392

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