UNDERSTANDING ROLE OF 9P21 GENE DESERT SNPS IN CANCER, AGING, DIABETES, AND CARDIO-VASCULAR DISEASES

Abstract

Aging has been largely thought of as a manifestation of metabolic malfunctions and physical and psychological changes accumulating over time in the body. Recent years have seen seminal research that indicates that changing epigenetic landscape of individual cells is also one of the main contributors to the process of aging, that lead to the term “cellular aging”. INK4/ARF locus on chromosome 9p21 has been implicated in aging, diabetes, heart diseases and multiple forms of cancer; making it an ideal model to study the basic rules of cellular aging. We identified 33 enhancers in the 9p21 locus, which have been associated to aging-related diseases in multiple GWAs studies. Using techniques like 5C and CRISPR, we have discovered an intricate network of interplay between some of the key enhancers in the locus. We observed that these enhancers make contacts with the INK4/ARF locus by looping and in turn regulate the expression of ANRIL, p14 and p16: important determinants of cellular aging. We also found out that this is a local effect spread over a few adjacent TADs, suggesting that multiple such “regulator domains” might be at work in the genome, to check the cellular aging. The findings of this study will shed light on how to develop new approaches to impact the architectural events and could provide targets to impede the aging process and development of diseases associated with aging, such as coronary artery disease, diabetes, and neuro-degenerative disease.