Epigenetic regulation of genomic stability in beta-cell homeostasis

Beckman Research Institute/City Of Hope, Duarte CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Both type 1 and type 2 diabetes result from insulin deficiency, in large part due to the loss of functional beta- cells. Despite significant advances in understanding beta-cell defects in diabetes, preserving and replenishing beta-cells for therapy remains a challenge. A major obstacle is our limited understanding of how beta-cells dynamically modulate their response to changing environment while protecting themselves from damage. Such modulation is essential to respond to developmental cues during beta-cell growth and maturation, and for adapting insulin secretion and maintaining beta-cell resilience in the face of varying metabolic needs and stressors. Understanding such mechanisms is critical, given the strong influence of environmental factors on diabetes risk. Processes associated with beta-cell growth and adaptation, such as replication, chromatin and transcriptional modulation, and metabolic stress can induce DNA breaks, which if unrepaired can lead to DNA damage and genomic instability. Recent studies show that metabolic stress-induced DNA damage is an early trigger for beta-cell failure in diabetes. Our pilot data point to neonatal beta-cell growth and adult beta-cell adaptation critical periods of vulnerability to DNA damage, both involving metabolic changes, transcriptional programming, and replication. Beta-cells are particularly susceptible to DNA damage due to their long lifespan. Failure to protect against DNA damage may thus impede beta-cell growth and impair long-term beta-cell viability and adaptation. This proposal aims to elucidate the mechanisms that protect beta-cells from damage during growth and adaptation to maintain homeostasis. Our preliminary studies suggest that epigenetic control by the Cohesin complex safeguards beta-cells against DNA damage and directs the transcriptional programming required for beta-cell growth, functional maturation, and adaptation to metabolic stress. We hypothesize that Cohesin dependent epigenetic regulation is critical for beta-cell homeostasis and its disruption leads to beta-cell failure in diabetes. We will employ mouse genetics, human islet studies, live-cell imaging, single-cell and spatial transcriptomics, and genome-wide epigenetic profiling methods to test this hypothesis. Specific Aim 1 will establish the requirement of Cohesin in beta-cell growth, functional maturation, and viability. Specific Aim 2 will define the contribution of Cohesin in beta-cell adaptation and failure in response to metabolic stress. The proposed studies will delineate a novel regulatory module that protects beta-cells against damage and promotes beta-cell growth and adaptation to stress. This work is expected to have a significant impact by providing novel insights into the roots of beta-cell failure and elucidating how early life events influence diabetes risk. These findings could pave the way for improved strategies focused on beta-cell rejuvenation and replacement, potentially advancing diabetes therapy.