# Epigenetic sex determinants of cardiometabolic disease and prevention

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $385,876

## Abstract

PROJECT 1: Epigenetic Sex Differences in Cardiometabolic Disease and Prevention
SUMMARY
Sex impacts the development of obesity and related cardiometabolic disorders. Sex also influences adverse
responses to statin drugs, which are widely prescribed to prevent cardiovascular disease. We have identified
genes on the sex chromosomes (X and Y) that have differential expression levels between males and females
and influence both adiposity and adverse effects of statin drugs. The sex chromosome genes Kdm5c, Kdm6a,
and Kdm5d encode histone demethylase enzymes, which regulate methyl marks on histone tails to modulate
transcription factor access to gene promoters and enhancers. We hypothesize that gene dosage of X and Y
chromosome histone demethylases impacts sex differences in cardiometabolic health by epigenetic
regulation of gene expression. We will define the mechanisms by which sex-specific gene dosage of these
enzymes influence adipose tissue biology and statin induced mitochondrial dysfunction. The goal of Aim1 is to
elucidate epigenetic sex differences in mouse adiposity and human adipocyte differentiation. We will
determine physiological and molecular effects of Kdm5c, Kdm6a and Kdm5d gene dosage on sex differences in
adiposity and adipocyte differentiation using mouse models, multi-omics analyses, and human induced
pluripotent stem cell (iPSC) lines. Specific objective include: determining the physiological mechanisms by which
Kdm6a influences adiposity exclusively in females, and Kdm5d influences adiposity exclusively in males;
identifying the genomic targets of KDM5C, KDM6A, and KDM5D in adipocytes by characterizing the
transcriptome, chromatin landscape, histone methylation, and histone demethylase genomic binding sites; and
identifying sex differences in human male and female preadipocyte differentiation and epigenetic landscape
using a unique resource of several dozen human iPS cell lines. The goal of Aim 2 is to evaluate epigenetic
determinants of sex-biased statin adverse effects. We will utilize human iPSCs from women with and without
statin new-onset diabetes to assess the role of KDM5 histone demethylase activity in statin-induced
mitochondrial dysfunction, and to identify transcriptomic and epigenomic modifications in statin-treated iPSCs
from women with or without statin new onset diabetes and mitochondrial dysfunction. These studies address the
understudied area of sex differences in adverse effects of widely prescribed drugs. We will translate our findings
on fundamental mechanisms underlying sex differences in cardiometabolic traits to humans through analysis of
extensive existing human genetic and –omics data, in collaboration with our Human Translational Bioinformatics
Core.

## Key facts

- **NIH application ID:** 10919841
- **Project number:** 5U54HL170326-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Karen Reue
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,876
- **Award type:** 5
- **Project period:** 2018-09-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919841

## Citation

> US National Institutes of Health, RePORTER application 10919841, Epigenetic sex determinants of cardiometabolic disease and prevention (5U54HL170326-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10919841. Licensed CC0.

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