# Mechanisms of enhancer regulation in aging and age-related diseases

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2022 · $99,950

## Abstract

PROJECT SUMMARY/ABSTRACT
My overarching goal is to understand the three-dimensional (3D) enhancer regulation of aging and age-related
diseases. Aging is accompanied by functional decline of tissues and an increased probability of many
diseases. Epigenetic alteration is one hallmark of aging. Several lines of evidence demonstrate that histone
acetylation levels elevate in senescent cells and global remodeling of the enhancer landscape occurs in aging
and senescence. However, there is poor understanding of the influence of three-dimensional (3D) enhancer
regulation changes during senescence. My preliminary data demonstrate that many enhancers connect
together to form large clusters, termed hubs. The enhancers and promoters included in hubs are different
between proliferation and senescence. The senescence-specific hubs ensure critical transcription programs for
senescent phenotypes. However, how enhancer hubs change in response to stress and the mechanisms and
functions of these alterations remain to be elucidated. The main goal of the proposed studies is to uncover
mechanisms underlying the 3D regulation of enhancer hubs under different sources of stress during
aging and age-related disease. I hypothesize that (1) during aging, key enhancers cluster together within
hubs to regulate stress-specific gene expression programs; (2) two enhancer regulatory pathways exist during
normal aging: one is cell intrinsic, and the other is cell extrinsic deriving from environmental inflammatory
signals which accelerate the intrinsic pathway. In the mentored K99 phase (Aim 1), I will study epigenetic
mechanisms regulating 3D enhancer hubs in senescence (Aim 1a) and test their generalization among
different types of senescence (Aim 1b). Completion of these aims will set the stage for my independent
research in aging and age-related metabolic disorder. In the R00 phase (Aim 2), in natural aging in liver,
utilizing a unique mouse model, I will dissect the intrinsic enhancer regulatory pathway in hepatocytes and the
extrinsic pathway stimulated by environmental inflammatory signals. This will provide potential targets to
ameliorate age-related metabolic disorders in future direction of my independent lab. Ultimately, the proposed
research will unveil new mechanisms underlying the interplay between inflammation and enhancer regulation
in aging and provide novel therapeutic targets for age-related diseases. The career development and training
components in K99 phase will expand my experience in aging, metabolism and immunology to provide a rich
foundation for my successful transition to an independent career.

## Key facts

- **NIH application ID:** 10600490
- **Project number:** 3K99AG065500-02S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lu Wang
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $99,950
- **Award type:** 3
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600490

## Citation

> US National Institutes of Health, RePORTER application 10600490, Mechanisms of enhancer regulation in aging and age-related diseases (3K99AG065500-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10600490. Licensed CC0.

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