# Combinatorial regulation of the enhancer codes in senescence

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $545,940

## Abstract

Abstract
Based on the importance of defining new insights into cellular senescence, we initiated studies to investigate
whether there might be a specific enhancer activation “code” that underlies cellular senescence for
identifying the responsible DNA binding transcription factors. While there is rapidly-emerging, and now
unassailable evidence, on the role of the 40-70,000 enhancers in each cell type in development, homeostasis
and, often, pathological events, their role in cellular senescence remains undefined. Furthermore, while cellular
senescence represents a fundamental process of aging and a known driver of pathologies, the causative role of
newly activated enhancer cohorts underlying progression of senescence remain poorly understood. Therefore,
the goal of this proposal, supported by extensive preliminary data, is to test a novel hypothesis that the de
novo appearance of two specific cohorts of enhancers sets into motion a progressive, functionally-
important, alteration in gene transcription programs. Based on our study of the altered enhancer and
chromosomal landscape during replicative senescence, we have begun to establish that the geroprotective
mTOR inhibitor, Rapamycin, markedly delays all aspects of cellular senescence, including the appearance
of new, functional, enhancers. Our focus is to elucidate the functional importance of a gained enhancer program
underlying cellular senescence, and identify the critical DNA binding transcription factors underlying the
transcriptional programs that are determinants of replicative senescence, based on the complementary expertise
of the Suh and Rosenfeld laboratories. Specifically: i) We will use unbiased screens to document that at least
two distinct activated enhancer networks independently regulate the proliferation arrest and SASP aspects
of replicative senescence, respectively. ii) We will identify combinatorial factors synergizing with the
previously-unrecognized transcription factors, NFI-A, NFI-C, to regulate the gained enhancers underling
proliferation arrest, and those that, with SMAD2/3 and NFkB, to regulate the SASP program. In parallel, we
can implicate the underlying signaling pathways. iii) We will identify previously unrecognized histone
modification signatures of, and their functional importance in replicative senescence . iv) We will Identify
Activin and Tgf2 as inhibitors of the proliferation and SASP enhancer programs, respectively. Our proposal
promises to provide transformative insights into molecular events that initiate and perpetuate the senescent cell
phenotypes, and help elucidate potential novel therapeutic modalities against the deleterious SASP program.

## Key facts

- **NIH application ID:** 10152492
- **Project number:** 5R01AG061521-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** MICHAEL G ROSENFELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $545,940
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152492

## Citation

> US National Institutes of Health, RePORTER application 10152492, Combinatorial regulation of the enhancer codes in senescence (5R01AG061521-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10152492. Licensed CC0.

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