# A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $698,375

## Abstract

ABSTRACT
The intersection of genotoxic stress and altered transcriptional programs impacts numerous disease and
disease risk events, but surprisingly little is mechanistically known in this regard, particularly with respect to
risk alleles for myocardial infarction. Based on our initial data, we can confirm that a single base alteration in
a CTCF site in the SIRT1 promoter can increase the risk of MI. We will investigate the hypothesis that this is
based on the functional importance of induced binding of CTCF to in response to hypoxia or genotoxic stress
to the cognate site in the SIRT1 promoter, licensing a promoter pause release that results in an acute
stimulation of SIRT1 transcription. The proposed research is directed at revealing a previously overlooked
strategy for signal-dependent transcriptional regulation based on redistribution of the critical chromosomal
architectural protein - CTCF- in activation of a large promoter pause release program with important biological
consequences, including the gene encoding critical regulator - SIRT1. We will investigate the hypothesis that
stress-induced increased transcription of SIRT1 and a global genomic program of response to oxidative stress
in cardiomyocytes is mediated by CTCF promoter recruitment and, in part, by long distance interactions based
on liquid-liquid phase separation of CTCF and lncRNAs in cardiomyocytes, which is lost in MI risk allele
carriers. We will investigate the stress-induced transcriptional program in iPSC-derived, genome-sequenced
cardiac myocytes and the test the hypothesis by assessing effects of introducing the risk allele in mice. With
the availability of iPSCs harboring the causative SNP for the SIRT1 risk allele, we are now in a position to
delve into the precise mechanism of these events, and assess the possibility that there is a large
cardiomyocyte pause-release program important with respect to cardiac response to acute insults. The idea
that a key arbiter of chromosome architecture is regulated by phosphorylation of a key architectural protein,
binding to a set of promoters harboring weak sites for CTCF and licensing increased transcription based of
promoter pause release events reveals an unappreciated signal-dependent mechanism for controlling
important biological program.

## Key facts

- **NIH application ID:** 9866571
- **Project number:** 1R01HL150521-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** MICHAEL G ROSENFELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $698,375
- **Award type:** 1
- **Project period:** 2019-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866571

## Citation

> US National Institutes of Health, RePORTER application 9866571, A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction (1R01HL150521-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9866571. Licensed CC0.

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