# Rtf1-dependent transcriptional regulation of heart development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $394,500

## Abstract

Project Summary
Understanding the molecular mechanisms that drive a pluripotent progenitor cell to differentiate into a
specific cell type is germane to Developmental Biology and has important significance in regenerative
medicine. Past studies have illustrated that dynamic cardiac transcription programs (CTPs) guide
cardiogenesis during development and support cardiac structure and function in homeostasis. While the
contributions of key cardiac-specific transcription factors and cardiogenic signaling pathways have been
clearly delineated, molecular mechanisms that coordinate the expression of cardiogenic genes to drive
myocardial cell specification and direct the maturation of cardiomyocytes remain elusive.
Our recent studies using both zebrafish and mouse models indicate that the multi-functional protein Rtf1 is a
transcription regulator that orchestrates cardiac gene programs responsible for myocardial specification and
differentiation. Knockdown of rtf1 in mouse embryonic stem cells inhibits the cardiac gene program and
prevents cardiac differentiation. In vivo, Rtf1 deficient zebrafish and mouse embryos lack myocardial
progenitor cells and cannot develop a heart. We also found that Rtf1 deficiency in committed
cardiomyocytes impairs cardiac gene program. Collectively, these findings demonstrate a need for Rtf1
activity in myocardial cells at multiple developmental stages. Insights into how Rtf1 regulates dynamic CTPs
come from our structure-function analysis showing differential requirements for Rtf1's Plus3 and HMD
domains in two temporally distinct cardiogenic events; the Plus3 domain is required for the activation of the
CTP and myocardial specification whereas the HMD domain influences histone modifications and directs
heart tube morphogenesis. These exciting findings lead to our overarching hypothesis that Rtf1 controls
dynamic transcriptional programs in myocardial cells during development by CTP activation and
epigenetic modulation. We will employ a set of new transgenic zebrafish lines to define the transcriptional
networks of Rtf1 in myocardial progenitors and committed cardiomyocytes. We will investigate how Rtf1's
Plus3 domain coordinates the expression of cardiogenic genes to drive the multi-potent mesodermal cells to
a myocardial fate (Aim1). We will also interrogate the hypothesis that the Rtf1's HMD domain controls heart
tube morphogenesis by influencing the propagation and/or maturation of newly differentiated
cardiomyocytes via epigenetic modulation (Aim 2). Successful completion of the proposed projects will
provide new mechanistic insights into the transcriptional regulation of myocardial specification and
differentiation and will pave the way for the development of novel therapeutic strategies to treat heart
diseases.

## Key facts

- **NIH application ID:** 9925246
- **Project number:** 5R01HL140472-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** JAU-NIAN CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,500
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925246

## Citation

> US National Institutes of Health, RePORTER application 9925246, Rtf1-dependent transcriptional regulation of heart development (5R01HL140472-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9925246. Licensed CC0.

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