# Dissecting a post-translational modification code in cardiac reprogramming

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $456,165

## Abstract

During development and evolution, cell fate changes are guided by cell’s ability to change its transcriptional
program with posttranslational modifications (PTMs) on both proteins and chromatin. PTMs of histones have
been extensively studied as a coding system to guide alterations in cell plasticity and cell fate, such as
differentiation/programming and de-differentiation/reprogramming. The histone PTM coding system includes
phosphorylation, acetylation, methylation, and ATP-dependent chromatin remodeling. In parallel, PTMs of free
proteins, such as phosphorylation and acetylation of transcription factors, are also essential for organ
development and cell differentiation. These PTMs in both histones and free proteins are often catalyzed by the
same set of epigenetic enzymes, strongly suggesting a dynamic interplay of PTM coding between histones and
epigenetic and transcription factors. However, few systematic studies have been pursued to define the
functional output of PTMs as a coding system. Furthermore, the potential synergistic effect of PTMs on both
histones and free factors in cell fate changes are poorly explored. Therefore, a deep understanding of the PTM
code on both free proteins (ie. key cardiac transcription factors and epigenetic factors) and histones and how
they work together will lead to novel insights into cell fate determination and cardiac reprogramming.
 Our investigation of cardiac reprogramming uncovered a unique phosphorylation code in 14-3-3 binding
motifs (PC14-3-3). We hypothesize that activation of a phosphorylation code in 14-3-3 binding motifs triggers a
re-arrangement of protein-protein interactome among PC14-3-3 containing reprogramming factors, epigenetic
factors, and chromatin, which work synergistically in stimulating cardiac reprogramming. Specific aims:
 Aim 1: Identify the key factors containing PC14-3-3 essential for cardiac reprogramming. We will test
the hypothesis that PC14-3-3 in key reprogramming, epigenetic and histone proteins plays a critical role in
reprogramming. These studies will build a knowledge foundation of PC14-3-3 in cardiac reprogramming.
 Aim 2: Determine PC14-3-3 guided molecular mechanism in stimulating cardiac reprogramming. We
will test the hypothesis that PC14-3-3 activation triggers a protein-protein dynamic interplay among PC14-3-3
code containing reprogramming factors (Mef2c and Gata4), epigenetic factors (Hdac4 and Brg1), and histones
H3 (H3S10 and H3S28). These studies will establish PC14-3-3 directed epigenetic and chromatin landscape
changes in driving cardiac reprogramming.
 Aim 3: Examine PC14-3-3-guided cardiac reprogramming toward therapeutic applications. We will
test the hypothesis that PC14-3-3 stimulates cardiac reprogramming in human cells and clinically relevant
animal models. These studies will establish the pre-clinical application of PC14-3-3 code in cardiac
reprogramming and build a novel and efficient platform for reprogramming-mediated heart repair.

## Key facts

- **NIH application ID:** 10831387
- **Project number:** 5R01HL163672-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Zhong Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $456,165
- **Award type:** 5
- **Project period:** 2022-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831387

## Citation

> US National Institutes of Health, RePORTER application 10831387, Dissecting a post-translational modification code in cardiac reprogramming (5R01HL163672-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831387. Licensed CC0.

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