# Cardiac interaction networks as determinants of transcriptional specificity

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $549,565

## Abstract

ABSTRACT
Congenital malformations, or structural birth defects, are now the leading cause of infant mortality in
the US and Europe. Of the congenital malformations, congenital heart disease (CHD) is the most
common. Mutations in the T-box transcription factor TBX5 have been found to be causative to a
range of human cardiac abnormalities including Tetrology of Fallot and Holt Oram Syndrome (HOS),
disease states associated associated with cardiac septal defects. While TBX5 is an essential
transcription factor for heart development and its disease relevance is well established, there are
many critical questions unanswered about the mechanism of how TBX5 functions. We do not
understand what proteins complex with TBX5 during different stages of cardiac development and
homeostasis, how these interactions regulate TBX5's choice of distinct transcriptional targets at
different times, or how these interactions function to activate and/or repress target gene transcription.
To this end, our labs recently initiated a directed proteomic-based approach to identify proteins that
function in association with TBX5. These studies demonstrate TBX5 interacts with the transcriptional
repression machinery of the Nucleosome Remodeling and Deacetylase (NuRD) complex. We further
demonstrated that TBX5 human disease mutations disrupt this interaction, leading to ectopic
expression of non-cardiac genes normally repressed by TBX5 and septal defects associated with Holt
Oram syndrome. Collectively, this work led to the central hypothesis that TBX5 function and thus its
suites of target genes are regulated during cardiac development through changes in the components
of the TBX5 interactome. To address this hypothesis, we will used an integrated systems based
approach to determine the mechanisms by which Tbx5 regulates distinct gene programs in the heart
by defining the endogenous cardiac TBX5 transcriptional complexes, establish the mechanisms of
TBX5 repression and activation and by determining the potential role of co-factors in TBX5
transcriptional regulation.

## Key facts

- **NIH application ID:** 10159116
- **Project number:** 5R01HD089275-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Frank Leo Conlon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $549,565
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159116

## Citation

> US National Institutes of Health, RePORTER application 10159116, Cardiac interaction networks as determinants of transcriptional specificity (5R01HD089275-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10159116. Licensed CC0.

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