# The Role of YAP1:TEAD Enhancers in the Retinoic Acid-Regulatory Network of Cardiac Progenitors

> **NIH NIH R56** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $468,721

## Abstract

ABSTRACT
Deciphering the molecular circuitries that guide cardiac progenitor cell (CPC) differentiation will contribute to
understand the causes of congenital heart disease (CHD). Vitamin A/Retinoic Acid (RA) signaling is a master
regulator of cell specification in the heart. RA induces posterior specification of the cardiac progenitor cells
(CPCs) of the Second Heart Field (pSHF), the pool that populates the atria and sinus venosus structures.
Consequently, VitaminA/RA deficiency and excess in this developmental window lead to structural
abnormalities in the heart. Thus, understanding the mechanisms that regulate RA signaling homeostasis is a
major goal in the heart field. Here, we adopted a functional genomic approach at single-cell resolution to
investigate the Retinoic Acid- regulatory network in human embryonic stem cell-derived CPCs (hESC-CPCs).
Our preliminary data suggest that the Hippo effectors YAP1 and TEAD4 are non-canonical effectors of RA
signaling critical for atrial cardiomyocyte differentiation. Our studies show that YAP deletion affects the
expression of RA-target genes and phenotypic properties of atrial cardiomyocytes (CMs). Furthermore, our
single-cell ATAC-seq analysis in WT versus YAP KO CPCs suggest that YAP facilitates accessibility of key
atrial transcription factors (TFs) to the chromatin, including MEIS2, HOXA1 and GATA6, supporting a pivotal
role of YAP in the TF composition of atrial enhancers (Aim1). Interestingly, our ongoing studies show that RA
signaling induces genome-wide de-novo recruitment of YAP:TEAD4 to atrial enhancers in CPCs,
independently of the activity of the Hippo-kinases. Our findings suggest that RA recruits YAP to the chromatin
through the RA-activated steroid nuclear receptor NR2F2. NR2F2 is a key RA-effector, that regulates the
acquisition of atrial lineages in hESC-CPCs and pSHF progenitors. Moreover human NR2F2 mutations lead to
CHD. Therefore, we will investigate a novel non-canonical function of YAP and TEAD4 as NR2F2 cofactors in
regulating atrial specification, highlighting the potential of YAP/TEAD as possible CHD modifiers (Aim2).
Accordingly, our ongoing studies in mouse models and iPSCs revealed that the 22q11.2 genetic deletion or
DiGeorge Syndrome (DGS) lead to the inactivation of YAP signaling. DGS is one of the main causes of human
CHD, which is largely attributed to the haploinsufficiency in TBX1 in concert with downstream pathways, such
as Vitamin A/RA. It has been shown that TBX1 loss in the SHF lead to unbalanced Vitamin A signaling, which
evokes in erratic specification of these cells and CHD. Therefore, YAP inactivation in DGS may contribute to
abnormal RA signaling in SHF cells and yet, CHD. Thus, we will examine whether restoring the activity of YAP
in a mouse model of DGS improves CHD phenotypes. Finally, in collaboration with the UCLA CHD Biocore, we
will validate the impact of the Retinoic Acid and YAP pathways in the phenotypes of biopsies of infants with
CHD and DGS (A...

## Key facts

- **NIH application ID:** 10683794
- **Project number:** 1R56HL163146-01
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Concepcion Estaras
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $468,721
- **Award type:** 1
- **Project period:** 2022-09-12 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683794

## Citation

> US National Institutes of Health, RePORTER application 10683794, The Role of YAP1:TEAD Enhancers in the Retinoic Acid-Regulatory Network of Cardiac Progenitors (1R56HL163146-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10683794. Licensed CC0.

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