# Defining the role of HOPX and genome-nuclear lamina interactions in cardiomyocyte commitment

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $32,610

## Abstract

PROJECT SUMMARY
My proposed work aims at elucidating fundamental molecular mechanisms underlying Homeobox-only protein
(HOPX) function in cardiac lineage commitment and the role of nuclear organization in shaping cell fate
decisions. Progressive lineage restriction occurs as undifferentiated cells develop into mature cell types. During
cardiogenesis, multipotent cardiac progenitors (CPCs), marked by Isl1 and Nkx2-5 expression, give rise to
endothelial, smooth muscle, and cardiomyocyte lineages. Work by our laboratory demonstrated that Hopx
expression is downstream of Nkx2-5 and defines a pool of CPCs that exclusively gives rise to cardiomyocytes.
However, it unknown if and how Hopx functions to restrict cell fate choice during cardiomyocyte lineage
commitment. HOPX is an atypical homeodomain-containing protein that lacks DNA binding capacity.
Interestingly, recent studies suggest that it may function as a transcriptional co-repressor, in part by recruiting
histone deacetylases to affect gene expression. Consistent with its repressive role, Hopx deletion during cardiac
differentiation of embryonic stem cells results in aberrant expression of genes relevant to unwanted lineages.
Recent data from our laboratory also demonstrates that key developmentally-regulated cardiac genes are
released from the nuclear periphery upon differentiation cardiac myocytes, adding to the mounting evidence that
the spatial organization of chromatin guides cell differentiation. Excitingly, preliminary experiments indicate that
Hopx interacts with nuclear lamina proteins. In this context, I hypothesize that HOPX regulates cardiac
myocyte commitment and coordinates spatial positioning of the genome to restrict alternative lineage
choices. Using a genetic lineage tracing approach, I aim to define the role of Hopx during cardiomyocyte
commitment. Studies to date suggest that a subset Hopx-/- progenitors cannot faithfully commit to the myocyte
lineage and instead adopt an endothelial cell fate in vivo. In addition, I aim to define regions of the genome that
associate with the nuclear lamina in murine cardiac myocytes and define changes upon loss of Hopx during
cardiogenesis. Taken together, our results will advance our understanding of how HOPX role in myocyte
commitment and nuclear lamina-chromatin interactions, thereby providing a window into how spatial organization
of the genome impacts coordinated gene regulation and cell fate choices.

## Key facts

- **NIH application ID:** 9933820
- **Project number:** 5F31HL147416-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ricardo Linares Saldana
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,610
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933820

## Citation

> US National Institutes of Health, RePORTER application 9933820, Defining the role of HOPX and genome-nuclear lamina interactions in cardiomyocyte commitment (5F31HL147416-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933820. Licensed CC0.

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