This is a competitive renewal application to study the role an atypical homeodomain protein called Hopx that is expressed in the heart. My laboratory discovered Hopx about 10 years ago, and we have shown that it functions, at least in part, by recruiting histone deacetylases (HDACs) to transcription complexes. This work, funded by this grant, led to numerous high-profile publications, patent applications, and it has spurred our efforts in collaboration with the private sector to translate the findings and bring new therapies for heart failure to the clinic. Our mechanistic studies have shown that Hopx does not bind directly to DNA, but that it is a component of cardiac repressor complexes. Hopx is expressed by cardiac progenitor cells at early time-points of murine embryogenesis, just after Nkx2-5, at ~E8.0, and inactivation of Hopx leads to partially penetrant embryonic lethality and thin myocardium. Cardiac progenitors that express Nkx2-5 are multipotent and can produce myocardial, smooth muscle or endothelial lineages. However, Hopx-expressing progenitors are committed to the myocardial lineage. Our data suggest that fate decisions of cardiac precursor cells are biased by Hopx dose and activity. We hypothesize that Hopx is an extremely early (perhaps the earliest) marker of committed myocardial cells and that Hopx functions to reinforce the myocardial lineage choice by recruiting HDACs and other transcription cofactors to repress critical mediators of alternate fates and of the multipotent state. Understanding how myocardial fate decisions are executed and reinforced will inform our ability to enhance regenerative therapies and instruct stem and progenitor cells to produce functional myocardium.
This project focuses on the regulation of expansion and differentiation of cardiac progenitor cells, which produce many of the cell types found in the adult heart including cardiac myocytes, smooth muscle and endothelial cells. The discovery of mechanisms to regulate expansion and differentiation of cardiac progenitor cells will enhance our ability to promote regenerative therapies for heart failure and heart attack patients.
|Epstein, Jonathan A (2018) CELL FATE DETERMINATION IN 3D: REGULATION OF GENE EXPRESSION VIA CHROMATIN INTERACTIONS WITH THE NUCLEAR MEMBRANE. Trans Am Clin Climatol Assoc 129:121-131|
|Jain, Rajan; Epstein, Jonathan A (2018) Competent for commitment: you've got to have heart! Genes Dev 32:4-13|
|Poleshko, Andrey; Shah, Parisha P; Gupta, Mudit et al. (2017) Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction. Cell 171:573-587.e14|
|Loh, Kyle M; Chen, Angela; Koh, Pang Wei et al. (2016) Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types. Cell 166:451-467|
|Li, Deqiang; Takeda, Norifumi; Jain, Rajan et al. (2015) Hopx distinguishes hippocampal from lateral ventricle neural stem cells. Stem Cell Res 15:522-529|
|Jones, Andrew; Opejin, Adeleye; Henderson, Jacob G et al. (2015) Peripherally Induced Tolerance Depends on Peripheral Regulatory T Cells That Require Hopx To Inhibit Intrinsic IL-2 Expression. J Immunol 195:1489-97|
|Jain, Rajan; Barkauskas, Christina E; Takeda, Norifumi et al. (2015) Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung. Nat Commun 6:6727|
|Zhou, Xiaoying; Crow, Amanda L; Hartiala, Jaana et al. (2015) The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice. Stem Cell Reports 5:125-38|
|Jain, Rajan; Li, Deqiang; Gupta, Mudit et al. (2015) HEART DEVELOPMENT. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts. Science 348:aaa6071|
|Li, Ning; Yousefi, Maryam; Nakauka-Ddamba, Angela et al. (2014) Single-cell analysis of proxy reporter allele-marked epithelial cells establishes intestinal stem cell hierarchy. Stem Cell Reports 3:876-91|
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