NIH grant: Post-transcriptional mechanisms of direct cardiac reprogramming (4R00HL175039-03)

retained text

NIH grant 4R00HL175039-03: Post-transcriptional mechanisms of direct cardiac reprogramming
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Yifang  Xie. Award: $249000.
Start: 2026-07-10T00:00:00.
Heart attacks, or myocardial infarctions (Ml), remain a leading cause of death worldwide. As adult human
hearts have limited regenerative capacity, cardiomyocytes (CMs) lost after Ml are replaced by fibrotic scar
tissue, leading to cardiac dysfunction and often heart failure. A promising approach to replace lost CMs is
direct reprogramming of cardiac fibroblasts (CFs) into induced cardiomyocyte-like cells (iCMs) using the
specific cardiac lineage transcription factors Mef2c, Gata4 and Tbx5 (MGT). Over the last decade,
considerable progress has been made in understanding the transcriptional and epigenetic regulation of iCM
generation. However, posttranscriptional processes, including translation and mRNA modification, are also
important to regulate gene expression. Post-transcriptional regulators have recently been shown to play
critical roles in cell fate determination, but their roles in direct cardiac reprogramming are largely unknown.
Dr. Xie identified the RNA binding protein Ybx1 and the m6a reader lgf2bp1 as critical post-transcriptional
barriers to iCM induction. During the K99 phase, Dr. Xie performed genome-wide m6A profiling of CFs
undergoing cardiac reprogramming and revealed that dynamic m6A changes were associated with activation
of cardiac programs and repression of fibroblast genes. Mechanistically, lgf2bp1 was found to bind and
regulate m6A-modified transcripts, including Aplp2, Nid1, Angptl7, and Adamtsl3. These results establish a
foundation for mechanistic studies of m6A-mediated post-transcriptional regulation during cardiac fate
conversion. In the R00 phase, Aim 1 will optimize the LNP-mRNA delivery system for in vivo cardiac
reprogramming. Aim 2 will further investigate how lgf2bp1-mediated m6A regulation control fibroblast fate
conversion. The proposed work will not only fill critical gaps in our mechanistic understanding of how posttranscriptional
regulation impacts cardiac fate conversion but also advance iCM reprogramming closer to
therapeutic application. With a highly supportive research environment at OSU, Dr. Xie will further develop
her independent research program and career, ensuring a strong foundation for future mechanistic studies
in cardiovascular research.

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