Investigating the role of transcription factor SNAIL1 in astyanax mexicanus heart regeneration (7) project summary/abstract with heart disease consistently being the leading cause of death globally…

The National Heart, Lung, and Blood Institute awarded $194,156 to the University of California, Berkeley on September 30, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of transcription factor SNAIL1 in heart regeneration using the fish model Astyanax mexicanus.

The research examines why heart regeneration capacity differs dramatically between two morphotypes of Astyanax mexicanus that diverged as recently as 20,000 years ago. Surface-dwelling river fish fully regenerate amputated heart tissue within 64 days, while cavefish develop permanent fibrotic scars with no tissue replacement. The study focuses on SNAIL1B, a transcription factor upregulated in cavefish hearts, and its relationship to metabolic shifts and epigenetic modifications that may prevent the mesenchymal-to-epithelial transition necessary for tissue repair. The hypothesis proposes that elevated glycolysis intrinsic to cavefish leads to lactylation and activation of SNAIL, increasing fibrosis and blocking heart regeneration. These findings could inform understanding of cardiac fibrosis in human heart disease, the leading cause of death globally.

Work is performed at UC Berkeley, Berkeley, California. The period of performance runs from September 30, 2025, through September 29, 2027. This is a Project Grant assistance type.

Investigating the role of transcription factor SNAIL1 in astyanax mexicanus heart regeneration (7) project summary/abstract with heart disease consistently being the leading cause of death globally each year, exploring heart regeneration across models has been a promising avenue for revealing how these abilities were evolutionarily gained or lost. Astyanax mexicanus provides a rare intra-species comparison of rapid heart regeneration loss between two morphotypes that diverged as recently as 20,000 years ago. While the river-dwelling surface fish fully regenerate amputated heart tissue within 64 days, the cavefish develop a permanent fibrotic scar with no tissue replacement. The transcription factor SNAI1B was found to be upregulated in cavefish compared to surface fish hearts in bulk RNA sequencing data. An upregulation of snail post-heart injury was associated with increased fibrosis and decreased cardiac function in mice, where the snail locus was labeled with histone lactylation, an epigenetic modification that correlates with open chromatin in migrating cells. Variable food and oxygen availability between the isolated caves and open river habitats caused a metabolic divergence, with cavefish preferring glycolysis over oxidative phosphorylation (oxphos). A similar shift in preference from oxphos to glycolysis occurs in migratory stem cells during epithelial-to-mesenchymal transition (EMT). This shift increases lactate and consequently lactylation of EMT-related genes, including snail. After migration, cells undergo a mesenchymal-to-epithelial transition (met) to reintegrate into the repaired tissue. However, since both oxphos and glycolysis decrease in cavefish upon injury, snail levels may remain elevated and met may not occur. I hypothesize that intrinsically raised glycolysis in cavefish leads to the lactylation and activation of snail, increasing fibrosis and EMT without met after heart injury. This interdisciplinary approach will combine studies of metabolism, gene regulation, and morphogenesis to understand the ability to regenerate cardiac tissue. Aim 1 will spatially survey glycolysis and oxphos post-ventricular amputation through immunohistochemistry (IHC), then pharmacologically target these processes and observe the effects on regeneration. Aim 2 will utilize IHC, atac sequencing, and cut & run to characterize lactylation and gene regulation in injured cave and surface fish hearts, followed by inhibition or induction of lactylation and evaluation of regeneration. Aim 3 centers on tracking EMT via IHC and using chemical inhibitors to suppress EMT and encourage met to assess their roles in a. Mexicanus cardiac regeneration. This project aims to uncover why some vertebrates can regenerate their hearts while others cannot. By comparing metabolic shifts, gene regulation, and EMT following injury within the same species, i will examine the role of the transcription factor snail in driving differential heart regeneration abilities, and uncover potential treatments to recapitulate regenerative phenotypes in a non-regenerative animal. Support from the F31 will enable me to not develop technical skills such as confocal microscopy, pharmacological trials, and bioinformatics, but will also provide me with opportunities to participate in international conferences and share my findings with the community.