Deciphering the molecular mechanisms governing cell fate transition and lineage commitment by H3K4ME1/2 demethylation

The National Institute of Child Health and Human Development awarded Case Western Reserve University $149,190 on July 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate the molecular mechanisms governing cell fate transition and lineage commitment through H3K4ME1/2 demethylation.

The recipient will dissect how the demethylase activity of LSD1 and LSD2 histone demethylases regulates gene expression and cellular differentiation using genome engineering, epigenetic profiling, transcriptomic analysis, and stem cell differentiation approaches. Research will focus on functional synergism between LSD1 and LSD2 catalytic activity in regulating H3K4ME1, a histone mark associated with enhancers that shape cell identity. The work aims to reveal molecular mechanisms underlying H3K4ME1 roles in gene regulation and cell fate transition, with implications for understanding pathogenesis of diseases driven by LSD1/2 loss-of-function.

Case Western Reserve University, operating through its Office of Research Administration in affiliation with University Hospitals of Cleveland, serves as the recipient. Performance occurs in Cleveland, Ohio 44106. The period of performance runs from July 1, 2026, through February 29, 2028. The award is classified as a Project Grant.

Abstract

Epigenetic modifiers govern cell fate transition during animal development and their mutations drive multiple human congenital disorders; however, the molecular mechanisms underlying the roles of epigenetic modifiers in these normal and pathological processes remain poorly understood. IT is widely believed that epigenetic modifiers function through the epigenetic marks they catalyze. Nevertheless, the discoveries of catalytic- independent role of epigenetic modifiers challenge this view, raising the question about the biological function of epigenetic marks. Mono-methylation of histone H3 at lysine 4 (H3K4ME1) is a reliable mark of enhancers that shape cell identity, and its reconfiguration accompanies the differentiation of pluripotent stem cells, suggesting that the regulation of H3K4ME1 plays an instructive role in cell fate transition. To examine this hypothesis, we investigated the catalytic function of LSD1 and LSD2, two paralogous histone demethylases targeting H3K4ME1, in regulating gene expression during cell fate transition. Using state-of-the-art approaches such as precise genome engineering, epigenetic and transcriptomic profiling, and stem cell differentiation, we demonstrate functional synergism between the demethylase activity of LSD1 and LSD2 in regulating cellular differentiation. Based on these compelling preliminary data, here we propose to dissect the molecular mechanisms underlying how the demethylase activity of LSD1/2 regulates cell fate transition. The results generated from our proposed studies will not only reveal novel molecular mechanisms underlying the roles of H3K4ME1 in gene regulation and cell fate transition, but also provide insights into understanding the pathogenesis of diseases driven by LSD1/2 loss-of-function. This research aligns with the NIH mission to advance our understanding of fundamental biological processes and contribute to knowledge relevant to developmental disorders and regenerative medicine.