Mechanisms of microbial metabolite signaling to chromatin in cell fate and gene regulation

The National Institute of General Medical Sciences awarded Case Western Reserve University $349,017 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859, Assistance Listing designation R35GM165496) to investigate mechanisms by which microbial metabolites signal to chromatin and regulate gene expression and cellular differentiation.

The research centers on microbiota-dependent histone modifications—specifically histone butyrylation and propionylation—and their roles in controlling gene expression programs across different tissue systems. The work will examine how these noncanonical posttranslational modifications regulate cellular identity and determine the molecular mechanisms by which microbiota-dependent histone marks control distinct gene expression patterns, using multiple models of cellular differentiation to test the hypothesis that these marks have distinct regulatory functions.

Case Western Reserve University's Office of Research Administration, operating in affiliation with University Hospitals of Cleveland, is the recipient. Performance occurs in Cleveland, Ohio through August 31, 2031.

Abstract

Cellular responses to environmental cues are essential for life and drive behaviors across species. These adaptations result in part from molecular responses that regulate gene expression and the chromatin landscape. The commensal microbiota plays significant wide-ranging roles in regulating human physiology and is linked to many human diseases and disorders. While microbial metabolites are a primary means by which microbes interact with their host, much remains to be understood about the mechanisms by which host- microbe interactions occur to impact homeostasis and disease. Chromatin serves as a dynamic integrator of environmental and cellular signals, orchestrating gene accessibility and expression programs. We previously discovered a new mode of microbiota-host communication via chromatin in the form of novel microbiota- dependent histone marks, including the modifications of histone butyrylation and propionylation. These noncanonical posttranslational modifications (ptms) are associated with gene expression, yet their mechanistic roles in gene regulation and their functions in tissues are still largely unknown. Our preliminary data demonstrates that different microbial metabolites regulate distinct gene expression programs and microbiota-dependent histone marks are associated with the expression of cell differentiation and development genes. My research program is centered around the hypothesis that these microbiota-dependent histone marks have distinct roles in regulating gene expression programs due to different mechanisms of PTM function, which impact cellular differentiation. We will investigate how these histone modifications regulate cellular identity across different tissue systems using multiple models of cellular differentiation. In addition, we will determine molecular mechanisms by which the microbiota-dependent histone marks control distinct gene expression programs. This proposed work will establish a mechanistic framework for understanding how microbial metabolites shape chromatin and cell identity, providing a foundation for numerous long-term directions and applications that can have widespread impact across the fields of host-microbe interactions, cell identity, and chromatin biology.