Faculty Mentor: Katharine Diehl (Medicinal Chemistry, University of Utah)

Histones are essential proteins that organize DNA into nucleosomes.¹ They are also important for gene expression due to their role in regulating compaction and accessibility of the genome.² Post-translational modifications (PTMs) on histones play a pivotal role in chromatin dynamics and transcriptional control.^1,3 Histone lactylation(Kla) is a recently discovered PTM.⁴ There is a lot of interest in its hypothesized ability to link cellular metabolism to chromatin regulation.⁵ Kla involves the addition of lactate to lysine residues on histones, with lactyl-CoA as the proposed intermediate.^6,7

Emerging evidence suggests that Kla functions as a dynamic epigenetic switch, modulating DNA accessibility and promoting gene transcription.⁴ Kla levels increase with glycolysis and lactate production and decrease when lactate is suppressed, making it a metabolic marker embedded in the chromatin landscape.⁴ Notably, Kla has been implicated in various biological processes, including macrophage polarization and tissue repair, and associated with diseases such as cancer, inflammatory disorders, and ocular melanoma, where it regulates oncogenes like YTHDF2.^8–10

While Kla is enriched at gene promoter regions and correlates with elevated mRNA levels, the mechanisms by which it influences chromatin dynamics remain unclear. Recent findings suggest that reader proteins, which specifically recognize Kla, could mediate its effects. Known readers and erasers of Kla include Sirtuin family proteins (SIRT2 and SIRT6) and class I histone deacetylases (HDACs).^11–13 These discoveries raise critical questions about the functional consequences of Kla interactions with chromatin-binding proteins and the regulatory pathways they control.

In this study, we used semisynthetic nucleosome probes containing lactylation or acetylation at H3K9 and H3K18 to identify proteins that preferentially bind to lactylated histones. Proteins pulled down via co-immunoprecipitation (Co-IP) with nuclear extracts were analyzed using proteomics LC/MS-MS. From the identified proteins, RRP8, BTF3, PRMTI, and BRD7 emerged as hits of interest. Experiments determining the functional relevance of these proteins are ongoing.

These findings identify histone lactylation (Kla) as a histone mark with potential dedicated reader proteins, supporting the model that Kla has unique functional roles in genome organization and gene regulation. Our work demonstrates the selective binding of specific proteins to lactylated histones, providing new insights into the chromatin landscape and its response to metabolic changes. Further research is ongoing to explore the mechanistic outcomes of these interactions and their implications for chromatin structure and function.

References

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