Coming to light: the transcriptional regulatory roles of histone lysine crotonylation in health and disease

Research on histone lysine crotonylation has evolved from identifying its core regulatory factors and mapping its genome-wide landscape to dissecting its functions in physiological and pathological contexts. Since its discovery nearly 15 years ago, extensive biochemical, structural, and genetic studies have deepened our understanding of how this evolutionarily conserved modification is integrated into intricate epigenetic regulatory networks. In this review, we first summarize mechanistic insights into the molecular basis of transcriptional regulation mediated by histone crotonylation, and discuss competitive crosstalk between this modification and histone acetylation in local chromatin regions. We then present an updated integrative framework to systematically delineate the regulatory roles of histone crotonylation across genes with distinct transcriptional states, as well as its functional implications in health and disease. Finally, we propose a unifying context-dependent model for histone crotonylation-mediated transcriptional regulation, and outline key challenges and future directions in the field.