Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development

Background Metabolites such as crotonyl-CoA and lactyl-CoA influence gene expression through covalently modifying histones, known as histone lysine crotonylation (Kcr) and histone lysine lactylation (Kla). However, their existence patterns, dynamic changes, biological functions, as well as associations with histone lysine acetylation (Kac) and gene expression during mammalian development remain largely unknown, which imped us from understanding the epigenetic regulations of histone lysine acylations. Results Histone Kcr and Kla are widely distributed and undergo global changes during neural development. By profiling genome-wide dynamics of H3K9ac, H3K9cr and H3K18la in combination with ATAC sequencing and RNA sequencing, we reveal that these histone marks cooperatively regulate chromatin state and gene expression, as well as promote transcriptome remodelling to favour cell fate transition in the developing telencephalon. Importantly, we demonstrate that global histone Kcr and Kla are not consequence of transcription and furtherly identify histone deacetylase 1-3 (HDAC1-3) as novel “erasers” of H3K18la. Taking advantage of induced differentiation system of P19 embryonal carcinoma (EC) cells, we find that a selective inhibitor of HDAC1-3, MS-275 pre-activates neural fate-related transcriptional programs via stimulating multiple histone lysine acylations simultaneously. Conclusions Our study uncover the interplays between histone lysine acylations to regulate gene expression and the differentiation-promoting functions of histone Kcr and Kla during development, and provide evidence that multiple histone lysine actlations synchronously alternate to orchestrate transcriptome responding under HDACs inhibition.