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

Abstract

Metabolites such as crotonyl-CoA and lactyl-CoA influence gene expression by covalently modifying histones, known as histone lysine crotonylation (Kcr) and lysine lactylation (Kla). However, their existence patterns, dynamic changes, biological functions，and associations with histone lysine acetylation and gene expression during mammalian development remain largely unknown. Here, we find that histone Kcr and Kla are widely distributed in the brain and undergo global changes during neural development. By profiling genome-wide dynamics of H3K9ac, H3K9cr and H3K18la in combination with ATAC and RNA sequencing, we reveal that these marks are tightly correlated with chromatin state and gene expression, and extensively involved in transcriptome remodeling to promote cell-fate transitions in the developing telencephalon. Importantly, we demonstrate that global Kcr and Kla levels are not the consequence of transcription and identify histone deacetylase (HDAC)1-3 as novel “erasers” of H3K18la. Using P19 cells as induced neural differentiation system, we find that HDAC1-3 inhibition by MS-275 pre-activates neuronal transcriptional programs through stimulating multiple histone lysine acylations simultaneously. These findings suggest histone Kcr and Kla play critical roles in the epigenetic regulation of neural development.

The role and mechanism of histone lactylation in health and diseases

“…For instance, a recent discovery indicates that histone lactylation and crotonylation are crucial for epigenetic regulation of brain development. In this work, lactylation and crotonylation were shown to have a synergistic effect on the processes of neural differentiation and cell proliferation ( Dai et al, 2022 ). Lactylation may also be related to butyrylation mediated by butyric acid because butyric acid contributes to an increased lactylation level of whole protein in Hela cells and may prevent lactylation via inhibiting a wide range of HDACs.…”

Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma

“…Histone Kla is also widely distributed in the brain, and the level of histone H1Kla in the brain increases in response to the expression of the neuronal activity marker c-Fos and the neural excitation induced by Repeated social defeat stress (SDS) (105). H3K18la is involved in remodeling transcriptome expression and activates transcription in brain neurons (97).…”

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

“…Furthermore, it has been shown that lactylation on the glycolytic enzyme ALDOA serves to allosterically inhibit its enzymatic activity, potentially mediating a negative feedback loop for the glycolysis pathway in the presence of excess lactic acid [ 283 ]. Finally, the functional relevance of lactylation has also been reported in RNA splicing, neurodevelopment, osteoblast differentiation, and cancer progression [ 285 , 286 , 287 , 288 ]. While there are no published studies of lactylation in PCa at this time, it is likely that this novel PTM will be validated as functionally relevant in promoting PCa progression, especially with respect to having regulatory effects on metabolic pathways and immunosuppressive effects on various components of anticancer immunity.…”