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SUMMARY Here we report the identification and verification of a β-hydroxybutyrate-derived protein modification, lysine β-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated β-hydroxybutyrate levels in cultured cells, and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters, and that the increased H3K9bhb levels that occur during starvation are associated with genes up-regulated in starvation-responsive metabolic pathways. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and the diverse functions of β-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia.

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Our results illustrate that DTI can be used in evaluating the integrity of corpus callosum in alcohol-exposed individuals. If future studies support these findings, diffusion anisotropy, represented by fractional anisotropy, has the potential to be used as a clinical marker in the diagnosis of FAS.

Lysine crotonylation (Kcr) is a recently identified post-translational modification (PTM) that is regulated by an acetyltransferase, p300. The p300-catalyzed histone Kcr is able to stimulate transcription to a greater degree than the well-studied histone lysine acetylation (Kac). Despite these progresses, the global Kcr substrates regulated by p300 remain largely unknown, hindering efforts to establish mechanistic links between Kcr and p300-mediated phenotypes. Here, a quantitative proteomics study to characterize the p300-regulated lysine crotonylome is reported. A total of 816 unique endogenous crotonylation sites are identified across 392 proteins, with 88 sites from 69 proteins being decreased by more than 0.7-fold (log2 < 0.5) and 31 sites from 17 proteins being increased by more than 1.4-fold (log2 > 0.5) in response to p300 knockout (KO). The most downregulated crotonylome alterations under p300 deficiency concern components of the nonsense-mediated decay, infectious disease, and viral/eukaryotic translation pathways. Moreover, some p300-targeted Kcr substrates are potentially linked to diseases such as cancer. Taken together, this study reveals the lysine crotonylome in response to p300, which sheds light on the role for lysine crotonylation in regulation of diverse cellular processes and provides new insights into mechanisms of p300 functions.

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