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Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance [CUT&TAG]

ABSTRACT: Glycolysis-derived lactate was identified as substrate for histone lactylation, which has been regarded as a significant role in transcriptional regulation in many tissues. However, the role of histone lactylation in the metabolic center, the hypothalamus, is still unknown. Here, we show that hypothalamic pro-opiomelanocortin (POMC) neuron-specific deletion of family with sequence similarity 172, member A (Fam172a) can increase histone lactylation and protect mice against diet-induced obesity (DIO) and related metabolic disorders. Conversely, overexpression of Fam172a in POMC neurons led to an obesity-like phenotype. Using RNA-seq and CUT&Tag chromatin profiling analyses, we find that knockdown of Fam172a activates the glycolytic process and increases peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-MSH, via H4K12la (histone lactylation). In addition, pharmacological inhibition of lactate production clearly abrogates the anti-obesity effect of PFKO (POMC-Cre, Fam172aloxP/loxP, POMC neurons Fam172a knockout). These findings highlight the importance of Fam172a and lactate in the development of obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE280695 | GEO | 2024/11/06

REPOSITORIES: GEO

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Project description:In a thermal proteome profiling experiment we have identified 300 unique proteins that become thermally stabilized or destabilized downstream of signal activation of the melanocortin 3 receptor (MC3R) when expressed in HEK293 cells. Upon stimulation with either one of the endogenous MC3R-agonists ACTH, alpha-, or gamma-MSH, derived from the pro-opiomelanocortin (POMC) prohormone, we found that the majority of these thermally affected proteins is related to immunoregulatory processes including signaling cascades up- and downstream of the key transcription factors IRF, STAT and NFkappaB. Here, we have developed a computational pipeline that allows assessment of thermal melting curves from data obtained with label-free quantitation from ion-mobility enhanced LC-MS data. It enables differential expression analysis within the data obtained from a thermal proteome profiling experiment, since all relative abundance information is retained. We found with principal component analysis that the three POMC-peptides act in very distinguished ways on the expression pattern in the MC3R-expressing HEK293 cells. This is consistent with our findings from thermal proteome profiling analysis where we identified 142, 107 and 95 proteins to be thermally affected by ACTH, alpha- and gamma-MSH, respectively, with only 4 proteins identified across all three agonists, and an additional 36 proteins shared pairwise between the agonists. Interestingly, we found proteins involved in immune responses to be enriched according to gene set enrichment analysis with Reactome pathways. As a result of these findings, we inferred transcription factor activities of the involved thermally affected transcription factors using Bayesian analysis based on differential expression data. Our findings on transcription factor activity were validated with patterns of peptide phosphorylation abundance analysis. These combined efforts revealed that all three agonists act via the cAMP-PKA-CREB pathway but that there are differences in the further downstream affected pathways and the identities of the thermally affected pathways proteins in particular kinases.

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Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance [CUT&TAG]

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