Integrative Proteome Analysis Revels 3-Hydroxybutyrate Exerts Neuroprotective Effect by Influencing Chromatin Bivalency

3-hydroxybutyrate (3OHB) has been proved to act as a neuroprotective molecule in multiple neurodegenerative diseases. Here, we employed a quantitative proteomics approach to assess the changes of the global protein expression pattern of neural cells upon 3OHB administration. In combination with a disease-related, protein-protein interaction network we pinpointed a hub marker, histone lysine 27 trimethylation, which is one of the key epigenetic markers in multiple neurodegenerative diseases. Integrative analysis of transcriptomic and epigenomic datasets highlighted the involvement of bivalent transcription factors in 3OHB-mediated disease protection and its alteration of neuronal development processes. Transcriptomic profiling revealed that 3OHB impaired the fate decision process of neural precursor cells by repressing differentiation and promoting proliferation. Our study provides a new mechanism of 3OHB's neuroprotective effect, in which chromatin bivalency is sensitive to 3OHB alteration and drives its neuroprotective function both in neurodegenerative diseases and in neural development processes.

Automated summary

In this study, the researchers used a quantitative proteomics approach to analyze the changes in protein expression in neural cells after treatment with 3-hydroxybutyrate (3OHB). They identified a key epigenetic marker called histone lysine 27 trimethylation and found that 3OHB affects the involvement of bivalent transcription factors and neuronal development processes. Transcriptomic profiling revealed that 3OHB impairs the fate decision process of neural precursor cells by repressing differentiation and promoting proliferation. This study provides insights into the mechanisms underlying the neuroprotective effects of 3OHB.