bims-meprid 2025-01-12 papers

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2025–01–12
two papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.
Lactate shuttling links histone lactylation to adult hippocampal neurogenesis in mice.

Nat Metab. 2025 Jan 09.

Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.

Michael Nshanian, Joshua J Gruber, Benjamin S Geller, Faye Chleilat, Samuel M Lancaster, Shannon M White, Ludmila Alexandrova, Jeannie M Camarillo, Neil L Kelleher, Yingming Zhao, Michael P Snyder.

The short-chain fatty acids (SCFAs) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. To better understand the function of these modifications, we used chromatin immunoprecipitation followed by sequencing to map the genome-wide location of four short-chain acyl histone marks, H3K18pr, H3K18bu, H4K12pr and H4K12bu, in treated and untreated colorectal cancer (CRC) and normal cells as well as in mouse intestines in vivo. We correlate these marks with open chromatin regions and gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate bind and act as promoters of genes involved in growth, differentiation and ion transport. We propose a mechanism involving direct modification of specific genomic regions by SCFAs resulting in increased chromatin accessibility and, in the case of butyrate, opposing effects on the proliferation of normal versus CRC cells.

DOI: https://doi.org/10.1038/s42255-024-01191-9
Dev Cell. 2025 Jan 02. pii: S1534-5807(24)00760-3. [Epub ahead of print]

Lactate shuttling links histone lactylation to adult hippocampal neurogenesis in mice.

Zhimin Li, Ziqi Liang, Huan Qi, Xing Luo, Min Wang, Zhuo Du, Weixiang Guo.

  Lactate has emerged as a central metabolic fuel and an important signaling molecule. Its availability participates in various brain functions. Although lactate homeostasis is vital for adult hippocampal neurogenesis and cognition, it is still unknown how shuttles lactate across the plasma membrane of neural stem cells (NSCs) to control their activity and neurogenic potential. In this study, we show that monocarboxylate transporter (MCT)1 and MCT2, respectively, control efflux and influx of lactate in the murine NSCs, thereby maintaining intracellular lactate homeostasis. Mechanistically, lactate shuttling links histone lactylation to govern NSC proliferation through MDM2-p53 signaling pathway. Notably, genetic ablation of MCT2 from NSCs or pharmacological inhibition of MDM2-P53 interaction prevents voluntary running-induced NSC proliferation in the murine adult hippocampus. Taken together, our findings demonstrate that lactate shuttling controls histone lactylation, which acts as a nexus for controlling adult hippocampal neurogenesis.

Keywords:  MDM2-p53 pathway; adult neurogenesis; histone lactylation; lactate shuttle; neural stem cells

DOI:  https://doi.org/10.1016/j.devcel.2024.12.021