Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina

Gaur, Mohita, Brooks, Matthew J, Liang, Xulong, Jiang, Ke, Kumari, Anjani, English, Milton A, Cifani, Paolo, Panepinto, Maria C, Nellissery, Jacob, Fariss, Robert N, Campello, Laura, Marchal, Claire, Swaroop, Anand (April 2026) Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina. PLoS Genetics, 22 (4). e1012100. ISSN 1553-7404

PDF 10.1371.journal.pgen.1012100.pdf - Published Version Available under License Creative Commons Public Domain Dedication. Download (3MB)

Abstract

High aerobic glycolysis in retinal photoreceptors, as in cancer cells, is implicated in mitigating energy and metabolic demands. Lactate, a product of glycolysis, can exert epigenetic regulation through histone lactylation in cancer. Here, we show that enhanced ATP production during mouse retinal development is achieved primarily through increase in glycolysis. Histone lactylation, especially H3K18La, parallels increased glycolysis and lactate levels in the developing retina. Multi-omics analyses, combined with confocal imaging, reveal the localization of H3K18La near H3K27Ac in the euchromatin at promoters of active retinal genes. In mouse retinal explants, glucose metabolism is associated with lactate levels as well as H3K18La and consequently gene expression. However, inhibition of glycolysis with 2-deoxyglucose (2-DG) reduces global H3K18La and H3K27Ac marks with somewhat distinct transcriptional changes. Evaluation of accessible chromatin at H3K18La-marked promoters uncovers an enrichment of GC-rich motifs for transcription factors of SP, KMT and KLF families, among others, indicating the specificity of H3K18La-mediated gene regulation. Our results indicate glycolysis/lactate/H3K18La as a potential axis for transcriptional response to changing metabolic conditions in the retina, especially photoreceptors.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > tissues types and functions > retina organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Cifani, Paolo
Communities:	CSHL labs > Cifani lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	8 April 2026
Date Deposited:	21 Apr 2026 13:45
Last Modified:	21 Apr 2026 13:45
PMCID:	PMC13095125
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42169

Actions (login required)

Administrator's edit/view item