Falling in love, kicking a football, and cell identity changes driven by metabolic reprogramming all have one thing in common – making a connection is vitally important! Now, a well-hooked-up new study reveals how lactate epigenetically links metabolism to the activation of a gene regulatory network that controls embryonic development.
A plugged-in team of researchers led by Marcos Simoes-Costa (Harvard Medical School) knew that metabolic reprogramming in specific embryonic cells induced changes in cell identity by affecting gene expression; however, the specific connection between metabolism and gene expression remained somewhat mysterious. The team chose to focus on lactate in their well-knitted-together new study, as this metabolic substrate becomes overproduced in highly glycolytic neural crest cells of the developing embryo. Interestingly, the deposition of histone lactylation – a histone modification derived from lactate – at gene promoters/enhancers correlates with tissue-specific and developmental-stage-specific gene expression. Now, the authors report that metabolic alterations in neural crest cells induce histone lactylation, which shapes the epigenetic landscape to promote neural crest cell-associated gene expression and modulate embryonic development.
Let’s hear more from Merkuri, Rothstein, and Simoes-Costa on how lactate makes an epigenetic connection:
- Immunofluorescence/CUT&RUN assays reveal the dynamic deposition of histone lactylation at enhancers of neural crest cell genes in the glycolytic tissues of developing chick embryos
- Histone lactylation occurs at these loci when cells upregulate glycolysis to promote enhanced chromatin accessibility at enhancers and activate a neural crest gene regulatory network (as evaluated by ATAC-seq/single-cell ATAC-seq) to drive neural crest cell behavior (e.g., epithelial-mesenchymal transition and cell migration)
- Overall findings reveal that histone lactylation plays a similar role to histone acetylation, although lactylated and acetylated regions are subject to differential regulation during neural crest cell development
- Reducing histone lactylation by reducing levels of/inhibiting the enzymes (lactate dehydrogenase A and B) responsible for synthesizing lactate from pyruvate downregulates neural crest gene expression and impairs cell migration
- At the mechanistic level, the SOX9 and YAP/TEAD transcription factors help to ensure the neural crest-specific histone lactylation of enhancer elements
- SOX9 loss-of-function prompts a significant loss in chromatin accessibility at lactylated genomic regions, while SOX9 overexpression results in a global increase of histone lactylation
These well-connected findings define how lactate – through histone lactylation – epigenetically links metabolism and gene expression to orchestrate embryonic development and define cell identity. The authors note the overall importance of this finding – metabolic perturbations during embryo development may disrupt basic epigenetic mechanisms, which would modulate gene regulatory network activity and interfere with the proper development of embryonic tissues.
To make more connections and review how lactate epigenetically links metabolism and gene expression, see Nature Communications, January 2024.