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Histone lactylation couples cellular metabolism with the activation of developmental gene regulatory networks [R-GNE-140 ATAC-seq]

ABSTRACT: Embryonic cells engage in diverse types of metabolism to execute specialized tasks in the developing embryo. Recent studies have demonstrated that metabolic reprogramming can also drive changes in cell identity and behavior by affecting the expression of developmental genes. However, the connection between cellular metabolism and differential gene expression is still not well understood. Here we report found that histone lactylation, an epigenetic mark derived from glycolysis-derived lactate, couples the metabolic state of embryonic cells with gene expression and the activation of gene regulatory networks. Embryonic tissues with high glycolytic flux, like the neural crest and the pre-somitic mesoderm, display high levels of lactylation. The lactylation mark is dynamically deposited in the loci of neural crest genes as these cells transition to a state of enhanced glycolysis. This process promotes accessibility of active enhancers and is necessary for proper deployment of the neural crest gene regulatory network. When we reduced the deposition of the mark by targeting LDHA and LDHB, lactylated genes were downregulated, and neural crest migration was impeded. Lactylation of neural crest enhancers is controlled by transcription factors SOX9 and YAP/TEAD, which are necessary and sufficient for the deposition of the mark. These findings define an epigenetic mechanism that integrates cellular metabolism with the gene regulatory networks that orchestrate embryonic development.

ORGANISM(S): Gallus gallus

PROVIDER: GSE228342 | GEO | 2023/11/22

REPOSITORIES: GEO

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Project description:Neural crest development is orchestrated by a complex and still poorly understood gene regulatory network. Premigratory neural crest is induced at the lateral border of the neural plate by the combined action of signaling molecules and transcription factors such as AP2, Gbx2, Pax3 and Zic1. Among them, Pax3 and Zic1 are both necessary and sufficient to trigger a complete neural crest developmental program. However, their gene targets in the neural crest regulatory network remain unknown. Here, through a transcriptome analysis of frog microdissected neural border, we identified an extended gene signature for the premigratory neural crest, and we defined novel potential members of the regulatory network. This signature includes 34 novel genes, as well as 44 known genes expressed at the neural border. Using another microarray analysis which combined Pax3 and Zic1 gain-of-function and protein translation blockade, we uncovered 25 Pax3 and Zic1 direct targets within this signature. We demonstrated that the neural border specifiers Pax3 and Zic1 are direct upstream regulators of neural crest specifiers Snail1/2, Foxd3, Twist1, and Tfap2b. In addition, they may modulate the transcriptional output of multiple signaling pathways involved in neural crest development (Wnt, Retinoic Acid) through the induction of key pathway regulators (Axin2 and Cyp26c1). We also found that Pax3 could maintain its own expression through a positive autoregulatory feedback loop. These hierarchical inductions, feedback loops, and pathway modulation provide novel tools to understand the neural crest induction network. The transcriptomes of neural border samples (stage 14 and 18) were compared to the transcriptome of anterior neural fold (stage 18), early neural plate (stage 12), and animal cap explants (stage14) to identify genes expressed specifically in neural border samples. Tissue samples from Xenopus laevis embryos were dissected, then total RNA was extracted and hybridized on Affymetrix microarrays. Selected tissue samples encompass the neural crest at different stages of its induction (early neural plate at stage 12, neural border at stage 14, neural border at stage 18), as well as reference tissues (anterior neural fold at stage 18, a tissue that belongs to the neural border but does not produce neural crest, and animal cap grown until stage 14 that differentiates into epidermis).

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Histone lactylation couples cellular metabolism with the activation of developmental gene regulatory networks [R-GNE-140 ATAC-seq]

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