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

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. Examination of the accessibility of genomic regions in neural crest cells from HH9 embryos.

胚胎细胞借助多样的代谢途径，在发育中的胚胎内执行特化功能。近期研究证实，代谢重编程还可通过调控发育基因的表达，改变细胞身份与细胞行为。然而，细胞代谢与基因差异表达之间的关联仍未得到充分阐释。本研究发现，组蛋白乳酸化（histone lactylation）——一种源自糖酵解产生的乳酸的表观遗传标记——可将胚胎细胞的代谢状态与基因表达及基因调控网络的激活过程相耦联。糖酵解通量较高的胚胎组织（如神经嵴与体节前中胚层）呈现高水平的乳酸化修饰。当这类细胞转向糖酵解增强状态时，神经嵴基因座上的乳酸化标记会发生动态沉积。该过程可促进活性增强子的染色质开放，对于神经嵴基因调控网络的正常激活至关重要。我们通过靶向抑制乳酸脱氢酶A（LDHA）与乳酸脱氢酶B（LDHB）以减少该修饰的沉积后，乳酸化修饰相关基因的表达出现下调，且神经嵴迁移受到阻碍。神经嵴增强子的乳酸化修饰受转录因子SOX9及YAP/TEAD调控，这两类因子对于该修饰的沉积既是必要条件，也是充分条件。上述发现揭示了一种将细胞代谢与调控胚胎发育的基因调控网络相整合的表观遗传机制。本研究还对HH9期胚胎神经嵴细胞的基因组区域染色质开放程度进行了检测。