Histone lactylation couples cellular metabolism with the activation of developmental gene regulatory networks [SOX9 MO 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 control morpholino and SOX9 morpholino transfected neural crest cells from HH9 embryos.

胚胎细胞在发育中的胚胎内依托多样的代谢模式执行特异性生物学功能。近期研究表明，代谢重编程（metabolic reprogramming）亦可通过调控发育基因的表达，进而改变细胞身份与细胞行为表型。然而，细胞代谢与差异基因表达之间的内在关联仍未被充分阐明。本研究发现，组蛋白乳酸化（histone lactylation）——一种源自糖酵解产物乳酸的表观遗传标记（epigenetic mark）——可将胚胎细胞的代谢状态与基因表达及基因调控网络（gene regulatory networks）的激活过程相耦联。糖酵解通量（glycolytic flux）较高的胚胎组织（如神经嵴（neural crest）与体节前中胚层（pre-somitic mesoderm））呈现高水平的乳酸化修饰。当这类细胞向糖酵解增强的状态转变时，神经嵴基因位点上的乳酸化修饰会发生动态沉积。该过程可提升活性增强子（active enhancers）的染色质可及性，对于神经嵴基因调控网络的正常启动与执行不可或缺。当我们通过靶向乳酸脱氢酶A（LDHA）与乳酸脱氢酶B（LDHB）以减少该修饰的沉积时，乳酸化修饰靶基因的表达出现下调，且神经嵴细胞的迁移受到阻滞。神经嵴增强子的乳酸化修饰受转录因子（transcription factors）SOX9与YAP/TEAD调控，这两类转录因子对于该修饰的沉积既是必要条件，也是充分条件。本研究结果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期胚胎来源的、分别经对照吗啉代寡核苷酸（morpholino）与SOX9吗啉代寡核苷酸转染（transfected）的神经嵴细胞的基因组区域染色质可及性进行了检测。