A BMP-controlled metabolic/epigenetic signaling cascade directs midfacial morphogenesis

Area of Science:

• Developmental Biology
• Genetics
• Metabolic Regulation

Background:

• Craniofacial anomalies, particularly midline defects, are common birth defects with significant health implications.
• The coordination of genetic, signaling, and metabolic pathways in craniofacial morphogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of bone morphogenetic protein (BMP) signaling in craniofacial development.
• To elucidate the mechanisms linking BMP signaling, metabolism, and epigenetics in cranial neural crest cells (CNCCs).

Main Methods:

• Utilized constitutively activated ACVR1 (ca-ACVR1) to manipulate BMP signaling in CNCCs.
• Assessed glycolytic activity, lactate production, and histone lactylation.
• Analyzed gene expression changes, including Pdgfra, in vitro and in vivo.

Main Results:

• Elevated BMP signaling suppressed glycolysis and lactate production via a p53-dependent pathway, leading to severe midline facial defects.
• BMP signaling-dependent lactate generation promoted histone lactylation, altering Pdgfra gene expression and regulating CNCC behavior.
• Established a link between BMP signaling, metabolic activity, and epigenetic modifications in craniofacial development.

Conclusions:

• BMP signaling orchestrates a metabolic and epigenetic cascade, involving lactate production and histone lactylation, essential for craniofacial morphogenesis.
• Dysregulation of this axis can cause congenital craniofacial birth defects.
• Modulating metabolic-driven histone lactylation offers potential preventive strategies for these defects.