Protein methylation pathways that control genetic susceptibility to environmental pollutants in the occurrence of craniofacial defects

University Of Southern California, Los Angeles CA

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Abstract

PROJECT SUMMARY / ABSTRACT Formation of the head and face is a complex process that is highly susceptible to disturbance as evidenced by the high incidence of craniofacial birth defects. Dysregulation in genetic and environmental factors are the main causes of craniofacial defects. However, less than 50% of craniofacial defect cases have identified genetic causes, and mechanisms of gene-environment interaction remains poorly understood. Therefore, molecular investigation is needed to increase understanding of craniofacial development. We recently identified a new regulator of craniofacial morphogenesis that interacts with environmental stress. This regulator, Protein Arginine Methyltransferase 1 (PRMT1), is an enzyme that methylates histone to generate a transcriptional activation mark H4R3me2a and methylation non-histone proteins on arginine residues. Prmt1 ablation in neural crest cells caused cleft palate and skull malformation. We further uncovered a role for PRMT1 in guarding against environmental toxin TCDD-induced cleft palate. In this proposal, we aim to determine PRMT1-dependent transcription and epigenetic mechanisms that regulated TCDD-induced cellular changes and developmental defects, using mouse genetic models, biochemical and cell biology approaches, RNA-seq, ChIP-seq and bioinformatic analysis.