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

项目摘要/摘要 头部和面部的形成是一个复杂的过程，非常容易受到干扰，这一点从以下几个方面得到了证明 头面部出生缺陷发生率高。遗传和环境因素的失调是主要原因 头面部缺陷的原因。然而，只有不到50%的头面部缺陷病例确定了遗传 基因-环境相互作用的原因和机制仍然知之甚少。因此，分子 需要进行调查以增加对颅面发育的了解。我们最近发现了一种新的 与环境压力相互作用的颅面形态发生的调节器。这种调节剂，蛋白质 精氨酸甲基转移酶1(PRMT1)，是一种甲基化组蛋白以产生转录 精氨酸残基上的活化标记H4R3me2a和甲基化非组蛋白。Prmt1消融 神经脊细胞导致腭裂和颅骨畸形。我们进一步揭示了PRMT1在 防范环境毒素TCDD诱发的腭裂。在这项提案中，我们的目标是确定 调节TCDD诱导的细胞变化的PRMT1依赖的转录和表观遗传学机制 和发育缺陷，使用小鼠遗传模型，生化和细胞生物学方法，RNA-seq， 芯片序列和生物信息学分析。

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.