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

项目总结/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，如以下所示： 颅面出生缺陷的高发病率。遗传和环境因素的失调是主要的 颅面缺损的原因然而，不到50%的颅面缺陷病例已确定遗传性， 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。这个调节器，蛋白质 精氨酸甲基转移酶1（PRMT 1）是一种使组蛋白甲基化以产生转录活性的酶。 激活标记H4 R3 me 2a和精氨酸残基上的甲基化非组蛋白蛋白。Prmt 1消融 神经嵴细胞引起腭裂和颅骨畸形。我们进一步揭示了PRMT 1在以下方面的作用： 预防环境毒素TCDD诱发腭裂。在本提案中，我们旨在确定 PRMT 1依赖的转录和表观遗传机制调节TCDD诱导的细胞变化 和发育缺陷，使用小鼠遗传模型，生物化学和细胞生物学方法，RNA-seq， ChIP-seq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.