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

控制颅面缺陷发生过程中环境污染物遗传易感性的蛋白质甲基化途径

基本信息

批准号：
10651798
负责人：
Jian Xu
金额：
$ 42.33万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651798
关键词：
3-Dimensional Ablation Affect Animal Model Area Arginine Aryl Hydrocarbon Receptor Biochemical Bioinformatics Blood Vessels Cellular biology ChIP-seq Cleft Palate Complex Congenital Abnormality Connective Tissue Craniofacial Abnormalities Cues Cytoprotection DNA Binding Defect Deformity Deposition Development Differentiation and Growth Dioxins Elements Environmental Pollutants Environmental Risk Factor Enzymes Epigenetic Process Exhibits Face Gene Expression Genes Genetic Genetic Models Genetic Predisposition to Disease Genetic Transcription Genomics Growth Head Incidence Investigation Ligands Mandible Maps Mediating Methylation Molecular Morphogenesis Mus Muscle Nerve Tissue Neural Crest Cell Nuclear Receptors Palate Pathway interactions Predisposition Prevention strategy Primordium Process Protein Methylation Protein-Arginine N-Methyltransferase Public Health Repression Research Risk Role Stress Structure Tetrachlorodibenzodioxin Toxic Environmental Substances Toxic effect Transcriptional Activation Xenobiotics bone loss cell behavior cofactor craniofacial craniofacial bone craniofacial development cranium gain of function gene environment interaction gene induction high risk population histone methylation improved liver injury loss of function malformation mouse genetics non-histone protein novel strategies novel therapeutics oxidative damage palatal shelves prevent pup receptor receptor binding response transcriptome transcriptome sequencing

项目摘要

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.

项目概要/摘要头部和面部的形成是一个复杂的过程，极易受到干扰，如下所示：颅面部出生缺陷的发生率很高。遗传和环境因素失调是主要原因颅面缺陷的原因。然而，只有不到 50% 的颅面缺陷病例已被确定为遗传因素。基因与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。我们最近发现了一个新的与环境压力相互作用的颅面形态发生的调节剂。这种调节剂，蛋白质精氨酸甲基转移酶 1 (PRMT1) 是一种将组蛋白甲基化以产生转录的酶精氨酸残基上的激活标记 H4R3me2a 和甲基化非组蛋白。 Prmt1 消融神经嵴细胞导致腭裂和颅骨畸形。我们进一步发现了 PRMT1 在以下方面的作用：预防环境毒素 TCDD 诱发的腭裂。在本提案中，我们的目标是确定 PRMT1依赖性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、生化和细胞生物学方法、RNA-seq、 ChIP-seq 和生物信息学分析。