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Role of PRMT7 in Genomic Imprinting

PRMT7 在基因组印记中的作用

基本信息

批准号：
10714206
负责人：
Taiping Chen
金额：
$ 34.83万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714206
关键词：
Ablation Adult Alleles Arginine Classification DNA Methylation DNA Modification Methylases DNMT3a Development Disease Embryonic Development Enzymes Epigenetic Process Exhibits Female Fertilization Gametogenesis Gene Expression Gene Order Genes Genetic study Genome Genomic DNA Genomic Imprinting Genomic Segment Germ Cells Germ Lines H19 gene Health Hydatidiform Mole Impairment Infertility Inherited Knowledge Laboratories Maintenance Malignant Neoplasms Mediating Methylation Mission Molecular Mus N-terminal Occupations Pathogenesis Pattern Play Public Health Regulation Repression Research Role Signal Transduction Specificity Spermatocytes Testing Tissues United States National Institutes of Health Work arginine methyltransferase embryonic stem cell experimental study genome-wide imprint improved innovation insight male mutant novel offspring paternal imprint public health relevance sexual dimorphism sperm cell

项目摘要

PROJECT SUMMARY/ABSTRACT Genomic imprinting is an epigenetic gene-marking phenomenon that causes a subset of mammalian genes (i.e. imprinted genes) to be expressed from only one of the two parental copies. The majority of imprinted genes are arranged in chromosomal clusters. Each cluster has an imprinting control region (ICR) with one or more differentially methylated regions (DMRs) - regions marked by DNA methylation on only one allele - which act as the epigenetic signal that controls monoallelic expression. Imprinted DMRs are classified as germline (primary) DMRs (gDMRs) and somatic (secondary) DMRs (sDMRs). gDMRs are established during gametogenesis, resulting from differential de novo methylation of male and female germ cells. sDMRs represents allele-specific methylation acquired during embryonic development. Genetic studies have demonstrated that the de novo DNA methyltransferase DNMT3A is responsible for the establishment of methylation imprints at gDMRs during germ cell development and that the maintenance enzyme DNMT1 is responsible for maintaining methylation imprints during embryonic development and in adult tissues. Despite these advances, fundamental questions remain to be answered, e.g. How sexually dimorphic patterns of DNA methylation in gametes are regulated? And how gDNAs control sDMRs? Preliminary studies in the applicant’s laboratory showed that conditional ablation of the arginine methyltransferase PRMT7 in male germ cells results in incomplete methylation of the gDMR at the H19-Igf2 imprinted locus in sperm. As a result, the progeny show biallelic repression of Igf2 and allelic switch in H19 and Gtl2 expression (Gtl2 is also a paternally imprinted gene). The applicant’s laboratory also showed that PRMT7 catalyzes monomethylation of DNMT3A at a conserved arginine residue in the N-terminal region that is important for functional specificity of DNMT3A. The applicant hypothesizes that PRMT7, through methylating DNMT3A, regulates DNMT3A-mediated de novo methylation, including the establishment of paternal imprints, during male germ cell development and that, in the absence of PRMT7, impaired DNA methylation on the paternal alleles causes secondary trans-effect changes on the maternal alleles after fertilization, resulting in allelic switch in the expression of some paternally imprinted genes. To test the hypothesis, the applicant proposes two specific aims: 1) Determine the role of PRMT7 in de novo DNA methylation during male germ cell development; and 2) Elucidate the mechanism underlying allelic switch of paternally imprinted genes in the offspring of PRMT7-deficient male mice. In the applicant’s opinion, the proposed research is innovative for its conceptual novelty. The project is significant, because results from the proposed studies are expected to provide novel insights into the regulation of de novo DNA methylation in the male germline and the crosstalk between the paternal and maternal alleles to control monoallelic expression of imprinted genes.

项目总结/摘要基因组印记是一种表观遗传的基因标记现象，它导致哺乳动物基因的一个子集（即，印记基因）仅从两个亲本拷贝中的一个表达。大多数印记基因排列成染色体簇。每个簇具有印迹控制区（ICR），其具有一个或多个差异甲基化区域（DMR）-仅在一个等位基因上标记DNA甲基化的区域-其作用作为控制单等位基因表达的表观遗传信号。印记DMR被归类为种系（原发性）DMR（gDMR）和体细胞（继发性）DMR（sDMR）。gDMR是在配子发生，由雄性和雌性生殖细胞的差异从头甲基化引起。sDMR代表在胚胎发育过程中获得的等位基因特异性甲基化。遗传学研究表明，从头DNA甲基转移酶DNMT 3A负责在gDMR处建立甲基化印记在生殖细胞发育过程中，维持酶DNMT 1负责维持甲基化印记在胚胎发育期间和在成人组织中。尽管取得了这些进展，还有一些问题有待回答，例如，配子中DNA甲基化的性二态模式是如何监管？gDNA如何控制sDMR？申请人实验室的初步研究表明，雄性生殖细胞中精氨酸甲基转移酶PRMT 7的条件性切除导致不完全的精子中H19-Igf 2印记基因座处gDMR的甲基化。结果，后代显示双等位基因 H19和Gtl 2表达中Igf 2和等位基因开关的抑制（Gtl 2也是父系印记基因）。的本申请人的实验室还显示PRMT 7催化DNMT 3A在保守的精氨酸上的单甲基化 N-末端区域中的残基，其对于DNMT 3A的功能特异性是重要的。申请人假设PRMT 7通过甲基化DNMT 3A调节DNMT 3A介导的从头甲基化，包括父系印记的建立，在男性生殖细胞发育过程中， PRMT 7，父本等位基因上受损的DNA甲基化导致PRMT 7上的继发性反式效应变化。受精后母体等位基因，导致一些父系印记基因表达的等位基因转换。为了检验该假设，申请人提出了两个具体目标：1）确定PRMT 7在从头开始的细胞中的作用。男性生殖细胞发育过程中的DNA甲基化; 2）阐明等位基因转换的机制 PRMT 7缺陷雄性小鼠后代中的父系印记基因。申请人认为，拟议的研究因其概念新奇而具有创新性。该项目意义重大，因为提出的研究预计将提供新的见解从头DNA甲基化的调控，在雄性生殖系和父系和母系等位基因之间的串扰，以控制印记基因