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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.

项目摘要/摘要基因组印记是一种表观遗传基因标记现象，它导致哺乳动物基因的子集(即印记基因)只能从两个亲本中的一个拷贝中表达。大多数印记基因都是排列成染色体簇。每个簇具有印迹控制区(ICR)，该印迹控制区具有一个或多个差异甲基化区域(DMRS)--仅由一个等位基因上的DNA甲基化标记的区域--起作用作为控制单等位基因表达的表观遗传信号。印记DMR被归类为生殖系 (初级)dmr(Gdmr)和体细胞(继发性)dmr(Sdmr)。GDMR在以下期间建立配子发生，由雄性和雌性生殖细胞的不同从头甲基化引起。SMRS代表在胚胎发育过程中获得的等位基因特异性甲基化。遗传学研究已经证明，从头DNA甲基转移酶DNMT3A负责在gDMRS上建立甲基化印记在生殖细胞发育过程中，维持酶DNMT1负责维持胚胎发育和成人组织中的甲基化印记。尽管有这些进步，但从根本上讲问题仍然有待回答，例如配子中DNA甲基化的性别二态模式是如何受监管？以及gDNA是如何控制sDMR的？申请人实验室的初步研究表明，在雄性生殖细胞中条件消融精氨酸甲基转移酶PRMT7导致不完全精子中H19-Igf2印迹基因gDMR甲基化的研究结果，后代表现出双等位基因抑制H19和Gtl2表达中的Igf2和等位基因开关(Gtl2也是父系印记基因)。这个申请人的实验室还表明，PRMT7在保守的精氨酸上催化DNMT3A的单甲基化 N-末端区域的残基对DNMT3A的功能特异性很重要。申请人假设PRMT7通过甲基化DNMT3A，调节DNMT3A介导的从头甲基化，包括在男性生殖细胞发育期间建立父系印记，以及在没有 PRMT7，父本等位基因上DNA甲基化受损导致继发性反式效应改变受精后母体的等位基因，导致一些父系印记基因的表达发生等位基因切换。为了验证这一假设，申请人提出了两个具体目标：1)确定PRMT7在从头开始中的作用雄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在PRMT7缺陷雄性小鼠的后代中父系印记基因的研究。按申请人的意见，拟议的研究因其概念上的新颖性而具有创新性。该项目意义重大，因为拟议的研究有望为调控从头DNA甲基化提供新的见解。父本和母本之间的串扰控制单等位基因的表达印记基因。