Identification of the DNA methylation/chromatin modifier Ssm1

DNA 甲基化/染色质修饰剂 Ssm1 的鉴定

基本信息

批准号：
7616702
负责人：
URSULA B STORB
金额：
$ 7.68万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7616702
关键词：
1p36 Affect Alleles Binding Biological Assay Breeding Candidate Disease Gene Chromatin Chromosomes, Human, Pair 4 Complex DNA DNA Methylation Defect Development Disease Embryo Embryonic Development Epigenetic Process Event Family Gene Expression Gene Silencing Gene Targeting Genes Genetic Variation Genome Genomics Grant Hand Health Host Defense Human Human Chromosomes Inbred Strain Individual Life Little&apos s Disease Mammals Maps Methyl-CpG-Binding Protein 2 Methylation Modeling Modification Mouse Strains Mus Neurologic Organism Orthologous Gene Overlapping Genes Pattern Play Protein Binding Proteins Recruitment Activity Repetitive Sequence Repression Research Research Personnel Role Site Structure System Testing Time Tissues Transgenes Transgenic Organisms Zinc Fingers cancer gene expression chromatin modification clinically relevant embryonic stem cell gene function gene replacement gene repression human ZNF45 protein insight man member nervous system disorder novel prevent research study tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Despite the importance of CpG methylation and chromatin modifications in normal development and in disease, little is known about how methylation and chromatin patterns are established in mammals, and, specifically, how sequences are marked for inactivation. The investigator discovered a locus, Ssm1 (strain-specific modifier), on chromosome 4 of the mouse that has a major effect on the methylation and chromatin modification of a complex transgene, HRD, and certain derivatives. Methylation and inactivation occurs in a subset of mouse strains, including C57BL/6 (B6), but not other strains, including DBA/2 (D2). Methylation is dominant; (B6xD2) F1 mice methylate the target. Ssm1 is one of the very few mammalian loci shown to affect the methylation/chromatin status of specific target sequences. Determining how Ssm1 acts will significantly advance our understanding of epigenetic mechanisms in mammalian development and health. Ssm1 may be a member of a regulatory system to mark sequences for inactivation, involving complex interactions of allelic and non-allelic modifiers that are encoded by different as well as overlapping genes in different mouse strains and, by inference, different human individuals. The investigator has mapped Ssm1 to a narrow genomic interval on mouse chromosome 4 that is syntenic with human chromosome 1p36, a region involved in tumorigenesis and neurological defects. The defined genomic interval contains several potential Ssm1 candidates, all are KRAB-zinc finger genes that may encode proteins that bind their DNA target via the zinc finger, and recruit repressive proteins via the KRAB domain. She proposes to eliminate the B6 allele of Ssm1 candidates by gene replacement with a neo gene to identify Ssm1 as that gene whose elimination prevents inactivation of the HRD target. These experiments should elucidate how DNA methylation and chromatin modifications are regulated during early embryonic development and throughout life. Ssm1 orthologs in man may have clinical relevance, e.g., for epigenetic events in tumorigenesis and tumor progression, as well as for modification of MeCp2 function in neurological disorders.

描述（由申请人提供）：尽管CpG甲基化和染色质修饰在正常发育和疾病中的重要性很重要，但对于如何在哺乳动物中建立了甲基化和染色质模式，鲜为人知，具体而言，如何标记序列是如何灭活的。研究者在小鼠的4染色体上发现了一个基因座SSM1（应变特异性修饰符），该基因座对复杂转基因，HRD和某些衍生物的甲基化和染色质修饰具有重大影响。甲基化和灭活发生在小鼠菌株的子集中，包括C57BL/6（B6），但不包括其他菌株，包括DBA/2（D2）。甲基化是主要的；（B6XD2）F1小鼠甲基化靶标。 SSM1是显示出特定靶序列的甲基化/染色质状态的极少数哺乳动物基因座之一。确定SSM1行为将如何显着提高我们对哺乳动物发育和健康中表观遗传机制的理解。 SSM1可能是标记灭活序列的调节系统的成员，涉及由不同小鼠菌株中不同和重叠基因编码的等位基因和非平行修饰符的复杂相互作用，并通过推断了不同的人体。研究者已将SSM1映射到与人类136染色体同步的小鼠染色体上的狭窄基因组间隔，该染色体与肿瘤发生和神经系统缺陷有关的区域。定义的基因组间隔包含几个潜在的SSM1候选物，它们都是Krab-Zinc指的基因，它们可能编码通过锌指结合其DNA靶的蛋白质，并通过KRAB结构域募集抑制性蛋白质。她建议通过用NEO基因替换基因替代SSM1候选的B6等位基因，以识别SSM1作为该基因的消除阻止HRD靶标的失活。这些实验应阐明在早期胚胎发育和整个生命中如何调节DNA甲基化和染色质修饰。人类中的SSM1直系同源物可能具有临床相关性，例如，对于肿瘤发生和肿瘤进展的表观遗传事件，以及MECP2在神经系统疾病中的修饰。