Identification of the DNA methylation/chromatin modifier Ssm1

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很重要，但关于甲基化和染色质模式如何在哺乳动物中建立，特别是如何标记序列以进行失活，我们知之甚少。 研究人员在小鼠4号染色体上发现了一个位点Ssm 1（品系特异性修饰物），该位点对复杂转基因HRD和某些衍生物的甲基化和染色质修饰具有重要影响。 甲基化和失活发生在小鼠品系的子集中，包括C57 BL/6（B6），但不包括DBA/2（D2）的其他品系。 甲基化占主导地位;（B6 xD 2）F1小鼠甲基化靶标。 Ssm 1是极少数哺乳动物基因座之一，显示影响特定靶序列的甲基化/染色质状态。 确定Ssm 1如何发挥作用将大大促进我们对哺乳动物发育和健康的表观遗传机制的理解。 Ssm 1可能是一个调控系统的成员，以标记序列失活，涉及复杂的相互作用的等位基因和非等位基因的修饰，编码的不同以及重叠的基因在不同的小鼠品系，并通过推理，不同的人类个体。 研究人员将Ssm 1定位于小鼠4号染色体上的一个狭窄的基因组区间，该区间与人类染色体1 p36共线，这是一个涉及肿瘤发生和神经缺陷的区域。 定义的基因组区间包含几个潜在的Ssm 1候选基因，它们都是KRAB-锌指基因，可能编码通过锌指结合其DNA靶标的蛋白质，并通过KRAB结构域募集抑制蛋白。 她建议通过用neo基因进行基因替换来消除Ssm 1候选者的B6等位基因，以鉴定Ssm 1是其消除阻止HRD靶标失活的基因。 这些实验应该阐明DNA甲基化和染色质修饰是如何在早期胚胎发育和整个生命过程中进行调节的。 人中的Ssm 1直系同源物可能具有临床相关性，例如，用于肿瘤发生和肿瘤进展中的表观遗传事件，以及用于神经障碍中MeCp 2功能的修饰。

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.