Identification of the DNA methylation/chromatin modifier Ssm1

描述(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，但对于哺乳动物中甲基化和染色质模式是如何建立的，特别是序列如何被标记为失活，人们知之甚少。研究人员在小鼠的4号染色体上发现了一个名为Ssm1(品系特异性修饰物)的基因座，它对复杂的转基因HRD及其某些衍生物的甲基化和染色质修饰有重要影响。甲基化和失活发生在包括C57BL/6(B6)在内的一部分小鼠品系中，但不包括其他品系，包括DBA/2(D2)。甲基化占主导地位；(B6xD2)F1小鼠甲基化为靶标。 Ssm1是少数几个影响特定靶序列甲基化/染色质状态的哺乳动物基因座之一。确定Ssm1如何发挥作用将极大地促进我们对哺乳动物发育和健康中的表观遗传机制的理解。Ssm1可能是标记失活序列的调控系统的成员，涉及不同小鼠品系以及不同人类个体中不同和重叠基因编码的等位基因和非等位基因的复杂相互作用。这位研究人员已将Ssm1定位于小鼠4号染色体上的一个狭窄基因组区间，该区间与人类染色体1p36同源，1p36是参与肿瘤发生和神经缺陷的区域。确定的基因组区间包含几个潜在的Ssm1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，并通过KRAB结构域招募抑制蛋白。她建议通过用neo基因替换基因来消除Ssm1候选基因的B6等位基因，以确定Ssm1是该基因，其消除阻止了HRD靶标的失活。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受到调节的。人类中的Ssm1同源基因可能与临床相关，例如，在肿瘤发生和肿瘤进展中的表观遗传学事件，以及在神经疾病中MeCP2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.