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失活，我们知之甚少。研究者在小鼠的4号染色体上发现了一个位点Ssm1（菌株特异性修饰因子），它对复杂转基因HRD和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小鼠菌株的一个子集中，包括C57BL/6 (B6)，但不发生在其他菌株中，包括DBA/2 （D2）。甲基化是显性的；（B6xD2） F1小鼠将靶标甲基化。

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.