Ivanova A V, Bonaduce M J, Ivanov S V, Klar A J
NCI-Frederick Cancer Research and Development Center, ABL-Basic Research Program, Gene Regulation and Chromosome Biology Laboratory, Frederick, Maryland 21702-1201, USA.
Nat Genet. 1998 Jun;19(2):192-5. doi: 10.1038/566.
Heritable inactivation of specific regions of the genome is a widespread, possibly universal phenomenon for gene regulation in eukaryotes. Self-perpetuating, clonally inherited chromatin structure has been proposed as the explanation for such phenomena as position-effect variegation (PEV) and control of segment determination and differentiation in flies, X-chromosome inactivation and parental imprinting in mammals, gene silencing by paramutation in maize and silencing of the mating-type loci in yeasts. We have now found that the clr4 gene, which is essential for silencing of centromeres and the mating-type loci in Schizosaccharomyces pombe, encodes a protein with high homology to the product of Su(var)3-9, a gene affecting PEV in Drosophila. Like Su(var)3-9p, Clr4p contains SET and chromo domains, motifs found in proteins that modulate chromatin structure. Site-directed mutations in the conserved residues of the chromo domain confirm that it is required for proper silencing and directional switching of the mating type, like SET domain. Surprisingly, RNA differential display experiments demonstrated that clr4+ can mediate transcriptional activation of certain other loci. These results show that clr4 plays a critical role in silencing at mating-type loci and centromeres through the organization of repressive chromatin structure and demonstrate a new, activator function for Clr4p.
基因组特定区域的可遗传失活是真核生物中广泛存在、甚至可能普遍存在的基因调控现象。自我延续、克隆遗传的染色质结构已被提出用于解释诸如位置效应斑驳（PEV）、果蝇中体节决定与分化的控制、哺乳动物中的X染色体失活及亲本印记、玉米中副突变导致的基因沉默以及酵母中交配型基因座的沉默等现象。我们现在发现，在粟酒裂殖酵母中，对于着丝粒和交配型基因座的沉默至关重要的clr4基因，编码一种与Su(var)3 - 9的产物具有高度同源性的蛋白质，Su(var)3 - 9是一个影响果蝇PEV的基因。与Su(var)3 - 9p一样，Clr4p含有SET和染色质结构域，这些基序存在于调节染色质结构的蛋白质中。染色质结构域保守残基的定点突变证实，它与SET结构域一样，对于交配型的正确沉默和定向转换是必需的。令人惊讶的是，RNA差异显示实验表明clr4 + 可以介导某些其他基因座的转录激活。这些结果表明，clr4通过抑制性染色质结构的组织在交配型基因座和着丝粒的沉默中起关键作用，并证明了Clr4p的一种新的激活功能。
