Lan Fei, Zaratiegui Mikel, Villén Judit, Vaughn Matthew W, Verdel André, Huarte Maite, Shi Yujiang, Gygi Steven P, Moazed Danesh, Martienssen Robert A, Shi Yang
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Mol Cell. 2007 Apr 13;26(1):89-101. doi: 10.1016/j.molcel.2007.02.023.
LSD1 represses and activates transcription by demethylating histone H3K4me and H3K9me, respectively. Genetic ablation of the S. pombe homologs, splsd1 and splsd2, resulted in slow growth and lethality, respectively, underscoring their physiological importance. spLsd1 and spLsd2 form a stable protein complex, which exhibits demethylase activity toward methylated H3K9 in vitro. Both proteins were associated with the heterochromatin boundary regions and euchromatic gene promoters. Loss of spLsd1 resulted in increased H3K9 methylation accompanied by reduced euchromatic gene transcription and heterochromatin propagation. Removal of the H3K9 methylase Clr4 partially suppressed the slow growth phenotype of splsd1Delta. Conversely, catalytically inactivating point mutations in the splsd1 and splsd2 genes partially mimicked the growth and heterochromatin propagation phenotypes. Taken together, these findings suggest the importance of both enzymatic and nonenzymatic roles of spLsd1 in regulating heterochromatin propagation and euchromatic transcription and also suggest that misregulation of spLsd1/2 is likely to impact the epigenetic state of the cell.
赖氨酸特异性去甲基化酶1（LSD1）分别通过使组蛋白H3K4me和H3K9me去甲基化来抑制和激活转录。粟酒裂殖酵母（S. pombe）同源物splsd1和splsd2的基因敲除分别导致生长缓慢和致死，突出了它们的生理重要性。spLsd1和spLsd2形成一个稳定的蛋白质复合物，该复合物在体外对甲基化的H3K9表现出去甲基酶活性。这两种蛋白质都与异染色质边界区域和常染色质基因启动子相关。spLsd1的缺失导致H3K9甲基化增加，同时常染色质基因转录减少和异染色质扩展。去除H3K9甲基转移酶Clr4部分抑制了splsd1Delta的生长缓慢表型。相反，splsd1和splsd2基因中的催化失活点突变部分模拟了生长和异染色质扩展表型。综上所述，这些发现表明spLsd1在调节异染色质扩展和常染色质转录中的酶促和非酶促作用都很重要，也表明spLsd1/2的失调可能会影响细胞的表观遗传状态。
