FMRI Epigenetic Silencing Commonly Occurs in Undifferentiated Fragile X-Affected Embryonic Stem Cells
FMRI Epigenetic Silencing Commonly Occurs in Undifferentiated Fragile X-Affected Embryonic Stem Cells
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DOI：
10.1016/j.stemcr.2014.09.001
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发表时间：
2014-11-11
影响因子：
5.9
通讯作者：
Eiges, Rachel
中科院分区：
文献类型：
--
作者：
Avitzour, Michal;Mor-Shaked, Hagar;Eiges, Rachel
脆性 X 综合征 (FXS) 是最常见的遗传性认知障碍形式。它是由 X 连锁 FMR1 基因的 5'-非翻译区 CGG 扩展导致的表观遗传沉默所致。利用大量受 FXS 影响的人胚胎干细胞 (HESC) 系和源自它们的同基因亚克隆，我们发现 FMRI 高甲基化通常发生在未分化状态（9 个系中的 6 个，范围从 24% 到 65%）。此外，我们证明高甲基化与未分化细胞中 FMR1 转录失活密切相关，与 H3K4me2 的丢失和 H3K9me3 的增加一致，并且与 CTCF 结合无关。总而言之，这些结果表明 FMR1 表观遗传基因沉默发生在 FXS HESC 中，并清楚地强调了在研究 FXS 和很可能的其他表观遗传调控疾病时检查多个细胞系的重要性。
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5'-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMRI hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.