Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
Stem Cell Reports. 2014 Nov 11;3(5):699-706. doi: 10.1016/j.stemcr.2014.09.001. Epub 2014 Oct 3.
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 FMR1 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.
脆性 X 综合征（FXS）是最常见的遗传性认知障碍形式。它是由于其 5'非翻译区的 CGG 扩展导致 X 连锁 FMR1 基因的表观遗传沉默所致。利用一大组 FXS 受影响的人类胚胎干细胞（HESC）系及其衍生的同基因亚克隆，我们表明 FMR1 超甲基化通常发生在未分化状态（九种中的六种，范围从 24%到 65%）。此外，我们证明超甲基化与未分化细胞中 FMR1 转录失活密切相关，与 H3K4me2 的丧失和 H3K9me3 的获得一致，与 CTCF 结合无关。总之，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 及很可能其他受表观遗传调控的疾病时，检查多个细胞系的重要性。
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