SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation
SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation
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DOI：
10.1038/ng.142
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发表时间：
2008-05-01
期刊：
影响因子：
30.8
通讯作者：
Whitelaw, Emma
中科院分区：
文献类型：
--
作者：
Blewitt, Marnie E.;Gendrel, Anne-Valerie;Whitelaw, Emma
X染色体失活是哺乳动物剂量补偿机制，通过该机制，X连锁基因的转录在雌性和雄性之间平衡。在一个N-乙基-N-亚硝基脲（ENU）诱变筛选小鼠的表观遗传重编程的修饰剂，我们确定了MommeD 1（小鼠亚稳态表观等位基因的修饰剂）突变作为一个半显性抑制杂色。MommeD 1表现出纯合子女性特异性妊娠中期致死性和X连锁基因Hprt 1的低甲基化，提示X失活缺陷（1）。在这里，我们报告说，致病点突变在于一个以前未知的基因，Smchd 1（结构维护的染色体铰链域包含1）。我们发现SmcHD 1不是正确表达Xist所必需的，但定位于失活X，并在维持X失活和与失活X相关的CpG岛超甲基化中发挥作用。这一发现将一组通常与染色体生物学结构相关的蛋白质与表观遗传基因沉默联系起来。
X-chromosome inactivation is the mammalian dosage compensation mechanism by which transcription of X-linked genes is equalized between females and males. In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen on mice for modifiers of epigenetic reprogramming, we identified the MommeD1 (modifier of murine metastable epialleles) mutation as a semidominant suppressor of variegation. MommeD1 shows homozygous female-specific mid-gestation lethality and hypomethylation of the X-linked gene Hprt1, suggestive of a defect in X inactivation(1). Here we report that the causative point mutation lies in a previously uncharacterized gene, Smchd1 (structural maintenance of chromosomes hinge domain containing 1). We find that SmcHD1 is not required for correct Xist expression, but localizes to the inactive X and has a role in the maintenance of X inactivation and the hypermethylation of CpG islands associated with the inactive X. This finding links a group of proteins normally associated with structural aspects of chromosome biology with epigenetic gene silencing.