Unbalanced X;autosome translocations provide evidence for sequence specificity in the association of XIST RNA with chromatin
Unbalanced X;autosome translocations provide evidence for sequence specificity in the association of XIST RNA with chromatin
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DOI：
10.1093/hmg/11.25.3157
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发表时间：
2002-12-01
影响因子：
3.5
通讯作者：
Lawrence, JB
中科院分区：
文献类型：
--
作者：
Hall, LL;Clemson, CM;Lawrence, JB
XIST RNA是否与染色体的序列内容无关是理解其染色体失活机制的基础。转基因Xist RNA似乎与整个常染色体结合并覆盖整个常染色体。然而，XIST RNA对天然存在的人Xi常染色体易位的行为尚未得到彻底研究。在此，在来自两名携带X;常染色体易位的患者的细胞中研究了人XIST RNA与常染色体染色质的关系，所涉及的常染色体在几乎完全三体性的背景下。由于14或9的三体在早期发育中是致命的，三体没有严重的表型后果表明易位的常染色体已经失活。令人惊讶的是，我们的分析表明，在成年患者的原代成纤维细胞中，XIST RNA不与大多数相关的常染色体相关，即使它的大部分表现出与XIST RNA相关区域以外的其他失活标志。虽然结果显示XIST RNA可以在一定程度上与人常染色体染色质结合，但一些观察结果表明这种相互作用可能是不稳定的，随着时间的推移逐渐丧失。因此，即使在选择常染色体失活而不是反对的情况下，XIST RNA对常染色体与X染色质的亲和力也存在根本差异。基于这些结果，我们提出，即使是在发育早期失活的常染色体染色质，也可能从XIST RNA开始逐步丧失失活标志。因此，与XIST RNA的相互作用受损可能是不完全或不稳定的常染色体失活的主要原因。
Whether XIST RNA is indifferent to the sequence content of the chromosome is fundamental to understanding its mechanism of chromosomal inactivation. Transgenic Xist RNA appears to associate with and inactivate an entire autosome. However, the behavior of XIST RNA on naturally occurring human X;autosome translocations has not been thoroughly investigated. Here, the relationship of human XIST RNA to autosomal chromatin is investigated in cells from two patients carrying X;autosome translocations in the context of almost complete trisomy for the involved autosome. Since trisomies of either 14 or 9 are lethal in early development, the lack of serious phenotypic consequences of the trisomy demonstrates that the translocated autosomes had been inactivated. Surprisingly, our analyses show that in primary fibroblasts from adult patients, XIST RNA does not associate with most of the involved autosome even though the bulk of it exhibits other hallmarks of inactivation beyond the region associated with XIST RNA. While results show that XIST RNA can associate with human autosomal chromatin to some degree, several observations indicate that this interaction may be unstable, with progressive loss over time. Thus, even where autosomal inactivation is selected for rather than against, there is a fundamental difference in the affinity of XIST RNA for autosomal versus X chromatin. Based on these results we propose that even autosomal chromatin that had been inactivated earlier in development may undergo a stepwise loss of inactivation hallmarks, beginning with XIST RNA. Hence compromised interaction with XIST RNA may be a primary cause of incomplete or unstable autosomal inactivation.