Roberts Amity R, Huang Edward, Jones Lincoln, Daxinger Lucia, Chong Suyinn, Whitelaw Emma
Queensland Institute of Medical Research, Herston, QLD, Australia.
Chromosoma. 2013 Dec;122(6):541-54. doi: 10.1007/s00412-013-0427-8. Epub 2013 Jul 18.
Studies using human and mouse cells have revealed some changes to non-telomeric chromatin and gene expression in response to abnormally short telomeres. To investigate this further, we studied the effect of inheriting shorter telomeres on transcription and genetic stability at non-telomeric sites in the mouse. Using multiple generations of Terc knockout mice, we show that inheriting shorter telomeres from one parent increases the likelihood of transcriptional silencing at a non-telomeric green fluorescent protein (GFP) transgene inherited from the other parent. In these cases, silencing must occur at or after zygote formation. In grand-offspring from a G3 Terc (-/-) parent, transgene expression was further reduced and associated with increased DNA methylation and, surprisingly, reduced copy number at the transgene array. In these cases, the transgene had been passed through the germline of a Terc-compromised parent, providing an opportunity for meiotic events. Furthermore, genome-wide microarray analysis of copy number variations revealed greater genetic instability in G3 Terc (-/-) mice than detected in wild-type mice of the same genetic background. Our results have implications for the molecular mechanisms underlying premature-ageing syndromes, such as dyskeratosis congenita. In autosomal-dominant dyskeratosis congenita, progressive telomere shortening is seen as it passes down the generations, and this is associated with anticipation, i.e. the disease becomes more severe earlier. The underlying mechanism is not known, but has been considered to be simply associated with decreases in telomere length. Epigenetic and/or genetic changes at non-telomeric regions could, in theory, be involved.
使用人类和小鼠细胞进行的研究揭示了非端粒染色质和基因表达因端粒异常缩短而发生的一些变化。为了进一步研究这一现象，我们研究了在小鼠中继承较短端粒对非端粒位点转录和遗传稳定性的影响。通过多代Terc基因敲除小鼠，我们发现从一方亲本继承较短端粒会增加从另一方亲本继承的非端粒绿色荧光蛋白（GFP）转基因发生转录沉默的可能性。在这些情况下，沉默必定发生在合子形成时或之后。在来自G3 Terc（-/-）亲本的孙代中，转基因表达进一步降低，并与DNA甲基化增加相关，令人惊讶的是，转基因阵列的拷贝数减少。在这些情况下，转基因通过了Terc功能受损亲本的生殖系，这为减数分裂事件提供了机会。此外，全基因组微阵列分析拷贝数变异显示，G3 Terc（-/-）小鼠比相同遗传背景的野生型小鼠具有更大的遗传不稳定性。我们的结果对诸如先天性角化不良等早衰综合征的分子机制具有启示意义。在常染色体显性先天性角化不良中，随着代际传递，端粒会逐渐缩短，这与疾病早现相关，即疾病会更早变得更严重。其潜在机制尚不清楚，但一直被认为仅仅与端粒长度的减少有关。理论上，非端粒区域的表观遗传和/或基因变化可能也参与其中。
