Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.
Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.
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DOI：
10.1101/gr.138032.112
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发表时间：
2013-02
期刊：
影响因子：
7
通讯作者：
Cao K
中科院分区：
文献类型：
--
作者：
McCord RP;Nazario-Toole A;Zhang H;Chines PS;Zhan Y;Erdos MR;Collins FS;Dekker J;Cao K
Hutchinson-Gilford早衰症(HGPS)是一种由LMNA基因1824位点突变引起的早衰性疾病。这种突变激活了外显子11上的一个隐蔽的剪接供体位点，并导致Prelamin A mRNA的框内缺失，并产生了一种显性阴性的Lamin A蛋白，称为孕激素。在这里，我们显示了原代HGPS皮肤成纤维细胞经历了全基因组范围内H3K27me3沉积模式的相关变化，DNA-lamin A/C关联，以及在传代后期，全基因组范围内活性和非活性染色质区域的空间区划的丧失。我们进一步证明了H3K27me3的变化与HGPS细胞中基因表达的变化有关。我们的结果支持一个模型，即核膜中孕激素的积累导致异染色质中H3K27me3标记的改变，可能是通过下调EZH2，并破坏异染色质-膜相互作用。这些变化可能导致转录失调，并最终引发晚期传代HGPS成纤维细胞空间染色质区域化的整体丧失。
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin–lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.
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