Petrov Andrei, Pirozhkova Iryna, Carnac Gilles, Laoudj Dalila, Lipinski Marc, Vassetzky Yegor S
Interactions Moléculaires et Cancer, Unité Mixte de Recherche 8126, Centre National de la Recherche Scientifique-Université Paris-Sud 11-Institut Gustave-Roussy, F-94805 Villejuif, France.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):6982-7. doi: 10.1073/pnas.0511235103. Epub 2006 Apr 21.
Fascioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder linked to partial deletion of integral numbers of a 3.3 kb polymorphic repeat, D4Z4, within the subtelomeric region of chromosome 4q. Although the relationship between deletions of D4Z4 and FSHD is well established, how this triggers the disease remains unclear. We have mapped the DNA loop domain containing the D4Z4 repeat cluster in human primary myoblasts and in murine-human hybrids. A nuclear matrix attachment site was found located in the vicinity of the repeat. Prominent in normal human myoblasts and nonmuscular human cells, this site is much weaker in muscle cells derived from FSHD patients, suggesting that the D4Z4 repeat array and upstream genes reside in two loops in nonmuscular cells and normal human myoblasts but in only one loop in FSHD myoblasts. We propose a model whereby the nuclear scaffold/matrix attached region regulates chromatin accessibility and expression of genes implicated in the genesis of FSHD.
面肩肱型肌营养不良症（FSHD）是一种常染色体显性神经肌肉疾病，与4号染色体长臂亚端粒区域内3.3kb多态性重复序列D4Z4的整数倍部分缺失有关。虽然D4Z4缺失与FSHD之间的关系已得到充分证实，但这种缺失如何引发疾病仍不清楚。我们已在人原代成肌细胞和鼠 - 人杂交细胞中绘制出包含D4Z4重复簇的DNA环结构域。在重复序列附近发现了一个核基质附着位点。该位点在正常人成肌细胞和非肌肉人类细胞中很显著，但在FSHD患者来源的肌肉细胞中则弱得多，这表明D4Z4重复序列阵列和上游基因在非肌肉细胞和正常人成肌细胞中位于两个环中，而在FSHD成肌细胞中仅位于一个环中。我们提出了一个模型，即核支架/基质附着区域调节与FSHD发病机制相关基因的染色质可及性和表达。
