SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy.
SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy.
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DOI：
10.1101/gr.190660.115
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发表时间：
2015-12
期刊：
影响因子：
7
通讯作者：
Shay JW
中科院分区：
文献类型：
--
作者：
Robin JD;Ludlow AT;Batten K;Gaillard MC;Stadler G;Magdinier F;Wright WE;Shay JW
DNA被组织成复杂的三维染色质结构，但这种空间组织如何调节基因表达仍然是一个核心问题。这些DNA/染色质环结构的大小可以从10 - 20kb（增强子/抑制子）到染色体内和染色体间相互作用中的许多兆碱基。最近，端粒长度对衰老前染色质组织的影响揭示了远程染色质环的存在，该环决定了距离端粒10 Mb的基因的表达（端粒位置效应- over Long distance [TPE-OLD]）。在这里，我们证明了在4q35位点存在一个端粒环，涉及sorbin和含有SH3结构域的蛋白2基因，SORBS2，一种骨骼肌蛋白，使用染色体构象捕获方法的修饰。该环揭示了一个顺式作用机制，可以修饰SORBS2的转录。该基因的表达在患有与年龄相关的遗传性疾病——面肩肱肌营养不良症（FSHD1A, MIM 158900）的患者的成肌细胞中被TPE-OLD改变。SORBS2在端粒较短的FSHD成肌细胞中表达，而在端粒较长的FSHD成肌细胞或无论端粒长度如何的健康成肌细胞中均未检测到。这表明TPE-OLD可能在致病环境中改变4q35位点的调控。分化后，FSHD和健康肌管均表达SORBS2，这表明SORBS2通常在骨骼肌成熟/分化过程中上调，而在FSHD成肌细胞中，tpe - old依赖性变异会导致SORBS2的失调。这些发现为FSHD的复杂性和年龄相关症状提供了额外的见解。
DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10–20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect–Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD.