Human Genetics Program and Department of Biochemistry and Tulane Cancer Center, Tulane Medical School, New Orleans, LA 70112, USA.
Nucleic Acids Res. 2009 Dec;37(22):7381-93. doi: 10.1093/nar/gkp833.
A subtelomeric region, 4q35.2, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant disease thought to involve local pathogenic changes in chromatin. FSHD patients have too few copies of a tandem 3.3-kb repeat (D4Z4) at 4q35.2. No phenotype is associated with having few copies of an almost identical repeat at 10q26.3. Standard expression analyses have not given definitive answers as to the genes involved. To investigate the pathogenic effects of short D4Z4 arrays on gene expression in the very gene-poor 4q35.2 and to find chromatin landmarks there for transcription control, unannotated genes and chromatin structure, we mapped DNaseI-hypersensitive (DH) sites in FSHD and control myoblasts. Using custom tiling arrays (DNase-chip), we found unexpectedly many DH sites in the two large gene deserts in this 4-Mb region. One site was seen preferentially in FSHD myoblasts. Several others were mapped >0.7 Mb from genes known to be active in the muscle lineage and were also observed in cultured fibroblasts, but not in lymphoid, myeloid or hepatic cells. Their selective occurrence in cells derived from mesoderm suggests functionality. Our findings indicate that the gene desert regions of 4q35.2 may have functional significance, possibly also to FSHD, despite their paucity of known genes.
一个端粒区域，4q35.2，与面肩肱型肌营养不良症（FSHD）有关，这种显性疾病被认为涉及染色质的局部致病性变化。FSHD 患者在 4q35.2 处的串联 3.3kb 重复序列（D4Z4）拷贝数过少。10q26.3 处几乎相同的重复序列拷贝数过少与任何表型都没有关联。标准表达分析未能明确确定涉及的基因。为了研究短 D4Z4 阵列对基因表达的致病影响，以及在基因非常稀少的 4q35.2 中找到转录控制的染色质标志，我们在 FSHD 和对照成肌细胞中绘制了 DNaseI 超敏（DH）位点。使用定制的平铺阵列（DNase-chip），我们在这个 4Mb 区域的两个大基因荒漠中发现了出乎意料多的 DH 位点。一个位点在 FSHD 成肌细胞中优先出现。其他几个位点位于已知在肌肉谱系中活跃的基因 0.7Mb 以上，也在培养的成纤维细胞中观察到，但不在淋巴样、骨髓样或肝细胞中观察到。它们在从中胚层衍生的细胞中选择性出现表明其具有功能性。我们的研究结果表明，尽管 4q35.2 的基因荒漠区域缺乏已知基因，但它们可能具有功能意义，也可能与 FSHD 有关。
