Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements
Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements
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DOI：
10.1038/sj.onc.1209268
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发表时间：
2006-04-13
期刊：
影响因子：
8
通讯作者：
Nikiforov, YE
中科院分区：
文献类型：
--
作者：
Gandhi, M;Medvedovic, M;Nikiforov, YE
复发性染色体重排在癌细胞中很常见，并且可能受到细胞核中重组倾向遗传基因座的非随机定位的影响。然而，负责特定位点的空间接近的机制是未知的。在这项研究中，我们使用10q11.2-21上的18 Mb区域，包含RET基因及其重组伙伴，H4和NCOA 4（ELE 1）基因，作为甲状腺癌中经常涉及RET/PTC重排的模型染色体区域。RET/PTC在暴露于电离辐射的儿童肿瘤中特别常见。使用荧光原位杂交和三维显微镜，定位。在正常人甲状腺细胞的间期核中定位了该区域的五个不同位点。我们发现RET和NCOA 4比基于其基因组分离的预期更接近彼此。在该区域中的染色体折叠的建模表明存在具有长度类似于8 Mb的线圈的染色体卷曲，其将RET基因定位在靠近NCOA 4和H4基因座两者的位置。成人和儿童甲状腺细胞之间的基因接近度没有显着变化。这项研究提供了大规模的染色体折叠的10q11.2-21区域，提供了一个结构基础的非随机定位和空间接近的潜在重组基因的染色体内位点的证据。
Recurrent chromosomal rearrangements are common in cancer cells and may be influenced by nonrandom positioning of recombination-prone genetic loci in the nucleus. However, the mechanism responsible for spatial proximity of specific loci is unknown. In this study, we use an 18Mb region on 10q11.2-21 containing the RET gene and its recombination partners, the H4 and NCOA4 (ELE1) genes, as a model chromosomal region frequently involved in RET/PTC rearrangements in thyroid cancer. RET/PTC is particularly common in tumors from children exposed to ionizing radiation. Using fluorescence in situ hybridization and three-dimensional microscopy, the locations of. five different loci in this region were mapped in interphase nuclei of normal human thyroid cells. We show that RET and NCOA4 are much closer to each other than expected based on their genomic separation. Modeling of chromosome folding in this region suggests the presence of chromosome coiling with coils of similar to 8Mb in length, which positions the RET gene close to both, the NCOA4 and H4, loci. There was no significant variation in gene proximity between adult and pediatric thyroid cells. This study provides evidence for large-scale chromosome folding of the 10q11.2-21 region that offers a structural basis for nonrandom positioning and spatial proximity of potentially recombinogenic intrachromosomal loci.