Departamento Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Instituto Investigación Sanitaria Puerta de Hierro-Majadahonda, 28222 Madrid, Spain.
Int J Mol Sci. 2020 May 12;21(10):3410. doi: 10.3390/ijms21103410.
Friedreich´s ataxia (FRDA) is an autosomal recessive disease caused by an abnormally expanded Guanine-Adenine-Adenine (GAA) repeat sequence within the first intron of the frataxin gene ). The molecular mechanisms associated with FRDA are still poorly understood and most studies on gene regulation have been focused on the region around the minimal promoter and the region in which triplet expansion occurs. Nevertheless, since there could be more epigenetic changes involved in the reduced levels of transcripts, the aim of this study was to obtain a more detailed view of the possible regulatory elements by analyzing data from ENCODE and Roadmap consortia databases. This bioinformatic analysis indicated new putative regulatory regions within the genomic locus, including exons, introns, and upstream and downstream regions. Moreover, the region next to the end of intron 4 is of special interest, since the enhancer signals in FRDA-affected tissues are weak or absent in this region, whilst they are strong in the rest of the analyzed tissues. Therefore, these results suggest that there could be a direct relationship between the absence of enhancer sequences in this specific region and their predisposition to be affected in this pathology.
弗里德赖希共济失调（FRDA）是一种常染色体隐性疾病，由 frataxin 基因第一内含子中异常扩展的鸟嘌呤-腺嘌呤-腺嘌呤（GAA）重复序列引起。与 FRDA 相关的分子机制仍知之甚少，大多数关于基因调控的研究都集中在最小启动子区域和三核苷酸扩展发生的区域。然而，由于在转录物水平降低的情况下可能涉及更多的表观遗传变化，因此本研究的目的是通过分析 ENCODE 和 Roadmap 联盟数据库的数据，获得对可能的调控元件的更详细的了解。该生物信息学分析表明，在基因组基因座内存在新的推定调控区域，包括外显子、内含子以及上下游区域。此外，紧邻 4 号内含子末端的区域特别有趣，因为在受影响的组织中，增强子信号在该区域较弱或不存在，而在其余分析的组织中则较强。因此，这些结果表明，在该特定区域缺乏增强子序列与其在该病理中易受影响之间可能存在直接关系。
