Department of Ophthalmology, Duke University, Duke Eye Center AERI Rm 4014, Durham, NC 27710, USA.
Duke Molecular Physiology Institute, Duke University, Durham, NC 27701 USA.
Hum Mol Genet. 2020 Jul 29;29(12):1986-1995. doi: 10.1093/hmg/ddaa021.
Individuals with pseudoexfoliation (PEX) syndrome exhibit various connective tissue pathologies associated with dysregulated extracellular matrix homeostasis. PEX glaucoma is a common, aggressive form of open-angle glaucoma resulting from the deposition of fibrillary material in the conventional outflow pathway. However, the molecular mechanisms that drive pathogenesis and genetic risk remain poorly understood. PEX glaucoma-associated single-nucleotide polymorphisms are located in and affect activity of the promoter of LOXL1-AS1, a long non-coding RNA (lncRNA). Nuclear and non-nuclear lncRNAs regulate a host of biological processes, and when dysregulated, contribute to disease. Here we report that LOXL1-AS1 localizes to the nucleus where it selectively binds to the mRNA processing protein, heterogeneous nuclear ribonucleoprotein-L (hnRNPL). Both components of this complex are critical for the regulation of global gene expression in ocular cells, making LOXL1-AS1 a prime target for investigation in PEX syndrome and glaucoma.
患有假性剥脱（PEX）综合征的个体表现出各种与细胞外基质稳态失调相关的结缔组织病理学。PEX 性青光眼是一种常见的、侵袭性的开角型青光眼，其发生是由于纤维状物质在传统的流出道中沉积。然而，导致发病机制和遗传风险的分子机制仍知之甚少。与 PEX 性青光眼相关的单核苷酸多态性位于 LOXL1-AS1 启动子的区域内，并影响其活性，LOXL1-AS1 是一种长非编码 RNA（lncRNA）。核内和核外 lncRNA 调节着一系列的生物学过程，当它们失调时，会导致疾病。在这里，我们报告 LOXL1-AS1 定位于细胞核内，在那里它选择性地结合到 mRNA 加工蛋白异质核核糖核蛋白-L（hnRNPL）上。该复合物的两个组成部分对于眼部细胞中全局基因表达的调控至关重要，这使得 LOXL1-AS1 成为 PEX 综合征和青光眼研究的主要目标。
