对转录超保守区域的首次全面分析揭示了胶质瘤中新型非编码转录本的重要调控功能。

A first comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas.

作者信息

Gibert Myron K, Zhang Ying, Saha Shekhar, Marcinkiewicz Pawel, Dube Collin, Hudson Kadie, Sun Yunan, Bednarek Sylwia, Chagari Bilhan, Sarkar Aditya, Roig-Laboy Christian, Neace Natalie, Saoud Karim, Setiady Initha, Hanif Farina, Schiff David, Kumar Pankaj, Kefas Benjamin, Hafner Markus, Abounader Roger

机构信息

University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA.

University of Virginia Department of Neurology, Charlottesville, VA, 22908, USA.

出版信息

Res Sq. 2024 Apr 18:rs.3.rs-4164642. doi: 10.21203/rs.3.rs-4164642/v1.

DOI:10.21203/rs.3.rs-4164642/v1

PMID:38699302

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11065071/

Abstract

Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new oncogene. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.

摘要

转录超保守区域（TUCRs）代表了一类研究严重不足的假定非编码RNA（ncRNAs），它们在多个物种中100%保守。我们首次对胶质母细胞瘤（GBM）和低级别胶质瘤（LGG）中的TUCRs进行了分析。我们利用大型人类数据集来确定所有481个TUCRs的基因组位置、染色质可及性、转录、差异表达、与生存的相关性以及预测功能，并鉴定出与胶质瘤生物学相关的TUCRs。其中，我们研究了上调程度最高的基因间TUCR，即uc.110的表达、功能和作用机制，将其鉴定为一种新的癌基因。Uc.110在GBM和LGG中高度过表达，促进了恶性肿瘤和肿瘤生长。Uc.110通过上调膜卷曲相关蛋白（MFRP）的表达，以及通过与肿瘤抑制性微小RNA miR-544结合，激活了WNT信号通路。这项开创性研究表明TUCRs在胶质瘤中具有重要作用，并为未来的TUCR研究提供了一个广泛的数据库和新方法。