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HIF1α-AS1 是一种 DNA:DNA:RNA 三链形成的长非编码 RNA，与 HUSH 复合物相互作用。

HIF1α-AS1 is a DNA:DNA:RNA triplex-forming lncRNA interacting with the HUSH complex.

机构信息

Institute for Cardiovascular Physiology, Goethe University, Frankfurt, Germany.

German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.

出版信息

Nat Commun. 2022 Nov 2;13(1):6563. doi: 10.1038/s41467-022-34252-2.

DOI:10.1038/s41467-022-34252-2
PMID:36323673
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9630315/
Abstract

DNA

DNA:RNA triplexes that are formed through Hoogsteen base-pairing of the RNA in the major groove of the DNA duplex have been observed in vitro, but the extent to which these interactions occur in cells and how they impact cellular functions remains elusive. Using a combination of bioinformatic techniques, RNA/DNA pulldown and biophysical studies, we set out to identify functionally important DNA:DNA:RNA triplex-forming long non-coding RNAs (lncRNA) in human endothelial cells. The lncRNA HIF1α-AS1 was retrieved as a top hit. Endogenous HIF1α-AS1 reduces the expression of numerous genes, including EPH Receptor A2 and Adrenomedullin through DNA:DNA:RNA triplex formation by acting as an adapter for the repressive human silencing hub complex (HUSH). Moreover, the oxygen-sensitive HIF1α-AS1 is down-regulated in pulmonary hypertension and loss-of-function approaches not only result in gene de-repression but also enhance angiogenic capacity. As exemplified here with HIF1α-AS1, DNA:DNA:RNA triplex formation is a functionally important mechanism of trans-acting gene expression control.

摘要

DNA

RNA 三链体是通过 RNA 在 DNA 双螺旋的大沟中形成的 Hoogsteen 碱基配对形成的，已经在体外观察到，但这些相互作用在细胞中发生的程度以及它们如何影响细胞功能仍然难以捉摸。我们使用生物信息学技术、RNA/DNA 下拉和生物物理研究的组合，旨在鉴定人内皮细胞中具有功能重要性的 DNA:DNA:RNA 三链体形成的长非编码 RNA（lncRNA）。lncRNA HIF1α-AS1 被检索为顶级命中。内源性 HIF1α-AS1 通过充当抑制性人类沉默中心复合物（HUSH）的衔接物，降低包括 EPH 受体 A2 和肾上腺髓质素在内的许多基因的表达，通过 DNA:DNA:RNA 三链体形成。此外，氧气敏感的 HIF1α-AS1 在肺动脉高压中下调，功能丧失方法不仅导致基因去抑制，而且还增强血管生成能力。正如这里以 HIF1α-AS1 为例所示，DNA:DNA:RNA 三链体形成是一种功能重要的反式基因表达调控机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/23db25a495d0/41467_2022_34252_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/459df117beba/41467_2022_34252_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/b9f608bdc449/41467_2022_34252_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/f27074a475d7/41467_2022_34252_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/0637e6a33c90/41467_2022_34252_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/6ab6becc767e/41467_2022_34252_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/23db25a495d0/41467_2022_34252_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/459df117beba/41467_2022_34252_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/b9f608bdc449/41467_2022_34252_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/f27074a475d7/41467_2022_34252_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/0637e6a33c90/41467_2022_34252_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/6ab6becc767e/41467_2022_34252_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4356/9630315/23db25a495d0/41467_2022_34252_Fig6_HTML.jpg

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