Ancestrally Duplicated Conserved Noncoding Element Suggests Dual Regulatory Roles of HOTAIR in cis and trans.

Chirag Nepal,Jesper B Andersen,Ferenc Müller,Yavor Hadzhiev,Piotr Mydel,Boris Lenhard,Sachin Pundhir,Andrzej Taranta

doi:10.1016/j.isci.2020.101008

Abstract

SummaryHOTAIR was proposed to regulate either HoxD cluster genes in trans or HoxC cluster genes in cis, a mechanism that remains unclear. We have identified a 32-nucleotide conserved noncoding element (CNE) as HOTAIR ancient sequence that likely originated at the root of vertebrate. The second round of whole-genome duplication resulted in one copy of the CNE within HOTAIR and another copy embedded in noncoding transcript of HOXD11. Paralogous CNEs underwent compensatory mutations, exhibit sequence complementarity with respect to transcripts directionality, and have high affinity in vitro. The HOTAIR CNE resembled a poised enhancer in stem cells and an active enhancer in HOTAIR-expressing cells. HOTAIR expression is positively correlated with HOXC11 in cis and negatively correlated with HOXD11 in trans. We propose a dual modality of HOTAIR regulation where transcription of HOTAIR and its embedded enhancer regulates HOXC11 in cis and sequence complementarity between paralogous CNEs suggests HOXD11 regulation in trans.

Highlights

Mammalian genomes are pervasively transcribed, giving rise to thousands of long noncoding RNAs (Hon et al, 2017; Iyer et al, 2015)
We have identified a 32nucleotide conserved noncoding element (CNE) as HOTAIR ancient sequence that likely originated at the root of vertebrate
The second round of wholegenome duplication resulted in one copy of the CNE within HOTAIR and another copy embedded in noncoding transcript of HOXD11

Summary

Introduction

Mammalian genomes are pervasively transcribed, giving rise to thousands of long noncoding RNAs (lncRNAs) (Hon et al, 2017; Iyer et al, 2015). Most early studies showed lncRNAs repress gene expression, some lncRNAs have enhancer-like functions and regulate genes in cis (Orom et al, 2010). Deletion of 12 genomic loci encoding various lncRNAs revealed 5 loci whose deletion affected the general process of transcription and enhancer-like activity, but no requirement for the lncRNA transcripts (Engreitz et al, 2016). Lincp locus previously thought to function through its RNA transcript was shown to include multiple enhancers and regulate genes in cis (Groff et al, 2016). Genomic and epigenomic functional annotation have revealed that most intergenic lncRNAs originate from enhancers (Hon et al, 2017). In line with enhancer function overlapping with lncRNAs, the Haunt lncRNA has dual roles (Yin et al, 2015), where its DNA encodes enhancers to activate HoxA genes and Haunt lncRNA prevents aberrant HoxA expression

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