Ancestrally Duplicated Conserved Noncoding Element Suggests Dual Regulatory Roles of HOTAIR in cis and trans
Chirag Nepal,
Andrzej Taranta,
Yavor Hadzhiev,
Sachin Pundhir,
Piotr Mydel,
Boris Lenhard,
Ferenc Müller,
Jesper B. Andersen
Affiliations
Chirag Nepal
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark; Corresponding author
Andrzej Taranta
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
Yavor Hadzhiev
Institute of Cancer and Genomics Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B15 2TT Birmingham, UK
Sachin Pundhir
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
Piotr Mydel
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, and Malopolska Centre of Biotechnology, Jagiellonian University, Karkow, Poland
Boris Lenhard
Institute of Clinical Sciences MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; Sars International Centre for Marine Molecular Biology, University of Bergen, 5008, Bergen, Norway
Ferenc Müller
Institute of Cancer and Genomics Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B15 2TT Birmingham, UK; Corresponding author
Jesper B. Andersen
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark; Corresponding author
Summary: HOTAIR 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. : Biological Sciences; Molecular Biology; Molecular Mechanism of Gene Regulation Subject Areas: Biological Sciences, Molecular Biology, Molecular Mechanism of Gene Regulation
