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Nucleic Acids Res. 2016 Dec 15;44(22):10631-10643. Epub 2016 Sep 14.

The lncRNA HOTAIR impacts on mesenchymal stem cells via triple helix formation.

Author information

1
Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH University Medical School, Aachen 52074, Germany.
2
Institute for Biomedical Technology - Cell Biology, RWTH University Medical School, Aachen 52074, Germany.
3
Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH University Medical School, Aachen 52074, Germany.
4
Institute of Organic Chemistry, RWTH Aachen University, Aachen 52056, Germany.
5
Department for Orthopedics, RWTH Aachen University Medical School, Aachen 52074, Germany.
6
Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, Bonn 53127, Germany.
7
Department of Women's Cancer, University College London Elizabeth Garrett Anderson Institute for Women's Health, University College London, London WC1E 6AU, UK.
8
Statistical Genomics Group, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
9
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
10
CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai 200031, China.
11
Institute for Biomedical Technology - Cell Biology, RWTH University Medical School, Aachen 52074, Germany ivan.costa@rwth-aachen.de.
12
Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH University Medical School, Aachen 52074, Germany wwagner@ukaachen.de.

Abstract

There is a growing perception that long non-coding RNAs (lncRNAs) modulate cellular function. In this study, we analyzed the role of the lncRNA HOTAIR in mesenchymal stem cells (MSCs) with particular focus on senescence-associated changes in gene expression and DNA-methylation (DNAm). HOTAIR binding sites were enriched at genomic regions that become hypermethylated with increasing cell culture passage. Overexpression and knockdown of HOTAIR inhibited or stimulated adipogenic differentiation of MSCs, respectively. Modification of HOTAIR expression evoked only very moderate effects on gene expression, particularly of polycomb group target genes. Furthermore, overexpression and knockdown of HOTAIR resulted in DNAm changes at HOTAIR binding sites. Five potential triple helix forming domains were predicted within the HOTAIR sequence based on reverse Hoogsteen hydrogen bonds. Notably, the predicted triple helix target sites for these HOTAIR domains were also enriched in differentially expressed genes and close to DNAm changes upon modulation of HOTAIR Electrophoretic mobility shift assays provided further evidence that HOTAIR domains form RNA-DNA-DNA triplexes with predicted target sites. Our results demonstrate that HOTAIR impacts on differentiation of MSCs and that it is associated with senescence-associated DNAm. Targeting of epigenetic modifiers to relevant loci in the genome may involve triple helix formation with HOTAIR.

PMID:
27634931
PMCID:
PMC5159544
DOI:
10.1093/nar/gkw802
[Indexed for MEDLINE]
Free PMC Article

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