Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes
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A Lot of HOTAIR: The roles of several classes of small (<50 nucleotides) noncoding RNAs are beginning to be defined in molecular detail, whereas the function of most of the long (∼200+ nucleotides), intergenic noncoding (linc)RNAs found in most eukaryotic genomes remains something of a mystery. The HOTAIR lincRNA, which is transcribed from the mouse HOXC locus, binds to the Polycomb Repressive Complex 2 (PRC2) and recruits it to HOXD and other genes, where its histone methylase activity acts to repress gene transcription. Tsai et al. (p. 689 , published online 8 July) now show that HOTAIR also binds to a histone demethylase enzyme, LSD1, part of the CoREST/REST repressor complex. LSD1 acts to remove transcription-activating histone marks, reinforcing the repressive activity of the PRC2 complex. HOTAIR thus functions as a platform for the coordinated binding of PRC2 and LSD1-containing complexes to genes, as revealed in a genome-wide analysis of PRC1/CoREST/REST co-regulated genes.
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Noncoding RNAs can regulate gene expression via translation or transcription of mRNAs, methylation of DNA and RNA, or as a modular scaffold of histone modification complexes.
“ncRNAs can regulate expression of genes via the translation or transcription of mRNAs, the methylation of DNA and RNA, or as a modular scaffold of histone modification complexes.219”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [219]
The Abstract (page unavailable) shows that the lincRNA HOTAIR acts as a modular scaffold for histone-modification complexes and links this activity to transcriptional silencing. It does not support the sentence’s additional claims about regulating mRNA translation or methylation of DNA or RNA; the methylation studied is of histones. (LLM, conf=0.88)
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“It seems that the lncRNA must serve two functions: (1) it must bind to a protein or protein complex, or at least facilitate the formation of a complex, perhaps acting as a scaffold [87]; and (2) the lncRNA must be able to target this complex to a specific DNA sequence.”
BackgroundBraveheart, a Long Noncoding RNA Required for Cardiovascular Lineage Commitment
Klattenhoff, C., Scheuermann, J. C., Surface, L. E., Bradley, R. K., Fields, P., Steinhauser, M. L., Ding, H., Butty, V. L., Sosa, L. T., Haas, S. F., et al. (2013) · Cell · doi:10.1016/j.cell.2013.01.003 · Cited by 910 · see citing works
“lncRNAs can act as molecular scaffolds by interacting with chromatin-modifying complexes (Guttman et al., 2011; Tsai et al., 2010).”
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“RNA pulldown was performed as described (Tsai et al., 2010).”
BackgroundNo-Nonsense Functions for Long Noncoding RNAs
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“Analysis of HOTAIR revealed that a 50 end domain binds PRC2 and a 30 end domain binds an LSD1 (H3K4me2 demethylase) containing complex (Tsai et al., 2010).”
BackgroundHistory, Discovery, and Classification of lncRNAs
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“This mechanism would be similar to that of the human HOX antisense intergenic RNA (HOTAIR RNA): this ncRNA mediates the assembly of different histone-modifying complexes and is necessary for their DNA binding and the resulting silencing of homeobox D cluster ( HOXD ) gene expressio”
Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesisPreprint
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BackgroundHOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer
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Non-coding RNAs as regulators of gene expression and epigenetics
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Integrated lncRNA function upon genomic and epigenomic regulation
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“In human cell lines, the HOTAIR lncRNA transcribed from the HOX C cluster inhibits transcription from HOX D cluster by guiding the recruitment of histone modifiers to specific chromatin in HOX D region [39,86,87].”
BackgroundLong Noncoding RNAs in Cardiovascular Diseases
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“From above results, authors proposed a model in which lincRNAs function as cell-type–specific flexible scaffolds to bring protein complexes (eg, epigenetic factors) to initiate transcriptional programs, which was previously proposed by Howard Chang’s group for HOTAIR.18 Of note, even low-expressed lncRNAs may exhibit…”
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The Long Noncoding RNAs NEAT1 and MALAT1 Bind Active Chromatin Sites
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Evolutionary conservation of long non-coding RNAs; sequence, structure, function
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Gene regulation in the immune system by long noncoding RNAs
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Self-citationGenome-Wide Analysis Uncovers Regulation of Long Intergenic Noncoding RNAs in Arabidopsis
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“Emerging evidence supports the view that lincRNAs play important roles in many fundamental biological processes (Hekimoglu and Ringrose, 2009; Chen and Carmichael, 2010; Tsai et al., 2010; K.C. Wang et al., 2011; Cabianca et al., 2012).”
BackgroundHow do lncRNAs regulate transcription?
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Multiple knockout mouse models reveal lincRNAs are required for life and brain development
Sauvageau, M., Goff, L. A., Lodato, S., Bonev, B., Groff, A. F., Gerhardinger, C., Sanchez-Gomez, D. B., Hacisuleyman, E., Li, E. V., Spence, M. C., et al. (2013) · eLife · doi:10.7554/elife.01749 · Cited by 674 · see citing works
“pluripotency) and regulating cell cycle and translation (Tsai et al., 2010; Guttman et al., 2011; Wang et al., 2011; Yoon et al., 2012).”
NONCODE 2016: an informative and valuable data source of long non-coding RNAs
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“[0-15] MEG3”
Functional interactions among microRNAs and long noncoding RNAs
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lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs
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“Biotin-labeled PCGEM1 RNA (14-1556) and PRNCR1 RNA fragments (1-3240, 3156-6428, 6331-9670 and 9531-12710) were in vitro transcribed with the Biotin RNA Labeling Mix (Roche) and T7 or SP6 RNA polymerase (Promega) and purified with RNeasy® Mini Kit (QIAGEN).”
MethodLong noncoding RNAs in cancer metastasis
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Long Intergenic Noncoding RNAs: New Links in Cancer Progression
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“LincRNAs such as HOTAIR serve as a structural scaffold for protein complexes and possess complex RNA structural motifs (21).”
BackgroundInfluentialSelf-citationEmerging functional and mechanistic paradigms of mammalian long non-coding RNAs
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“HOTAIR guides as well as serves as a scaffold for PRC2 and LSD1/CoREST complexes at their endogenous target genes (54).”
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“Notably, accumulating evidence shows that lncRNAsmodulate gene expression as epigenetic modifiers (Kaneko et al., 2014; Klattenhoff et al., 2013; Prensner et al., 2013; Tsai et al., 2010; Zhu et al., 2013).”
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“Recent studies have reported that lncRNAs recruit polycomb-group proteins to target genes.(12,20) Twenty percent of all human lncRNAs have been shown to physically associate with Polycomb Repressive Complex 2 (PRC2 complex),(23) suggesting that lncRNAs may have a general role in recruiting polycomb-group proteins to t…”
BackgroundMethodTopological organization of multichromosomal regions by the long intergenic noncoding RNA Firre
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Posttranscriptional Gene Regulation by Long Noncoding RNA
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Non-coding RNAs as regulators of embryogenesis
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“107 ) and the H3K4me2/3-demethylating lysine-specific demethylase1 (LSD1)–CoREST–REST comple”
Readers of histone modifications
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The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer
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Targeting RNA structures with small molecules
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“…genes in trans by associating with chromatin modification complexes such as PRC2, LSD1, and CoREST/REST (Khalil et al., 2009; Rinn et al., 2007; Tsai et al., 2010) and to be overexpressed in breast cancer and regulate metastasis by reprogramming chromatin via polycomb complexes (Gupta et al.,…”
BackgroundThe long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL
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“LincRNAs are thought to function primarily through specific interactions with cellular proteins, and a panel of these proteins have been identified (6, 10, 11, 15, 16).”
BackgroundLong non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression
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Long non-coding RNAs and complex diseases: from experimental results to computational models
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Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease
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NONCODEV5: a comprehensive annotation database for long non-coding RNAs
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“Ezh2 enhances methylation of H3K27, leading to gene silencing involved in cancer progression and metastasis (35).”
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“also showed that HOTAIR physically interacts with PRC2 to selectively inhibit gene expression [13].”
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“Deletions of microRNA-101, a negative regulator of EZH2 expression, have been described in prostate cancer, thus providing a mechanism for EZH2 overexpression (32).”
BackgroundInfluential
- Authors
- Tsai, M.-C., Manor, O., Wan, Y., Mosammaparast, N., Wang, J. K., Lan, F., Shi, Y., Segal, E., & Chang, H. Y.
- Affiliations
- Howard Hughes Medical Institute (US)
- Weizmann Institute of Science (IL)
- Boston Children's Hospital (US)
- Corresponding author
- Chang, Howard Y.
- ORCID
- Venue
- Science
- Published
- 2010-08-06
- Volume
- 329
- Issue
- 5992
- Pages
- 689-693
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2967777
- OpenAlex
- W2126504590
- Cited by
- 3,290
- References
- 28
- Citations by year
- 2026: 70 · 2025: 90 · 2024: 128 · 2023: 150 · 2022: 192 · 2021: 276 · 2020: 247 · 2019: 221 · 2018: 249 · 2017: 288 · 2016: 251 · 2015: 302 · 2014: 267 · 2013: 244 · 2012: 155
- FWCI
- 55.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01ca119176-10)
- National Human Genome Research Institute (R01HG004361)
- National Cancer Institute (R01CA118487, R01-CA119176, R01CA118750)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- HOTAIR, long intergenic non-coding RNA, polycomb repressive complex 2, LSD1, histone demethylation, histone methylation, transcriptional repression, PRC1, co-regulated genes
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, RE1-Silencing Transcription Factor, Binding Sites, Carrier Proteins, Cell Line, Cells, Cultured, Chromatin, DNA-Binding Proteins, HeLa Cells, Histones, Humans, Methylation, Mutation, Neoplasm Proteins, Nerve Tissue Proteins, Nuclear Proteins, Nucleic Acid Conformation, Promoter Regions, Genetic, Protein Binding, Repressor Proteins, Transcription Factors, Transcription, Genetic, RNA, Untranslated, RNA Interference, Chromatin Immunoprecipitation, Histone Demethylases, Co-Repressor Proteins, Polycomb-Group Proteins, Polycomb Repressive Complex 2
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