A large fraction of extragenic RNA pol II transcription sites overlap enhancers
| Autor: | Gioacchino Natoli, Francesca De Santa, Flore Mietton, Chia-Lin Wei, Iros Barozzi, Betsabeh Khoramian Tusi, Sara Polletti, Heiko Muller, Serena Ghisletti, Jiannis Ragoussis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Lipopolysaccharides
RNA Untranslated Transcription Genetic QH301-705.5 Immunology/Innate Immunity Enhancer RNAs RNA polymerase II Regulatory Sequences Nucleic Acid Biology Molecular Biology/Histone Modification General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Transcription (biology) Genetics and Genomics/Epigenetics Transcriptional regulation Animals Humans Cell Biology/Leukocyte Signaling and Gene Expression Biology (General) Promoter Regions Genetic Enhancer Gene Transcription factor Cell Biology/Gene Expression 030304 developmental biology Genetics 0303 health sciences Binding Sites General Immunology and Microbiology General Neuroscience Macrophage Activation Non-coding RNA Gene Expression Regulation 030220 oncology & carcinogenesis biology.protein Female RNA Polymerase II General Agricultural and Biological Sciences Research Article |
| Zdroj: | PLoS Biology, Vol 8, Iss 5, p e1000384 (2010) PLoS Biology PLoS Biology; Vol 8 |
| Popis: | A substantial fraction of extragenic Pol II transcription sites coincides with transcriptional enhancers, which may be relevant for functional annotation of mammalian genomes. Mammalian genomes are pervasively transcribed outside mapped protein-coding genes. One class of extragenic transcription products is represented by long non-coding RNAs (lncRNAs), some of which result from Pol_II transcription of bona-fide RNA genes. Whether all lncRNAs described insofar are products of RNA genes, however, is still unclear. Here we have characterized transcription sites located outside protein-coding genes in a highly regulated response, macrophage activation by endotoxin. Using chromatin signatures, we could unambiguously classify extragenic Pol_II binding sites as belonging to either canonical RNA genes or transcribed enhancers. Unexpectedly, 70% of extragenic Pol_II peaks were associated with genomic regions with a canonical chromatin signature of enhancers. Enhancer-associated extragenic transcription was frequently adjacent to inducible inflammatory genes, was regulated in response to endotoxin stimulation, and generated very low abundance transcripts. Moreover, transcribed enhancers were under purifying selection and contained binding sites for inflammatory transcription factors, thus suggesting their functionality. These data demonstrate that a large fraction of extragenic Pol_II transcription sites can be ascribed to cis-regulatory genomic regions. Discrimination between lncRNAs generated by canonical RNA genes and products of transcribed enhancers will provide a framework for experimental approaches to lncRNAs and help complete the annotation of mammalian genomes. Author Summary Mammalian genomes contain vast intergenic regions that are extensively transcribed and generate various types of short and long non-coding RNAs (ncRNAs). Although in some cases specific functions have been assigned to intergenic transcripts, the functional significance of this transcriptional output remains largely unknown, and the possibility exists that part of this transcription reflects noise generated by random collisions of the transcriptional machinery with the genome to generate meaningless transcription. In this study we used chromatin signatures to characterize extragenic transcription sites targeted by RNA Polymerase II (RNA Pol II) in a highly regulated response—endotoxin activation of macrophages. We found that a significant portion of extragenic transcription sites are associated with the chromatin signature characteristic of enhancers. Consistent with their chromatin signature, we found that these extragenic transcription sites are under purifying selection and contain binding sites for inflammatory transcription factors, as well as for PU.1, a hematopoietic transcription factor that marks enhancers in macrophages. Moreover, much of this extragenic transcription is regulated by stimulation. We also identified hundreds of transcribed regions with a signature of canonical RNA genes. Our data indicate that extragenic transcription sites can be efficiently classified using chromatin signatures, which will be relevant for functional annotation of mammalian genomes. |
| Databáze: | OpenAIRE |
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