Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs
Cell signaling events triggered by androgen hormone in prostate cells is dependent on activation of the androgen receptor (AR) transcription factor. Androgen hormone binding to AR promotes its displacement from the cytoplasm to the nucleus and AR binding to DNA motifs, thus inducing activatory and i...
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| Format: | Article |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Genetics |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fgene.2018.00132/full |
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| author | Lucas F. daSilva Lucas F. daSilva Felipe C. Beckedorff Felipe C. Beckedorff Ana C. Ayupe Murilo S. Amaral Murilo S. Amaral Vinícius Mesel Alexandre Videira Alexandre Videira Eduardo M. Reis João C. Setubal João C. Setubal Sergio Verjovski-Almeida Sergio Verjovski-Almeida |
| author_facet | Lucas F. daSilva Lucas F. daSilva Felipe C. Beckedorff Felipe C. Beckedorff Ana C. Ayupe Murilo S. Amaral Murilo S. Amaral Vinícius Mesel Alexandre Videira Alexandre Videira Eduardo M. Reis João C. Setubal João C. Setubal Sergio Verjovski-Almeida Sergio Verjovski-Almeida |
| author_sort | Lucas F. daSilva |
| collection | DOAJ |
| description | Cell signaling events triggered by androgen hormone in prostate cells is dependent on activation of the androgen receptor (AR) transcription factor. Androgen hormone binding to AR promotes its displacement from the cytoplasm to the nucleus and AR binding to DNA motifs, thus inducing activatory and inhibitory transcriptional programs through a complex regulatory mechanism not yet fully understood. In this work, we performed RNA-seq deep-sequencing of LNCaP prostate cancer cells and found over 7000 expressed long intergenic non-coding RNAs (lincRNAs), of which ∼4000 are novel lincRNAs, and 258 lincRNAs have their expression activated by androgen. Immunoprecipitation of AR, followed by large-scale sequencing of co-immunoprecipitated RNAs (RIP-Seq) has identified in the LNCaP cell line a total of 619 lincRNAs that were significantly enriched (FDR < 10%, DESeq2) in the anti-Androgen Receptor (antiAR) fraction in relation to the control fraction (non-specific IgG), and we named them Androgen-Receptor-Associated lincRNAs (ARA-lincRNAs). A genome-wide analysis showed that protein-coding gene neighbors to ARA-lincRNAs had a significantly higher androgen-induced change in expression than protein-coding genes neighboring lincRNAs not associated to AR. To find relevant epigenetic signatures enriched at the ARA-lincRNAs’ transcription start sites (TSSs) we used a machine learning approach and identified that the ARA-lincRNA genomic loci in LNCaP cells are significantly enriched with epigenetic marks that are characteristic of in cis enhancer RNA regulators, and that the H3K27ac mark of active enhancers is conspicuously enriched at the TSS of ARA-lincRNAs adjacent to androgen-activated protein-coding genes. In addition, LNCaP topologically associating domains (TADs) that comprise chromatin regions with ARA-lincRNAs exhibit transcription factor contents, epigenetic marks and gene transcriptional activities that are significantly different from TADs not containing ARA-lincRNAs. This work highlights the possible involvement of hundreds of lincRNAs working in synergy with the AR on the genome-wide androgen-induced gene regulatory program in prostate cells. |
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| publishDate | 2018-04-01 |
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| spelling | doaj.art-b0acb982f933435783967a0aa8f18fcd2022-12-22T00:21:05ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-04-01910.3389/fgene.2018.00132354705Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAsLucas F. daSilva0Lucas F. daSilva1Felipe C. Beckedorff2Felipe C. Beckedorff3Ana C. Ayupe4Murilo S. Amaral5Murilo S. Amaral6Vinícius Mesel7Alexandre Videira8Alexandre Videira9Eduardo M. Reis10João C. Setubal11João C. Setubal12Sergio Verjovski-Almeida13Sergio Verjovski-Almeida14Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilLaboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilLaboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilLaboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, BrazilLaboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilLaboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilBiocomplexity Institute of Virginia Tech, Blacksburg, VA, United StatesDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, BrazilLaboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, BrazilCell signaling events triggered by androgen hormone in prostate cells is dependent on activation of the androgen receptor (AR) transcription factor. Androgen hormone binding to AR promotes its displacement from the cytoplasm to the nucleus and AR binding to DNA motifs, thus inducing activatory and inhibitory transcriptional programs through a complex regulatory mechanism not yet fully understood. In this work, we performed RNA-seq deep-sequencing of LNCaP prostate cancer cells and found over 7000 expressed long intergenic non-coding RNAs (lincRNAs), of which ∼4000 are novel lincRNAs, and 258 lincRNAs have their expression activated by androgen. Immunoprecipitation of AR, followed by large-scale sequencing of co-immunoprecipitated RNAs (RIP-Seq) has identified in the LNCaP cell line a total of 619 lincRNAs that were significantly enriched (FDR < 10%, DESeq2) in the anti-Androgen Receptor (antiAR) fraction in relation to the control fraction (non-specific IgG), and we named them Androgen-Receptor-Associated lincRNAs (ARA-lincRNAs). A genome-wide analysis showed that protein-coding gene neighbors to ARA-lincRNAs had a significantly higher androgen-induced change in expression than protein-coding genes neighboring lincRNAs not associated to AR. To find relevant epigenetic signatures enriched at the ARA-lincRNAs’ transcription start sites (TSSs) we used a machine learning approach and identified that the ARA-lincRNA genomic loci in LNCaP cells are significantly enriched with epigenetic marks that are characteristic of in cis enhancer RNA regulators, and that the H3K27ac mark of active enhancers is conspicuously enriched at the TSS of ARA-lincRNAs adjacent to androgen-activated protein-coding genes. In addition, LNCaP topologically associating domains (TADs) that comprise chromatin regions with ARA-lincRNAs exhibit transcription factor contents, epigenetic marks and gene transcriptional activities that are significantly different from TADs not containing ARA-lincRNAs. This work highlights the possible involvement of hundreds of lincRNAs working in synergy with the AR on the genome-wide androgen-induced gene regulatory program in prostate cells.http://journal.frontiersin.org/article/10.3389/fgene.2018.00132/fulllong intergenic non-coding RNAsandrogen receptorandrogen receptor associated lincRNAsgenome-wide profilingepigenetic marksLNCaP prostate cancer cell line |
| spellingShingle | Lucas F. daSilva Lucas F. daSilva Felipe C. Beckedorff Felipe C. Beckedorff Ana C. Ayupe Murilo S. Amaral Murilo S. Amaral Vinícius Mesel Alexandre Videira Alexandre Videira Eduardo M. Reis João C. Setubal João C. Setubal Sergio Verjovski-Almeida Sergio Verjovski-Almeida Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs Frontiers in Genetics long intergenic non-coding RNAs androgen receptor androgen receptor associated lincRNAs genome-wide profiling epigenetic marks LNCaP prostate cancer cell line |
| title | Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs |
| title_full | Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs |
| title_fullStr | Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs |
| title_full_unstemmed | Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs |
| title_short | Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs |
| title_sort | chromatin landscape distinguishes the genomic loci of hundreds of androgen receptor associated lincrnas from the loci of non associated lincrnas |
| topic | long intergenic non-coding RNAs androgen receptor androgen receptor associated lincRNAs genome-wide profiling epigenetic marks LNCaP prostate cancer cell line |
| url | http://journal.frontiersin.org/article/10.3389/fgene.2018.00132/full |
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