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High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity
Transcription initiates at both coding and noncoding genomic elements, including mRNA and long noncoding RNA (lncRNA) core promoters and enhancer RNAs (eRNAs). However, each class has a different expression profile with lncRNAs and eRNAs being the most tissue specific. How these complex differences...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396428/ https://www.ncbi.nlm.nih.gov/pubmed/30683753 http://dx.doi.org/10.1101/gr.242222.118 |
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author | Mattioli, Kaia Volders, Pieter-Jan Gerhardinger, Chiara Lee, James C. Maass, Philipp G. Melé, Marta Rinn, John L. |
author_facet | Mattioli, Kaia Volders, Pieter-Jan Gerhardinger, Chiara Lee, James C. Maass, Philipp G. Melé, Marta Rinn, John L. |
author_sort | Mattioli, Kaia |
collection | PubMed |
description | Transcription initiates at both coding and noncoding genomic elements, including mRNA and long noncoding RNA (lncRNA) core promoters and enhancer RNAs (eRNAs). However, each class has a different expression profile with lncRNAs and eRNAs being the most tissue specific. How these complex differences in expression profiles and tissue specificities are encoded in a single DNA sequence remains unresolved. Here, we address this question using computational approaches and massively parallel reporter assays (MPRA) surveying hundreds of promoters and enhancers. We find that both divergent lncRNA and mRNA core promoters have higher capacities to drive transcription than nondivergent lncRNA and mRNA core promoters, respectively. Conversely, intergenic lncRNAs (lincRNAs) and eRNAs have lower capacities to drive transcription and are more tissue specific than divergent genes. This higher tissue specificity is strongly associated with having less complex transcription factor (TF) motif profiles at the core promoter. We experimentally validated these findings by testing both engineered single-nucleotide deletions and human single-nucleotide polymorphisms (SNPs) in MPRA. In both cases, we observe that single nucleotides associated with many motifs are important drivers of promoter activity. Thus, we suggest that high TF motif density serves as a robust mechanism to increase promoter activity at the expense of tissue specificity. Moreover, we find that 22% of common SNPs in core promoter regions have significant regulatory effects. Collectively, our findings show that high TF motif density provides redundancy and increases promoter activity at the expense of tissue specificity, suggesting that specificity of expression may be regulated by simplicity of motif usage. |
format | Online Article Text |
id | pubmed-6396428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63964282019-03-18 High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity Mattioli, Kaia Volders, Pieter-Jan Gerhardinger, Chiara Lee, James C. Maass, Philipp G. Melé, Marta Rinn, John L. Genome Res Research Transcription initiates at both coding and noncoding genomic elements, including mRNA and long noncoding RNA (lncRNA) core promoters and enhancer RNAs (eRNAs). However, each class has a different expression profile with lncRNAs and eRNAs being the most tissue specific. How these complex differences in expression profiles and tissue specificities are encoded in a single DNA sequence remains unresolved. Here, we address this question using computational approaches and massively parallel reporter assays (MPRA) surveying hundreds of promoters and enhancers. We find that both divergent lncRNA and mRNA core promoters have higher capacities to drive transcription than nondivergent lncRNA and mRNA core promoters, respectively. Conversely, intergenic lncRNAs (lincRNAs) and eRNAs have lower capacities to drive transcription and are more tissue specific than divergent genes. This higher tissue specificity is strongly associated with having less complex transcription factor (TF) motif profiles at the core promoter. We experimentally validated these findings by testing both engineered single-nucleotide deletions and human single-nucleotide polymorphisms (SNPs) in MPRA. In both cases, we observe that single nucleotides associated with many motifs are important drivers of promoter activity. Thus, we suggest that high TF motif density serves as a robust mechanism to increase promoter activity at the expense of tissue specificity. Moreover, we find that 22% of common SNPs in core promoter regions have significant regulatory effects. Collectively, our findings show that high TF motif density provides redundancy and increases promoter activity at the expense of tissue specificity, suggesting that specificity of expression may be regulated by simplicity of motif usage. Cold Spring Harbor Laboratory Press 2019-03 /pmc/articles/PMC6396428/ /pubmed/30683753 http://dx.doi.org/10.1101/gr.242222.118 Text en © 2019 Mattioli et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Mattioli, Kaia Volders, Pieter-Jan Gerhardinger, Chiara Lee, James C. Maass, Philipp G. Melé, Marta Rinn, John L. High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity |
title | High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity |
title_full | High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity |
title_fullStr | High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity |
title_full_unstemmed | High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity |
title_short | High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity |
title_sort | high-throughput functional analysis of lncrna core promoters elucidates rules governing tissue specificity |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396428/ https://www.ncbi.nlm.nih.gov/pubmed/30683753 http://dx.doi.org/10.1101/gr.242222.118 |
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