Enhancers in the Peril lincRNA locus regulate distant but not local genes
Abstract Background Recently, it has become clear that some promoters function as long-range regulators of gene expression. However, direct and quantitative assessment of enhancer activity at long intergenic noncoding RNA (lincRNA) or mRNA gene bodies has not been performed. To unbiasedly assess the...
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doaj-1a21e73afd074263a18e41a2df8460062020-11-25T02:01:42ZengBMCGenome Biology1474-760X2018-12-0119111410.1186/s13059-018-1589-8Enhancers in the Peril lincRNA locus regulate distant but not local genesAbigail F. Groff0A. Rasim Barutcu1Jordan P. Lewandowski2John L. Rinn3Department of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityAbstract Background Recently, it has become clear that some promoters function as long-range regulators of gene expression. However, direct and quantitative assessment of enhancer activity at long intergenic noncoding RNA (lincRNA) or mRNA gene bodies has not been performed. To unbiasedly assess the enhancer capacity across lincRNA and mRNA loci, we performed a massively parallel reporter assay (MPRA) on six lincRNA loci and their closest protein-coding neighbors. Results For both gene classes, we find significantly more MPRA activity in promoter regions than in gene bodies. However, three lincRNA loci, Lincp21, LincEnc1, and Peril, and one mRNA locus, Morc2a, display significant enhancer activity within their gene bodies. We hypothesize that such peaks may mark long-range enhancers, and test this in vivo using RNA sequencing from a knockout mouse model and high-throughput chromosome conformation capture (Hi-C). We find that ablation of a high-activity MPRA peak in the Peril gene body leads to consistent dysregulation of Mccc1 and Exosc9 in the neighboring topologically associated domain (TAD). This occurs irrespective of Peril lincRNA expression, demonstrating this regulation is DNA-dependent. Hi-C confirms long-range contacts with the neighboring TAD, and these interactions are altered upon Peril knockout. Surprisingly, we do not observe consistent regulation of genes within the local TAD. Together, these data suggest a long-range enhancer-like function for the Peril gene body. Conclusions A multi-faceted approach combining high-throughput enhancer discovery with genetic models can connect enhancers to their gene targets and provides evidence of inter-TAD gene regulation.http://link.springer.com/article/10.1186/s13059-018-1589-8lincRNAMouse modelsMPRACis-regulationEnhancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Abigail F. Groff A. Rasim Barutcu Jordan P. Lewandowski John L. Rinn |
spellingShingle |
Abigail F. Groff A. Rasim Barutcu Jordan P. Lewandowski John L. Rinn Enhancers in the Peril lincRNA locus regulate distant but not local genes Genome Biology lincRNA Mouse models MPRA Cis-regulation Enhancer |
author_facet |
Abigail F. Groff A. Rasim Barutcu Jordan P. Lewandowski John L. Rinn |
author_sort |
Abigail F. Groff |
title |
Enhancers in the Peril lincRNA locus regulate distant but not local genes |
title_short |
Enhancers in the Peril lincRNA locus regulate distant but not local genes |
title_full |
Enhancers in the Peril lincRNA locus regulate distant but not local genes |
title_fullStr |
Enhancers in the Peril lincRNA locus regulate distant but not local genes |
title_full_unstemmed |
Enhancers in the Peril lincRNA locus regulate distant but not local genes |
title_sort |
enhancers in the peril lincrna locus regulate distant but not local genes |
publisher |
BMC |
series |
Genome Biology |
issn |
1474-760X |
publishDate |
2018-12-01 |
description |
Abstract Background Recently, it has become clear that some promoters function as long-range regulators of gene expression. However, direct and quantitative assessment of enhancer activity at long intergenic noncoding RNA (lincRNA) or mRNA gene bodies has not been performed. To unbiasedly assess the enhancer capacity across lincRNA and mRNA loci, we performed a massively parallel reporter assay (MPRA) on six lincRNA loci and their closest protein-coding neighbors. Results For both gene classes, we find significantly more MPRA activity in promoter regions than in gene bodies. However, three lincRNA loci, Lincp21, LincEnc1, and Peril, and one mRNA locus, Morc2a, display significant enhancer activity within their gene bodies. We hypothesize that such peaks may mark long-range enhancers, and test this in vivo using RNA sequencing from a knockout mouse model and high-throughput chromosome conformation capture (Hi-C). We find that ablation of a high-activity MPRA peak in the Peril gene body leads to consistent dysregulation of Mccc1 and Exosc9 in the neighboring topologically associated domain (TAD). This occurs irrespective of Peril lincRNA expression, demonstrating this regulation is DNA-dependent. Hi-C confirms long-range contacts with the neighboring TAD, and these interactions are altered upon Peril knockout. Surprisingly, we do not observe consistent regulation of genes within the local TAD. Together, these data suggest a long-range enhancer-like function for the Peril gene body. Conclusions A multi-faceted approach combining high-throughput enhancer discovery with genetic models can connect enhancers to their gene targets and provides evidence of inter-TAD gene regulation. |
topic |
lincRNA Mouse models MPRA Cis-regulation Enhancer |
url |
http://link.springer.com/article/10.1186/s13059-018-1589-8 |
work_keys_str_mv |
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