Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells

Gene expression varies widely between individuals of a population, and regulatory change can underlie phenotypes of evolutionary and biomedical relevance. A key question in the field is how DNA sequence variants impact gene expression, with most mechanistic studies to date focused on the effects of...

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Main Authors:	Yoon, Oh Kyu, Hsu, Tiffany Y., Im, Joo Hyun, Brem, Rachel B.
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420953/

id	pubmed-3420953
recordtype	oai_dc
spelling	pubmed-34209532012-08-22 Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells Yoon, Oh Kyu Hsu, Tiffany Y. Im, Joo Hyun Brem, Rachel B. Research Article Gene expression varies widely between individuals of a population, and regulatory change can underlie phenotypes of evolutionary and biomedical relevance. A key question in the field is how DNA sequence variants impact gene expression, with most mechanistic studies to date focused on the effects of genetic change on regulatory regions upstream of protein-coding sequence. By contrast, the role of RNA 3′-end processing in regulatory variation remains largely unknown, owing in part to the challenge of identifying functional elements in 3′ untranslated regions. In this work, we conducted a genomic survey of transcript ends in lymphoblastoid cells from genetically distinct human individuals. Our analysis mapped the cis-regulatory architecture of 3′ gene ends, finding that transcript end positions did not fall randomly in untranslated regions, but rather preferentially flanked the locations of 3′ regulatory elements, including miRNA sites. The usage of these transcript length forms and motifs varied across human individuals, and polymorphisms in polyadenylation signals and other 3′ motifs were significant predictors of expression levels of the genes in which they lay. Independent single-gene experiments confirmed the effects of polyadenylation variants on steady-state expression of their respective genes, and validated the regulatory function of 3′ cis-regulatory sequence elements that mediated expression of these distinct RNA length forms. Focusing on the immune regulator IRF5, we established the effect of natural variation in RNA 3′-end processing on regulatory response to antigen stimulation. Our results underscore the importance of two mechanisms at play in the genetics of 3′-end variation: the usage of distinct 3′-end processing signals and the effects of 3′ sequence elements that determine transcript fate. Our findings suggest that the strategy of integrating observed 3′-end positions with inferred 3′ regulatory motifs will prove to be a critical tool in continued efforts to interpret human genome variation. Public Library of Science 2012-08-16 /pmc/articles/PMC3420953/ /pubmed/22916029 http://dx.doi.org/10.1371/journal.pgen.1002882 Text en © 2012 Yoon et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Yoon, Oh Kyu Hsu, Tiffany Y. Im, Joo Hyun Brem, Rachel B.
spellingShingle	Yoon, Oh Kyu Hsu, Tiffany Y. Im, Joo Hyun Brem, Rachel B. Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells
author_facet	Yoon, Oh Kyu Hsu, Tiffany Y. Im, Joo Hyun Brem, Rachel B.
author_sort	Yoon, Oh Kyu
title	Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells
title_short	Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells
title_full	Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells
title_fullStr	Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells
title_full_unstemmed	Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells
title_sort	genetics and regulatory impact of alternative polyadenylation in human b-lymphoblastoid cells
description	Gene expression varies widely between individuals of a population, and regulatory change can underlie phenotypes of evolutionary and biomedical relevance. A key question in the field is how DNA sequence variants impact gene expression, with most mechanistic studies to date focused on the effects of genetic change on regulatory regions upstream of protein-coding sequence. By contrast, the role of RNA 3′-end processing in regulatory variation remains largely unknown, owing in part to the challenge of identifying functional elements in 3′ untranslated regions. In this work, we conducted a genomic survey of transcript ends in lymphoblastoid cells from genetically distinct human individuals. Our analysis mapped the cis-regulatory architecture of 3′ gene ends, finding that transcript end positions did not fall randomly in untranslated regions, but rather preferentially flanked the locations of 3′ regulatory elements, including miRNA sites. The usage of these transcript length forms and motifs varied across human individuals, and polymorphisms in polyadenylation signals and other 3′ motifs were significant predictors of expression levels of the genes in which they lay. Independent single-gene experiments confirmed the effects of polyadenylation variants on steady-state expression of their respective genes, and validated the regulatory function of 3′ cis-regulatory sequence elements that mediated expression of these distinct RNA length forms. Focusing on the immune regulator IRF5, we established the effect of natural variation in RNA 3′-end processing on regulatory response to antigen stimulation. Our results underscore the importance of two mechanisms at play in the genetics of 3′-end variation: the usage of distinct 3′-end processing signals and the effects of 3′ sequence elements that determine transcript fate. Our findings suggest that the strategy of integrating observed 3′-end positions with inferred 3′ regulatory motifs will prove to be a critical tool in continued efforts to interpret human genome variation.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420953/
_version_	1611550375836385280

Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells

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