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A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis

Pimentel, Harold and Parra, Marilyn and Gee, Sherry L. and Mohandas, Narla and Pachter, Lior and Conboy, John G. (2016) A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis. Nucleic Acids Research, 44 (2). pp. 838-851. ISSN 0305-1048. PMCID PMC4737145. https://resolver.caltech.edu/CaltechAUTHORS:20170303-131213123

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Abstract

Differentiating erythroblasts execute a dynamic alternative splicing program shown here to include extensive and diverse intron retention (IR) events. Cluster analysis revealed hundreds of developmentally-dynamic introns that exhibit increased IR in mature erythroblasts, and are enriched in functions related to RNA processing such as SF3B1 spliceosomal factor. Distinct, developmentally-stable IR clusters are enriched in metal-ion binding functions and include mitoferrin genes SLC25A37 and SLC25A28 that are critical for iron homeostasis. Some IR transcripts are abundant, e.g. comprising ∼50% of highly-expressed SLC25A37 and SF3B1 transcripts in late erythroblasts, and thereby limiting functional mRNA levels. IR transcripts tested were predominantly nuclear-localized. Splice site strength correlated with IR among stable but not dynamic intron clusters, indicating distinct regulation of dynamically-increased IR in late erythroblasts. Retained introns were preferentially associated with alternative exons with premature termination codons (PTCs). High IR was observed in disease-causing genes including SF3B1 and the RNA binding protein FUS. Comparative studies demonstrated that the intron retention program in erythroblasts shares features with other tissues but ultimately is unique to erythropoiesis. We conclude that IR is a multi-dimensional set of processes that post-transcriptionally regulate diverse gene groups during normal erythropoiesis, misregulation of which could be responsible for human disease.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1093/nar/gkv1168DOIArticle
https://academic.oup.com/nar/article/44/2/838/2468136/A-dynamic-intron-retention-program-enriched-in-RNAPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737145/PubMed CentralArticle
ORCID:
AuthorORCID
Pachter, Lior0000-0002-9164-6231
Additional Information:© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Received April 10, 2015; Revised October 5, 2015; Accepted October 21, 2015. Author Contributions: J.G.C. and L.P. designed the research; H.P., M.P., S.L.G. performed research and analyzed data; and J.G.C., H.P., N.M., and L.P. wrote the article. FUNDING: National Institutes of Health [DK094699 to J.G.C., L.P.; DK32094 and DK26263 to N.M.]; Director, Office of Science and Office of Biological & Environmental Research of the US Department of Energy [DE-AC02-05CH1123]. Funding for open access charge: National Institutes of Health. Conflict of interest statement. None declared.
Funders:
Funding AgencyGrant Number
NIHDK094699
NIHDK32094
NIHDK26263
Department of Energy (DOE)DE-AC02-05CH11231
Issue or Number:2
PubMed Central ID:PMC4737145
Record Number:CaltechAUTHORS:20170303-131213123
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170303-131213123
Official Citation:Harold Pimentel, Marilyn Parra, Sherry L. Gee, Narla Mohandas, Lior Pachter, John G. Conboy; A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis. Nucleic Acids Res 2016; 44 (2): 838-851. doi: 10.1093/nar/gkv1168
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74705
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:03 Mar 2017 23:43
Last Modified:24 Feb 2020 10:30

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