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RNA. 2018 Oct;24(10):1326-1338. doi: 10.1261/rna.066712.118. Epub 2018 Jul 24.

Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT.

Author information

1
Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
2
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
3
Department of Integrative Biology and Physiology and the Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA.

Abstract

The epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM-ESRP1 coregulated exons identifies guanine-uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis-elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.

KEYWORDS:

EMT; ESRP1; RNA binding proteins; alternative splicing; hnRNPM

PMID:
30042172
PMCID:
PMC6140460
DOI:
10.1261/rna.066712.118
[Indexed for MEDLINE]
Free PMC Article

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