date: 2023-06-12T01:34:00Z
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pdf:docinfo:title: Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A
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Keywords: alternative splicing; histone demethylase; histone methylation; cancer biology; chromatin; proteomics; bladder cancer
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subject: The UTX/KDM6A histone H3K27 demethylase plays an important role in development and is frequently mutated in cancers such as urothelial cancer. Despite many studies on UTX proteins, variations in mRNA splicing have been overlooked. Using Nanopore sequencing, we present a comprehensive analysis of UTX/KDM6A splicing events in human cell lines and in tissue samples from bladder cancer cases and normal epithelia. We found that the central region of UTX mRNAs encoded by exons 12 to 17 undergoes extensive alternative splicing. Up to half of all stable mRNAs (8?48% in bladder tissues and 18?58% in cell lines) are represented by the UTX canonical isoform lacking exon 14 encoding a nuclear localization sequence, and hence exon 14-containing UTX isoforms exclusively localize to the nucleus, unlike the cytonuclear localization of the canonical isoform. Chromatin association was also higher for exon-14-containing isoforms compared to the canonical UTX. Using quantitative mass spectrometry, we found that all UTX isoforms integrated into the MLL3 and MLL4, PR-DUB and MiDAC complexes. Interestingly, one of the novel UTX isoforms, which lacks exons 14 and 16, fails to interact with PR-DUB and MiDAC complex members. In conclusion, UTX mRNAs undergo extensive alternative splicing, which controls the subcellular localization of UTX and its interactions with other chromatin regulatory complexes.
dc:creator: Omid Fotouhi, Sheikh Nizamuddin, Stephanie Falk, Oliver Schilling, Ruth Knüchel-Clarke, Martin L. Biniossek and H. T. Marc Timmers
dcterms:created: 2023-06-12T01:31:18Z
Last-Modified: 2023-06-12T01:34:00Z
dcterms:modified: 2023-06-12T01:34:00Z
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title: Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A
Last-Save-Date: 2023-06-12T01:34:00Z
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pdf:docinfo:keywords: alternative splicing; histone demethylase; histone methylation; cancer biology; chromatin; proteomics; bladder cancer
pdf:docinfo:modified: 2023-06-12T01:34:00Z
meta:save-date: 2023-06-12T01:34:00Z
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dc:title: Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A
modified: 2023-06-12T01:34:00Z
cp:subject: The UTX/KDM6A histone H3K27 demethylase plays an important role in development and is frequently mutated in cancers such as urothelial cancer. Despite many studies on UTX proteins, variations in mRNA splicing have been overlooked. Using Nanopore sequencing, we present a comprehensive analysis of UTX/KDM6A splicing events in human cell lines and in tissue samples from bladder cancer cases and normal epithelia. We found that the central region of UTX mRNAs encoded by exons 12 to 17 undergoes extensive alternative splicing. Up to half of all stable mRNAs (8?48% in bladder tissues and 18?58% in cell lines) are represented by the UTX canonical isoform lacking exon 14 encoding a nuclear localization sequence, and hence exon 14-containing UTX isoforms exclusively localize to the nucleus, unlike the cytonuclear localization of the canonical isoform. Chromatin association was also higher for exon-14-containing isoforms compared to the canonical UTX. Using quantitative mass spectrometry, we found that all UTX isoforms integrated into the MLL3 and MLL4, PR-DUB and MiDAC complexes. Interestingly, one of the novel UTX isoforms, which lacks exons 14 and 16, fails to interact with PR-DUB and MiDAC complex members. In conclusion, UTX mRNAs undergo extensive alternative splicing, which controls the subcellular localization of UTX and its interactions with other chromatin regulatory complexes.
pdf:docinfo:subject: The UTX/KDM6A histone H3K27 demethylase plays an important role in development and is frequently mutated in cancers such as urothelial cancer. Despite many studies on UTX proteins, variations in mRNA splicing have been overlooked. Using Nanopore sequencing, we present a comprehensive analysis of UTX/KDM6A splicing events in human cell lines and in tissue samples from bladder cancer cases and normal epithelia. We found that the central region of UTX mRNAs encoded by exons 12 to 17 undergoes extensive alternative splicing. Up to half of all stable mRNAs (8?48% in bladder tissues and 18?58% in cell lines) are represented by the UTX canonical isoform lacking exon 14 encoding a nuclear localization sequence, and hence exon 14-containing UTX isoforms exclusively localize to the nucleus, unlike the cytonuclear localization of the canonical isoform. Chromatin association was also higher for exon-14-containing isoforms compared to the canonical UTX. Using quantitative mass spectrometry, we found that all UTX isoforms integrated into the MLL3 and MLL4, PR-DUB and MiDAC complexes. Interestingly, one of the novel UTX isoforms, which lacks exons 14 and 16, fails to interact with PR-DUB and MiDAC complex members. In conclusion, UTX mRNAs undergo extensive alternative splicing, which controls the subcellular localization of UTX and its interactions with other chromatin regulatory complexes.
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pdf:docinfo:creator: Omid Fotouhi, Sheikh Nizamuddin, Stephanie Falk, Oliver Schilling, Ruth Knüchel-Clarke, Martin L. Biniossek and H. T. Marc Timmers
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creator: Omid Fotouhi, Sheikh Nizamuddin, Stephanie Falk, Oliver Schilling, Ruth Knüchel-Clarke, Martin L. Biniossek and H. T. Marc Timmers
meta:author: Omid Fotouhi, Sheikh Nizamuddin, Stephanie Falk, Oliver Schilling, Ruth Knüchel-Clarke, Martin L. Biniossek and H. T. Marc Timmers
dc:subject: alternative splicing; histone demethylase; histone methylation; cancer biology; chromatin; proteomics; bladder cancer
meta:creation-date: 2023-06-12T01:31:18Z
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meta:keyword: alternative splicing; histone demethylase; histone methylation; cancer biology; chromatin; proteomics; bladder cancer
Author: Omid Fotouhi, Sheikh Nizamuddin, Stephanie Falk, Oliver Schilling, Ruth Knüchel-Clarke, Martin L. Biniossek and H. T. Marc Timmers
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