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  Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A

Fotouhi, O., Nizamuddin, S., Falk, S., Schilling, O., Knüchel-Clarke, R., Biniossek, M. L., et al. (2023). Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A. Cancers / Molecular Diversity Preservation International (MDPI), 15: 3117. doi:10.3390/cancers15123117.

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10.3390_cancers15123117.pdf (Verlagsversion), 4MB
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10.3390_cancers15123117.pdf
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Copyright Datum:
2023
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by the authors

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https://www.mdpi.com/2072-6694/15/12/3117 (Verlagsversion)
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 Urheber:
Fotouhi, Omid1, Autor
Nizamuddin, Sheikh1, Autor
Falk, Stephanie2, Autor
Schilling, Oliver1, Autor
Knüchel-Clarke, Ruth1, Autor
Biniossek, Martin L1, Autor
Timmers, H T Marc1, Autor
Affiliations:
1External Organizations, ou_persistent22              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243648              

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Schlagwörter: alternative splicing; bladder cancer; cancer biology; chromatin; histone demethylase; histone methylation; proteomics.
 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2023-06-08
 Publikationsstatus: Online veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.3390/cancers15123117
 Art des Abschluß: -

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Titel: Cancers / Molecular Diversity Preservation International (MDPI)
  Kurztitel : Cancers (Basel)
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: Basel : Molecular Diversity Preservation International (MDPI)
Seiten: - Band / Heft: 15 Artikelnummer: 3117 Start- / Endseite: - Identifikator: ISSN: 2072-6694
CoNE: https://pure.mpg.de/cone/journals/resource/2072-6694