Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5

Yanran Chen; Haomiao Su; Jianing Zhao; Zhenkun Na; Kevin Jiang; Antonella Bacchiocchi; Ken H. Loh; Ruth Halaban; Zhentian Wang; Xiongwen Cao; Sarah A. Slavoff

Cell Reports (Sep 2023)

Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5

Yanran Chen,
Haomiao Su,
Jianing Zhao,
Zhenkun Na,
Kevin Jiang,
Antonella Bacchiocchi,
Ken H. Loh,
Ruth Halaban,
Zhentian Wang,
Xiongwen Cao,
Sarah A. Slavoff

Affiliations

Yanran Chen: Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China; Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Sciences, East China Normal University, Shanghai 200062, China
Haomiao Su: Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA
Jianing Zhao: Frontier Innovation Center, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200433, China; Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200433, China
Zhenkun Na: Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA
Kevin Jiang: Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA
Antonella Bacchiocchi: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA
Ken H. Loh: Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
Ruth Halaban: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA
Zhentian Wang: Frontier Innovation Center, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200433, China; Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200433, China
Xiongwen Cao: Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China; Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Sciences, East China Normal University, Shanghai 200062, China; Corresponding author
Sarah A. Slavoff: Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06529, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 9
p. 113145

Abstract

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Summary: The conserved WD40-repeat protein WDR5 interacts with multiple proteins both inside and outside the nucleus. However, it is currently unclear whether and how the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein EMBOW (endogenous microprotein binder of WDR5) dually encoded in the human SCRIB gene interacts with WDR5 and regulates its binding to multiple interaction partners, including KMT2A and KIF2A. EMBOW is cell cycle regulated, with two expression maxima at late G1 phase and G2/M phase. Loss of EMBOW decreases WDR5 interaction with KIF2A, aberrantly shortens mitotic spindle length, prolongs G2/M phase, and delays cell proliferation. In contrast, loss of EMBOW increases WDR5 interaction with KMT2A, leading to WDR5 binding to off-target genes, erroneously increasing H3K4me3 levels, and activating transcription of these genes. Together, these results implicate EMBOW as a regulator of WDR5 that regulates its interactions and prevents its off-target binding in multiple contexts.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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