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

doi:10.1016/j.celrep.2023.113145

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

Cell Rep. 2023 Sep 26;42(9):113145. doi: 10.1016/j.celrep.2023.113145. Epub 2023 Sep 19.

Authors

Affiliations

¹ 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.
² Department of Chemistry, Yale University, New Haven, CT 06520, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA.
³ 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.
⁴ Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
⁵ 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.
⁶ 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. Electronic address: xwcao@bio.ecnu.edu.cn.
⁷ 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. Electronic address: sarah.slavoff@yale.edu.

Abstract

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.

Keywords: CP: Cell biology; CP: Molecular biology; WDR5; histone H3K4me3; microprotein; mitosis; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Chromatin*
Humans
Intracellular Signaling Peptides and Proteins* / genetics
Kinesins / genetics
Micropeptides
Spindle Apparatus

Substances

Chromatin
Intracellular Signaling Peptides and Proteins
KIF2A protein, human
Kinesins
WDR5 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding