A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals
- Ryan Rickels1,
- Lu Wang1,
- Marta Iwanaszko1,
- Patrick A. Ozark1,
- Marc A. Morgan1,
- Andrea Piunti1,
- Natalia Khalatyan2,
- Shimaa H.A. Soliman1,
- Emily J. Rendleman1,
- Jeffrey N. Savas2,
- Edwin R. Smith1 and
- Ali Shilatifard1
- 1Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
- Corresponding author: ash{at}northwestern.edu
Abstract
Catalytic-inactivating mutations within the Drosophila enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80-amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential noncatalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.339762.120.
- Received April 25, 2020.
- Accepted September 9, 2020.
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