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 Rickels; Lu Wang; Marta Iwanaszko; Patrick A. Ozark; Marc A. Morgan; Andrea Piunti; Natalia Khalatyan; Shimaa H.A. Soliman; Emily J. Rendleman; Jeffrey N. Savas; Edwin Richard Smith; Ali Shilatifard

doi:10.1101/gad.339762.120

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 Rickels, Lu Wang, Marta Iwanaszko, Patrick A. Ozark, Marc A. Morgan, Andrea Piunti, Natalia Khalatyan, Shimaa H.A. Soliman, Emily J. Rendleman, Jeffrey N. Savas, Edwin Richard Smith, Ali Shilatifard^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1493-1502
Number of pages	10
Journal	Genes and Development
Volume	34
Issue number	21-22
DOIs	https://doi.org/10.1101/gad.339762.120
State	Published - Nov 1 2020

Keywords

COMPASS
Chromatin
Epigenetics
Transcription

ASJC Scopus subject areas

Genetics
Developmental Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1101/gad.339762.120

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Rickels, R., Wang, L., Iwanaszko, M., Ozark, P. A., Morgan, M. A., Piunti, A., Khalatyan, N., Soliman, S. H. A., Rendleman, E. J., Savas, J. N., Smith, E. R., & Shilatifard, A. (2020). 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. Genes and Development, 34(21-22), 1493-1502. https://doi.org/10.1101/gad.339762.120

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title = "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",

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.",

keywords = "COMPASS, Chromatin, Epigenetics, Transcription",

author = "Ryan Rickels and Lu Wang and Marta Iwanaszko and Ozark, {Patrick A.} and Morgan, {Marc A.} and Andrea Piunti and Natalia Khalatyan and Soliman, {Shimaa H.A.} and Rendleman, {Emily J.} and Savas, {Jeffrey N.} and Smith, {Edwin Richard} and Ali Shilatifard",

note = "Funding Information: We thank Nicole Ethen for assistance with illustrations. R.R. was supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) F99CA222988. A.P. was supported by NIH/ NCI K99CA234434. E.R.S. was supported by NIH/NCI R50CA211428. This study was supported in part by Outstanding Investigator Award R35CA197569 from the NCI to A.S. Publisher Copyright: {\textcopyright} 2020 Rickels et al.",

year = "2020",

month = nov,

day = "1",

doi = "10.1101/gad.339762.120",

language = "English (US)",

volume = "34",

pages = "1493--1502",

journal = "Genes and Development",

issn = "0890-9369",

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Rickels, R, Wang, L , Iwanaszko, M, Ozark, PA, Morgan, MA, Piunti, A, Khalatyan, N, Soliman, SHA, Rendleman, EJ, Savas, JN, Smith, ER & Shilatifard, A 2020, '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', Genes and Development, vol. 34, no. 21-22, pp. 1493-1502. https://doi.org/10.1101/gad.339762.120

TY - JOUR

T1 - 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

AU - Rickels, Ryan

AU - Wang, Lu

AU - Iwanaszko, Marta

AU - Ozark, Patrick A.

AU - Morgan, Marc A.

AU - Piunti, Andrea

AU - Khalatyan, Natalia

AU - Soliman, Shimaa H.A.

AU - Rendleman, Emily J.

AU - Savas, Jeffrey N.

AU - Smith, Edwin Richard

AU - Shilatifard, Ali

N1 - Funding Information: We thank Nicole Ethen for assistance with illustrations. R.R. was supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) F99CA222988. A.P. was supported by NIH/ NCI K99CA234434. E.R.S. was supported by NIH/NCI R50CA211428. This study was supported in part by Outstanding Investigator Award R35CA197569 from the NCI to A.S. Publisher Copyright: © 2020 Rickels et al.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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.

AB - 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.

KW - COMPASS

KW - Chromatin

KW - Epigenetics

KW - Transcription

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AN - SCOPUS:85095414113

SN - 0890-9369

VL - 34

SP - 1493

EP - 1502

JO - Genes and Development

JF - Genes and Development

IS - 21-22

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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