A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer

Marc A.J. Morgan; Irina K. Popova; Anup Vaidya; Jonathan M. Burg; Matthew R. Marunde; Emily J. Rendleman; Zachary J. Dumar; Rachel Watson; Matthew J. Meiners; Sarah A. Howard; Natalia Khalatyan; Robert M. Vaughan; Scott B. Rothbart; Michael C. Keogh; Ali Shilatifard

doi:10.1101/gad.348766.121

A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer

Marc A.J. Morgan^*, Irina K. Popova, Anup Vaidya, Jonathan M. Burg, Matthew R. Marunde, Emily J. Rendleman, Zachary J. Dumar, Rachel Watson, Matthew J. Meiners, Sarah A. Howard, Natalia Khalatyan, Robert M. Vaughan, Scott B. Rothbart, Michael C. Keogh, Ali Shilatifard

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

4 Scopus citations

Abstract

Mutations in the PHIP/BRWD2 chromatin regulator cause the human neurodevelopmental disorder Chung-Jansen syndrome, while alterations in PHIP expression are linked to cancer. Precisely how PHIP functions in these contexts is not fully understood. Here we demonstrate that PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds to chromatin through a trivalent reader domain consisting of a H3K4-methyl binding Tudor domain and two bromodomains (BD1 and BD2). Using semisynthetic nucleosomes with defined histone post-translational modifications, we characterize PHIPs BD1 and BD2 as respective readers of H3K14ac and H4K12ac, and identify human disease-associated mutations in each domain and the intervening linker region that likely disrupt chromatin binding. These findings provide new insight into the biological function of this enigmatic chromatin protein and set the stage for the identification of both upstream chromatin modifiers and downstream targets of PHIP in human disease.

Original language	English (US)
Pages (from-to)	1642-1656
Number of pages	15
Journal	Genes and Development
Volume	35
Issue number	23-24
DOIs	https://doi.org/10.1101/gad.348766.121
State	Published - Dec 1 2021

Keywords

Chromatin
Histone
Neurodevelopmental disorder
Neuroepigenetics

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.348766.121

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Morgan, M. A. J., Popova, I. K., Vaidya, A., Burg, J. M., Marunde, M. R., Rendleman, E. J., Dumar, Z. J., Watson, R., Meiners, M. J., Howard, S. A., Khalatyan, N., Vaughan, R. M., Rothbart, S. B., Keogh, M. C., & Shilatifard, A. (2021). A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer. Genes and Development, 35(23-24), 1642-1656. https://doi.org/10.1101/gad.348766.121

@article{1518cdbd1b0345b2bbf7616366cabec4,

title = "A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer",

abstract = "Mutations in the PHIP/BRWD2 chromatin regulator cause the human neurodevelopmental disorder Chung-Jansen syndrome, while alterations in PHIP expression are linked to cancer. Precisely how PHIP functions in these contexts is not fully understood. Here we demonstrate that PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds to chromatin through a trivalent reader domain consisting of a H3K4-methyl binding Tudor domain and two bromodomains (BD1 and BD2). Using semisynthetic nucleosomes with defined histone post-translational modifications, we characterize PHIPs BD1 and BD2 as respective readers of H3K14ac and H4K12ac, and identify human disease-associated mutations in each domain and the intervening linker region that likely disrupt chromatin binding. These findings provide new insight into the biological function of this enigmatic chromatin protein and set the stage for the identification of both upstream chromatin modifiers and downstream targets of PHIP in human disease.",

keywords = "Chromatin, Histone, Neurodevelopmental disorder, Neuroepigenetics",

author = "Morgan, {Marc A.J.} and Popova, {Irina K.} and Anup Vaidya and Burg, {Jonathan M.} and Marunde, {Matthew R.} and Rendleman, {Emily J.} and Dumar, {Zachary J.} and Rachel Watson and Meiners, {Matthew J.} and Howard, {Sarah A.} and Natalia Khalatyan and Vaughan, {Robert M.} and Rothbart, {Scott B.} and Keogh, {Michael C.} and Ali Shilatifard",

note = "Funding Information: Research in the Shilatifard laboratory is supported by National Institutes of Health (NIH) grant R35CA197569. Research at EpiCy-pher, Inc., is supported by NIH grants 2R44GM117683, 2R44CA214076, and 2R44GM116584. Research in the Rothbart laboratory is supported by NIH grant R35GM124736. R.M.V. is supported by NIH fellowship F99CA245821 from the National Cancer Institute. We thank colleagues for the kind supply of reagents (see the Material and Methods), Jeffrey N. Savas for expertise and advice in mass spectrometry analysis, Nabiha Khan for next-generation sequencing library preparation, Siddhartha Das for bioinformatics analysis, and Sanjukta Guha Thakurta for TMT MS instrumentation and analysis. Publisher Copyright: {\textcopyright} 2021 Morgan et al.",

year = "2021",

month = dec,

day = "1",

doi = "10.1101/gad.348766.121",

language = "English (US)",

volume = "35",

pages = "1642--1656",

journal = "Genes and Development",

issn = "0890-9369",

publisher = "Cold Spring Harbor Laboratory Press",

number = "23-24",

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Morgan, MAJ, Popova, IK, Vaidya, A, Burg, JM, Marunde, MR, Rendleman, EJ, Dumar, ZJ, Watson, R, Meiners, MJ, Howard, SA, Khalatyan, N, Vaughan, RM, Rothbart, SB, Keogh, MC & Shilatifard, A 2021, 'A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer', Genes and Development, vol. 35, no. 23-24, pp. 1642-1656. https://doi.org/10.1101/gad.348766.121

TY - JOUR

T1 - A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer

AU - Morgan, Marc A.J.

AU - Popova, Irina K.

AU - Vaidya, Anup

AU - Burg, Jonathan M.

AU - Marunde, Matthew R.

AU - Rendleman, Emily J.

AU - Dumar, Zachary J.

AU - Watson, Rachel

AU - Meiners, Matthew J.

AU - Howard, Sarah A.

AU - Khalatyan, Natalia

AU - Vaughan, Robert M.

AU - Rothbart, Scott B.

AU - Keogh, Michael C.

AU - Shilatifard, Ali

N1 - Funding Information: Research in the Shilatifard laboratory is supported by National Institutes of Health (NIH) grant R35CA197569. Research at EpiCy-pher, Inc., is supported by NIH grants 2R44GM117683, 2R44CA214076, and 2R44GM116584. Research in the Rothbart laboratory is supported by NIH grant R35GM124736. R.M.V. is supported by NIH fellowship F99CA245821 from the National Cancer Institute. We thank colleagues for the kind supply of reagents (see the Material and Methods), Jeffrey N. Savas for expertise and advice in mass spectrometry analysis, Nabiha Khan for next-generation sequencing library preparation, Siddhartha Das for bioinformatics analysis, and Sanjukta Guha Thakurta for TMT MS instrumentation and analysis. Publisher Copyright: © 2021 Morgan et al.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Mutations in the PHIP/BRWD2 chromatin regulator cause the human neurodevelopmental disorder Chung-Jansen syndrome, while alterations in PHIP expression are linked to cancer. Precisely how PHIP functions in these contexts is not fully understood. Here we demonstrate that PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds to chromatin through a trivalent reader domain consisting of a H3K4-methyl binding Tudor domain and two bromodomains (BD1 and BD2). Using semisynthetic nucleosomes with defined histone post-translational modifications, we characterize PHIPs BD1 and BD2 as respective readers of H3K14ac and H4K12ac, and identify human disease-associated mutations in each domain and the intervening linker region that likely disrupt chromatin binding. These findings provide new insight into the biological function of this enigmatic chromatin protein and set the stage for the identification of both upstream chromatin modifiers and downstream targets of PHIP in human disease.

AB - Mutations in the PHIP/BRWD2 chromatin regulator cause the human neurodevelopmental disorder Chung-Jansen syndrome, while alterations in PHIP expression are linked to cancer. Precisely how PHIP functions in these contexts is not fully understood. Here we demonstrate that PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds to chromatin through a trivalent reader domain consisting of a H3K4-methyl binding Tudor domain and two bromodomains (BD1 and BD2). Using semisynthetic nucleosomes with defined histone post-translational modifications, we characterize PHIPs BD1 and BD2 as respective readers of H3K14ac and H4K12ac, and identify human disease-associated mutations in each domain and the intervening linker region that likely disrupt chromatin binding. These findings provide new insight into the biological function of this enigmatic chromatin protein and set the stage for the identification of both upstream chromatin modifiers and downstream targets of PHIP in human disease.

KW - Chromatin

KW - Histone

KW - Neurodevelopmental disorder

KW - Neuroepigenetics

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U2 - 10.1101/gad.348766.121

DO - 10.1101/gad.348766.121

M3 - Article

C2 - 34819353

AN - SCOPUS:85121814148

SN - 0890-9369

VL - 35

SP - 1642

EP - 1656

JO - Genes and Development

JF - Genes and Development

IS - 23-24

ER -

A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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