An Embryonic Stem Cell-Specific NuRD Complex Functions through Interaction with WDR5

Ly-Sha Ee; Kurtis N McCannell; Yang Tang; Nancy Fernandes; W Rod Hardy; Michael R Green; Feixia Chu; Thomas G Fazzio

doi:10.1016/j.stemcr.2017.04.020

An Embryonic Stem Cell-Specific NuRD Complex Functions through Interaction with WDR5

Stem Cell Reports. 2017 Jun 6;8(6):1488-1496. doi: 10.1016/j.stemcr.2017.04.020. Epub 2017 May 18.

Authors

Ly-Sha Ee¹, Kurtis N McCannell¹, Yang Tang², Nancy Fernandes², W Rod Hardy¹, Michael R Green³, Feixia Chu², Thomas G Fazzio⁴

Affiliations

¹ Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
² Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH 03824, USA.
³ Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁴ Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: thomas.fazzio@umassmed.edu.

Abstract

The Nucleosome Remodeling and Deacetylase (NuRD) complex is a chromatin regulatory complex that functions as a transcriptional co-repressor in metazoans. The NuRD subunit MBD3 is essential for targeting and assembly of a functional NuRD complex as well as embryonic stem cell (ESC) pluripotency. Three MBD3 isoforms (MBD3A, MBD3B, and MBD3C) are expressed in mouse. Here, we find that the MBD3C isoform contains a unique 50-amino-acid N-terminal region that is necessary for MBD3C to specifically interact with the histone H3 binding protein WDR5. Domain analyses of WDR5 reveal that the H3 binding pocket is required for interaction with MBD3C. We find that while Mbd3c knockout ESCs differentiate normally, MBD3C is redundant with the MBD3A and MBD3B isoforms in regulation of gene expression, with the unique MBD3C N terminus required for this redundancy. Together, our data characterize a unique NuRD complex variant that functions specifically in ESCs.

Keywords: Mbd3; NuRD; Wdr5; chromatin; differentiation.

MeSH terms

Amino Acid Sequence
Animals
Cell Differentiation
Cells, Cultured
Chromatin / chemistry
Chromatin / metabolism
Chromatography, High Pressure Liquid
DNA-Binding Proteins / analysis
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Embryoid Bodies / cytology
Embryoid Bodies / metabolism
Gene Expression Regulation
Gene Knockout Techniques
Histones / metabolism
Intracellular Signaling Peptides and Proteins
Mi-2 Nucleosome Remodeling and Deacetylase Complex / chemistry
Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
Mice
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism*
Pluripotent Stem Cells / cytology
Pluripotent Stem Cells / metabolism
Protein Binding
Protein Isoforms / analysis
Protein Isoforms / genetics
Protein Isoforms / metabolism
Proteins / analysis
Proteins / metabolism*
Sequence Alignment
Tandem Mass Spectrometry
Transcription Factors / analysis
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Chromatin
DNA-Binding Proteins
Histones
Intracellular Signaling Peptides and Proteins
Mbd3 protein, mouse
Protein Isoforms
Proteins
Transcription Factors
Wdr5 protein, mouse
Mi-2 Nucleosome Remodeling and Deacetylase Complex

Abstract

MeSH terms

Substances

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