An amino terminal phosphorylation motif regulates intranuclear compartmentalization of Olig2 in neural progenitor cells

Dimphna H. Meijer, Department of Neurobiology, Harvard Medical School and Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
Yu Sun, Department of Neurobiology, Harvard Medical School and Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
Tao Liu, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02215.
Michael F. Kane, Department of Neurobiology, Harvard Medical School and Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
John A. Alberta, Department of Neurobiology, Harvard Medical School and Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
Guillaume Adelmant, Departments of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Cancer Biology, Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
Robert Kupp, Department of Neurosurgery, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013.Follow
Jarrod A. Marto, Departments of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Cancer Biology, Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
David H. Rowitch, Departments of Pediatrics and Neurological Surgery, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143, and.
Yoshihiro Nakatani, Department of Neurobiology, Harvard Medical School and Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
Charles D. Stiles, Department of Neurobiology, Harvard Medical School and Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, Charles_stiles@dfci.harvard.edu Shwetal.Mehta@dignityhealth.org.
Shwetal Mehta, Department of Neurosurgery, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013 Charles_stiles@dfci.harvard.edu Shwetal.Mehta@dignityhealth.org.

Document Type

Article

Abstract

The bHLH transcription factor Olig2 is expressed in cycling neural progenitor cells but also in terminally differentiated, myelinating oligodendrocytes. Sustained expression of Olig2 is counterintuitive because all known functions of the protein in expansion of neural progenitors and specification of oligodendrocyte progenitors are completed with the formation of mature white matter. How are the biological functions of Olig2 suppressed in terminally differentiated oligodendrocytes? In previous studies, we have shown that a triple serine motif in the amino terminus of Olig2 is phosphorylated in cycling neural progenitors but not in their differentiated progeny. We now show that phosphorylation of the triple serine motif regulates intranuclear compartmentalization of murine Olig2. Phosphorylated Olig2 is preferentially localized to a transcriptionally active "open" chromatin compartment together with coregulator proteins essential for regulation of gene expression. Unphosphorylated Olig2, as seen in mature white matter, is localized mainly within a transcriptionally inactive, chromatin fraction characterized by condensed and inaccessible DNA. Of special note is the observation that the p53 tumor suppressor protein is confined to the open chromatin fraction. Proximity ligation assays show that phosphorylation brings Olig2 within 30 nm of p53 within the open chromatin compartment. The data thus shed light on previously noted promitogenic functions of phosphorylated Olig2, which reflect, at least in part, an oppositional relationship with p53 functions.

Keywords

NuRD complex, Olig2, bHLH, intranuclear localization, p53, phosphorylation

Medical Subject Headings

Amino Acid Motifs (physiology); Animals; Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism, physiology); Cell Nucleus (chemistry, genetics, metabolism); Cells, Cultured; Female; Male; Mice; Mice, Knockout; Nerve Tissue Proteins (genetics, metabolism, physiology); Neural Stem Cells (chemistry, metabolism); Oligodendrocyte Transcription Factor 2; Phosphorylation (genetics); Pregnancy

Publication Date

6-18-2014

Publication Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

E-ISSN

1529-2401

Volume

34

Issue

25

First Page

8507

Last Page

18

PubMed ID

24948806

Digital Object Identifier (DOI)

10.1523/JNEUROSCI.0309-14.2014

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