Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 18, Pages 7487-7492Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1015341108
Keywords
epigenetics; gene regulation
Categories
Funding
- American Society of Hematology
- American Cancer Society [IRG-73-001]
- National Institutes of Health [R01 DK029902]
- National Cancer Institute Cancer Center [P30 CA016059]
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Nucleosome remodeling complexes comprise several large families of chromatin modifiers that integrate multiple epigenetic control signals to play key roles in cell type-specific transcription regulation. We previously isolated a methyl-binding domain protein 2 (MBD2)-containing nucleosome remodeling and deacetylation (NuRD) complex from primary erythroid cells and showed that MBD2 contributes to DNA methylation-dependent embryonic and fetal beta-type globin gene silencing during development in vivo. Here we present structural and biophysical details of the coiled-coil interaction between MBD2 and p66 alpha, a critical component of the MBD2-NuRD complex. We show that enforced expression of the isolated p66 alpha coiled-coil domain relieves MBD2-mediated globin gene silencing and that the expressed peptide interacts only with a subset of components of the MBD2-NuRD complex that does not include native p66a or Mi-2. These results demonstrate the central importance of the coiled-coil interaction and suggest that MBD2-dependent DNA methylation-driven gene silencing can be disrupted by selectively targeting this coiled-coil complex.
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