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Human Molecular Genetics Advance Access originally published online on March 4, 2008
Human Molecular Genetics 2008 17(12):1774-1782; doi:10.1093/hmg/ddn067
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Monoallele deletion of CBP leads to pericentromeric heterochromatin condensation through ESET expression and histone H3 (K9) methylation

Junghee Lee1,4, Sean Hagerty1,4, Kerry A. Cormier1,4, Jinho Kim1,4, Andrew L. Kung5, Robert J. Ferrante1,2,3,4 and Hoon Ryu1,4,*

1 Department of Neurology 2 Department of Pathology 3 Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA 4 Geriatric Research Education and Clinical Center, Bedford Veteran's Affairs Medical Center, Bedford, MA 01730, USA 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA

* To whom correspondence should be addressed at: Department of Neurology, Boston University School of Medicine, 200 Springs Road, Bedford, MA 01730, USA. Tel: +1 7816872922; Fax: +1 7816873515; Email: hoonryu{at}bu.edu

Received October 25, 2007; Accepted February 29, 2008

Chromatin remodeling is tightly controlled under physiological conditions. Alterations in chromatin structure are involved in the pathogenesis of neuronal systems. We found that the monoallelic deletion of CREB binding protein (CBP) results in the induction of ERG-associated protein with SET domain (ESET) and increases trimethylation of histone H3 (K9) and condensation of pericentromeric heterochromatin structure in neurons. Nested deletion and mutational analysis of the ESET promoter further demonstrated that the Ets-2 transcription factor regulates transcriptional activity of the ESET gene. In CBP+/– mice, Ets-2 occupancy in the ESET promoter DNA was markedly elevated. Our results suggest that CBP is a transcriptional repressor of ESET gene expression by limiting Ets-2 transcriptional activity, while CBP siRNA enhances basal and Ets-2-dependent ESET transcriptional activity. Altered expression of the ESET gene and hypertrimethylation of H3 (K9) correlate with striatal neuron atrophy and dysfunction in CBP+/– mice. These results establish an alternative pathway that loss of CBP leads to the pericentric heterochromatin condensation through ESET expression and trimethylation of H3 (K9).


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