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Scientist: Child Health Research Institute, London Health Sciences Centre, London, Ontario
Assistant Professor: Department of Biochemistry, University of Western Ontario, London, Ontario
Cross Appointments: Department of Paediatrics
University Website: http://publish.uwo.ca/~nberube/home.html
London Regional Cancer Program
Room A4-138, Cancer Research Laboratory Program
790 Commissioners Rd. E.
Canada N6A 4L6
Tel: 519-685-8500 ext. 55066
Epigenetic regulation of brain development through the study of proteins that modulate chromatin structure
Current work centers on the epigenetic regulation of brain development through the study of proteins that dictate chromatin structure, cell cycle progression and in neuronal function. Her recent work on ATRX gain and loss-of function mouse models has greatly advanced the understanding of the role of chromatin remodelling complexes in neuronal survival and differentiation. Her current work centers on the ATRX protein and its role as an epigenetic regulator of gene transcription by modulating chromatin accessibility and DNA methylation
ATRX gene mutations give rise to several X-linked mental retardation (XLMR) syndromes. The study of ATRX and other genetic factors that underlie mental retardation syndromes can significantly contribute to our understanding of neuronal development and ultimately, human cognition. Dr. Berube's laboratory is currently using mouse and cell culture models to study the outcome of ATRX loss-of-function on heterochromatin structure, gene expression and cell cycle progression. Future goals of the laboratory include the identification of ATRX target genes in the hippocampus and the study of ATRX function in neuronal differentiation.
Chromatin structure and the cell cycle
ATRX is a chromatin remodelling protein of the SWI/SNF family that is required for normal embryonic development. The protein is characterized by several recognizable chromatin motifs - a PHD zinc finger and the SNF2 ATPase domain. Both domains are frequently mutated in X-linked mental retardation (XLMR) syndromes, suggesting that they are essential for normal ATRX function during development. ATRX is located at very distinct sites within the cell nucleus. First, ATRX associates with Daxx, SSRP1, and heterochromatin protein 1 alpha (HP1a) at sites of heterochromatin replication. ATRX is also found at PML-NBs and at ribosomal DNA (rDNA) repeats on the short arm of acrocentric chromosomes. Dr. Berube's team is currently investigating the role of the ATRX in modulating chromatin structure during the cell cycle.
Chromatin structure and brain development
The use of mouse models is critical to elucidate the molecular targets of chromatin proteins such as ATRX in the pathogenesis of X-linked mental retardation (XLMR). We have recently demonstrated that ATRX is required for normal brain development in the mouse. (Berube et al, JCI, 2005). The Cre/loxP system represents a unique approach to achieve controlled temporal and spatial gene deletion and can be used to bypass the early lethal effects of ATRX deficiency. The most remarkable outcome of ATRX-deficiency in the hippocampus is the reduction of glutamatergic pyramidal neurons of the CA fields and the loss of granule neurons of the dentate gyrus. We are currently using mouse and cell culture systems to further study the role of ATRX in hippocampal development and to identify the downstream effectors of ATRX essential for dentate granule cell development.