Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Developmental Biology

Supervisor

Dr. Nathalie Bérubé

Abstract

Alpha-thalassemia mental retardation, X-linked (ATRX) is a SWI/SNF-like chromatin remodeling protein, enriched at heterochromatic regions of the genome. Disruption of ATRX in humans causes a neurodevelopmental disorder known as ATR‐X Syndrome, and has been linked to paediatric neuronal cancers, suggesting an important role for ATRX in the regulation of chromatin structure in the developing brain. At the outset of this study direct ATRX target genes had not yet been identified. This thesis identifies imprinted genes as targets of ATRX in the developing brain, and explores the mechanism of ATRX regulation at these sites, using the H19/Igf2 imprinted domain as a model. The findings indicate that in the forebrain ATRX localizes to the maternal allele of the H19 imprinting control region (H19 ICR) with methyl CpG binding protein 2 (MeCP2), CCCTC‐binding factor (CTCF) and Cohesin, three important regulators of chromatin structure. ATRX is recruited by MeCP2 to the H19 ICR, where it then governs the profile of post‐translational histone modifications and nucleosome occupancy to maintain CTCF and Cohesin binding. CTCF and Cohesin are essential constituents of the cis and trans chromatin interactions that regulate the expression of imprinted genes. Loss of either ATRX or MeCP2 disrupts cis chromosomal interactions across H19/Igf2. A role for ATRX in cis at several imprinted genes is supported by its ability to bind directly to many imprinted domains. Taken together, these findings indicate that ATRX can regulate the expression of target genes in the brain by altering nucleosome positioning to control local chromatin interactions.

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