The role of ATRX in alpha-globin expression
ATRX is a chromatin remodeller involving in a wide range of nuclear processes, including transcription. Mutations in ATRX give rise to alpha-thalassaemia/mental retardation X-linked (ATR-X) syndrome and downregulate alpha-globin expression through a mechanism which is poorly understood. It is known that ATRX binds to a G-rich tandem repeat upstream of the alpha-globin cluster and that in the presence of an ATRX mutation the expression of the alpha-globin related genes is reduced in a length and distance-dependent manner; the gene closest to repeat is most downregulated and the degree of downregulation depends on the length of the repeat.
My project aims to develop a cellular system to recapitulate the in vivo observation and to determine the manner by which gene expression is perturbed in this genetic disease. With little access to primary patient cells, the approach taken in this project is to mutate ATRX in wildtype CD34+ cells and immortalized erythroid progenitor cell lines by CRISPR/Cas9 genome engineering, and to differentiate these down the erythroid pathway. These cells will be assayed to see if the G-rich interstitial repeats bound by ATRX are associated with chromatin accessibility change as well as characterizing the epigenetic profile of the nearby genes to elucidate how the expression of these genes is perturbed.
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