UBC Theses and Dissertations
Identification of regulatory mechanisms in governing gene expression from the inactivated X chromosome Leung, Tiffany Ying
X chromosome inactivation (XCI) is the process in which one copy of the X chromosomes in females (XX) is randomly silenced to achieve dosage compensation of gene expression from X chromosome of males (XY). XCI is known to be incomplete, resulting in a subset of genes on the inactive X (Xi) being expressed. Genes along the X chromosome are classified into three categories based upon their expression from the Xi: subject, escape and variable. Escape genes, corresponding to 15% of X-linked genes, are generally expressed from the Xi at a substantially lower level compared to the active X (Xa). The underlying mechanisms in controlling escape from the heterochromatic state of Xi has been a long-standing question. While there is evidence that supports a role for intrinsic DNA elements in the escape XCI, they have not yet been identified. With increasing amounts of data for transcription factor (TF) binding sites, the objective of this thesis was to identify the regulatory TFs facilitating the ability of genes to escape XCI via a bioinformatics approach using empirical data. ChIP-seq peaks of 155 TFs from the ReMap database were assessed for enrichment at regulatory regions of 55 escape genes. 19 TFs were identified via enrichment analysis in the transcription start site regions of escape genes. Co-binding of pairs of enriched TFs were characterized by gene set similarity between the target genes. Of the 155 TFs examined, ZFP36, an RNA binding protein that alters RNA stability, showed importance in both enrichment analysis and co-binding analysis. An initial exploration of methods to compare the structures of Xi and Xa were undertaken using ChIA-PET data, providing insights into the limitations of current data resources and opportunities for future studies to inform the topographical organization of escape genes within Xi. The results of this thesis refined our knowledge on cis-regulatory elements and trans-acting factors potentially involved in escape of XCI. This list of enriched TF may be useful in future analyses, experimental or computational, to further determine their sufficiency and necessity in the escape of XCI.
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