Evaluation of the Epigenetic Regulation of Two X-linked, Autism Candidate Genes: X-linked Lymphocyte Regulated 3b and Transketolase-Like 1

According to the CDC the prevalence of Autism Spectrum Disorder (ASD) in males compared to females is approximately 5:1. Skuse et al. hypothesized that imprinted genes on the X chromosome could account for this sex bias. Genomic imprinting is defined as differential gene expression dependent upon the parental origin of the allele. While genomic imprinting on autosomes has been well classified, no imprinting mechanism on the sex chromosomes has been discovered. This work presents an investigation into the regulation of expression governing the imprinted locus of X-Linked Lymphocyte Regulated 3b/4b/4c (Xlr3/4), and closely linked ASD candidate gene, Transketolase-Like 1 (TKTL1), in the developing central nervous system of the laboratory mouse. Examination of epigenetic signatures and the chromatin environment including differential DNA methylation, differential nucleosome positioning, H3.3 deposition and G-quadruplex formation, suggests that epimutations in these loci may underlie disease association. Transketolases play a pivotal role in the Pentose Phosphate Pathway (PPP), and dysfunction in the non-oxidative phase of the PPP has been linked to neurodegenerative disorders and cancers. This work explores the expression of TKTL1 in human brain sub-regions of ASD patients compared to neurotypical individuals as well as the functional role TKTL1 plays in the PPP. It is observed that TKTL1 may not function as a transketolase in the pathway, but may play a critical regulatory role as a competitive inhibitor