Date of Completion

8-9-2019

Embargo Period

8-1-2019

Keywords

Genomics, Autism, Epigenetics, Genomic Imprinting, Nuclear Organization, Chromosome Conformation Capture

Major Advisor

Michael O'Neill

Associate Advisor

Rachel O'Neill

Associate Advisor

John Malone

Field of Study

Molecular and Cell Biology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

X-linked imprinted genes have been hypothesized to contribute parent-of-origin influences on social cognition. A cluster of imprinted genes Xlr3b, Xlr4b, and Xlr4c, implicated in cognitive defects, are maternally expressed and paternally silent in the murine brain. These genes defy classic mechanisms of autosomal imprinting, suggesting a novel method of imprinted gene regulation. Using Xlr3b and Xlr4c as bait, this study uses 4C-Seq on neonatal whole brain of a 39,XO mouse model, to provide the first in-depth analysis of chromatin dynamics surrounding an imprinted locus on the X-chromosome. Significant differences in long-range contacts exist between XM and XP monosomic samples. In addition, XM interaction profiles contact a greater number of genes linked to cognitive impairment, abnormality of the nervous system, and abnormality of higher mental function.

This is not a pattern that is unique to the imprinted Xlr3/4 locus. Additional 4C-Seq experiments show that other genes on the X-chromosome, implicated in intellectual disability and/or ASD, also produce more maternal contacts to other X-linked genes linked to cognitive impairment. The observation that there are differences between the maternal and paternal X interactomes is bolstered by potential variation in Atrx binding and H3K27me3 enrichment between XM and XP, suggesting that there may be broad-scale differences of the X-chromosome, related to parent-of-origin effects. Taken together, these results provide intriguing insight into the maternal X susceptibility to cognitive and social impairment.

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