Date of Completion

4-30-2013

Embargo Period

4-30-2013

Major Advisor

Dr. Michael J O'Neill

Co-Major Advisor

Dr. Rachel J O'Neill

Associate Advisor

Dr. Charlie Giardina

Associate Advisor

Dr. Andrew Pask

Associate Advisor

Dr. Barbara Mellone

Field of Study

Genetics and Genomics

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Genomic imprinting is defined as the mono-allelic expression of a gene based on parental origin. Eutherian mammals utilize a differentially methylated region, or DMR as an epigenetic mark to regulate transcription initiation events at all autosomal imprinted loci. However, an X-linked imprinted locus, X-linked lymphocyte regulated 3b, defies the classical mechanism of epigenetic regulation as no DMR has been identified. A recent finding at the Xlr3/4/5 locus shows that imprinted expression is only observed at the 3’ end of the Xlr3b primary transcript suggesting that paternal silencing is accomplished through a co-transcriptional mechanism.

This study offers the first investigation into the potential imprinting mechanism by exploring the behavior of RNA Polymerase II (PolII) during transcription elongation. The observation that PolII is perturbed as it transits across the paternal copy of Xlr3b is further supported by H3K36me3 enrichment at the precise location of the stall, suggesting it too may play a role in the imprinting mechanism. The chromatin environment at the locus is not maintained by known allele specific histone modifications and histone methyltransferases that influence proper transcription elongation do not seem to play a role in the imprinting mechanism either. This work establishes a model where maternally biased gene expression is accomplished by severely impeding PolII at the paternal copy of Xlr3b during transcription elongation.

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