Linking genome organization to nuclear function in astrocytes and muscle cells

Higher-order chromatin structures have been identified in the genome. These structures have been linked to nuclear processes, including transcription. However, how dynamic these chromatin structures change throughout mammalian development remains to be determined. I have mapped genome-wide chromatin interactions in mouse muscle progenitor cells (myoblasts) and in terminally differentiated muscle cells (myotubes) using HiC, in order to uncover chromatin reorganization patterns during muscle development. I observe extensive switches between A and B compartments during muscle development on a global scale. Additionally local changes in the interaction profiles of certain DNA regions are directly correlated with the transcriptional changes that accompany the muscle development. Interestingly, muscle specific genes show a tendency to interact with other muscle specific genes upon muscle cell differentiation. I also tested for the presence of physical interactions between mitochondrial and nuclear DNA (i.e. mito-nDNA interactions) in mammalian cells. Similar mito-nDNA connections have been linked to functional outcomes within fission and Baker’s yeast. Therefore, I evaluated chromosomal interactions captured by HiC and Circular Chromosome Conformation Capture (4C) for mito-nDNA interactions in order to determine if they are random. I show that the mito-nDNA interactions captured in mammalian cells are statistically significant and shared between biological and technical replicates. The most frequent interactions occur with repetitive DNA sequences, including centromeres in human cell lines and the 18S rDNA in mouse cortical astrocytes. My results demonstrate a degree of selective regulation in the identity of the interacting mitochondrial partners confirming that mito-nDNA interactions in mammalian cells are not random. The mechanism/s underlying the relationship between 3D organization and transcription remains to be further identified.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Molecular Medicine

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2016

Author dc:creator

• Doynova, Malina

Advisors dc:contributor.advisor

• O’Sullivan, JM
• Vickers, M

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/31426

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/31426