Public Defence: Jane Spirkoski
M.Sc. Jane Spirkoski at at Institute of Basic Medical Sciences will be defending the thesis “PML defines a new type of heterochromatic domain” for the degree of PhD (Philosophiae Doctor).
Trial lecture - time and place
See Trial Lecture.
- First opponent: Professor Jorrit Enserink,
Second opponent: Professor Valérie Lallemand-Breitenbach, Paris Diderot University, France
- Third member and chair of the evaluation committee: Professor Manuela Zucknick, University of Oslo
Chair of defence
Professor Anne Carine Østvold, University of Oslo
Professor Philippe Collas, University of Oslo
The spatial organization of the genome is critical for many physiological processes and mutations or deregulation of genome-organizing proteins often lead to disease. Promyelocytic leukemia (PML) protein is a tumor suppressor which forms intra-nuclear structures called PML nuclear bodies. PML bodies are involved in many cellular activities including control of cell growth, protein processing, autophagy, genome stability, gene expression and immune functions. Earlier work from our laboratory has shown that PML bodies are also a transit site for a specific histone protein – histone variant H3.3, as part of its incorporation into chromatin. PML also interacts with specific genes, but what has remained unknown is whether it is involved in genome organization in a broader sense.
The aim of this thesis was to reveal PML’s interactions with chromatin genome-wide and how PML impacts H3.3 incorporation in chromatin. Using a chromatin immunoprecipitation and high-throughput sequencing approach, we show that in mouse cells PML associates with broad chromatin regions which we call PML-associated domains (PADs). These novel domains mostly consist of inactive regions marked by specific repressive chromatin modifications and are devoid of H3.3. Functional studies, relying on knock-out and knock-down experiments, showed that PML is implicated in the regulation of epigenetic histone modifications in PADs, ensuring the maintenance of a repressive state in these domains. Our results also show an involvement of PML in the regulation of H3.3 deposition in PADs and in telomeric and centromeric repeat regions that are essential for maintenance of genome integrity.
Altogether, our results highlight previously undepreciated role of PML on genome architecture. The emerging role of PML in the assembly and maintenance of heterochromatin needs to be further elucidated in the epigenetic landscape of normal and cancer cells, as PML is downregulated in many tumors.
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