Investigation of Damage Responsive KRAB Zinc Finger Proteins

Lead Research Organisation: University of Cambridge
Department Name: Genetics


Background to the Project (January 2019):
The aim of my PhD project is to investigate why some members of the KRAB zinc finger protein (KZFP) family are transcriptionally modulated in response to DNA damage. KZFPs are the largest family of DNA binding proteins in humans and mice, yet are poorly understood. Primarily, KZFPs bind to the conserved remnants of ancient transposable elements (TEs) which have invaded the human genome during the millions of years of evolutionary history. Approximately 50% of the human genome is comprised of these transposable elements which present a source of genetic variation and regulatory effects, each containing binding sites for negative and positive regulators of transcription, acting as enhancers or alternative promoters. Over evolutionary time, most of these TEs have degraded to a state of inactivity, however specific subsequences of ancient inactive TEs are conserved in the human genome, retaining KZFP and transcription factor binding sites. It has already been demonstrated that a few of these degraded yet conserved TEs have been domesticated and can influence the expression of nearby genes. The hypothesis of the lab is that in many cases KZFPs participate in their regulation between cell types and/or facilitate the ability of conserved TE remnants to affect gene expression, together contributing to the establishment of new transcriptional regulation networks.

The initial focus of this project is the marsupial-conserved KZFP Znf79 which is significantly upregulated upon DNA damage, presenting the tantalising prospect that it is implicated in the response to DNA damage and modulates the effect of damage associated TE-derived enhancers and alternative promoters. Ultimately, this project will provide greater understanding of the regulatory events governing the DNA damage response which has far reaching implications for cell biology and diseases such as cancer. Furthermore, it will offer novel insights into evolution the relationships between transposable elements and our genome.

General Outline of the Initial Plan (January 2019):
My aim is to investigate Znf79 as a model of DNA damage responsive KZFP, utilising public datasets to understand expression patterns, identify regulatory mechanisms and potential targets.

Next, using gene manipulation techniques I will generate model systems in order to assess the effect of Znf79 on gene regulation and cellular characteristics.

Subsequently, I will characterise the epigenetic signature of the Znf79 perturbation models which will offer insight into the potential mechanisms of target gene regulation.

Finally, genome-wide mutation data from cancer patients will be interrogated in order to identify any disease association and clinical relevance.


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