Current research

This project is a collaboration with Christina Schmidt from the Frezza lab. We are analysing the regulatory programs of FH-deficient kidney cells that Christina developed during her PhD. FH is a component of the TCA cycle, with mutations in FH leading to a specific hereditary form of kidney cancer. Given FH is integral to the metabolic process, cells that lack FH under-go a metabolic transformation. The Frezza lab have found that epigenetic changes such as pre- and post-translational modifications play an important role in the cellular transformation initiated by FH loss. In order to analyse on what level genes are regulated (and by which modifications), Christina produced a number of biological assays on the FH-deficient cell-line. Given the complexity of disentangling the regulatory programs we developed R and python based software to analyse on which level each gene is regulated. We do this in a semi-supervised manner, coupling biological knowledge of regulatory programs with the unbiased integrative power of variational-autoencoders. This work has been presented at Vizbi 2021 and we will be releasing a paper soon. We are working on extending the model to publicly available data in TCGA and CPTAC. Given our method is amenable to small datasets we are investigating the capacity of our model to determine regulatory patterns in underrepresented populations in TCGA.

This project is a collaboration with Stefan Thor, and my main lab, with Mikael Boden. Stefan and his lab developed a comprehensive transcriptome dataset that spans across the anterior-posterior (A-P) developmental axis in mice. A key feature of organisms with a central nervous system, in particular those with a distinct brain and spinal cord, is the distinctive overgrowth of the brain (the anterior region). Human’s, mice, and flies all belong to this category (bilateria), however, the amount of cells and complexity of the brain regions increases with the complexity of the animal. How does the brain expand? How are specific cell types generated at just the right time during development? And what distinguishes different brain regions, such as the forebrain, midbrain and hindbrain? It is known that epigenetics (dynamic changes that can determine which genes will be expressed) plays an integral role in controlling this system. One particular protein, PRC2, which applies an epigenetic mark (H3K27me3) that acts to repress (“turn off”) genes is of particular interest as it selectively applies H3K27me3 during development. We seek to increase the understanding of PRC2’s tissue specific control during embryonic development by 1) developing a comprehensive transcriptome dataset of a wild-type, and also knock-out of PRC2 (by knocking out a key gene Eed). Given we are testing so many different conditions there were too many pairwise comparisons for correlation based analyses. To overcome this, we used a variational-autoencoder to build a generative model of the PRC2 landscape for each gene. This landscape was used to understand how genes express, and are regulated across mouse brain development. We will be releasing our paper on this soon.