Understanding the mechanisms that suppress the transcription of the non-coding genome

The decoding of our genome through the process of gene transcription ultimately dictates the form and activity of the cells in our body. However, for this to proceed correctly, our genome needs to be spatially organised in a correct and appropriate manner. To maintain this spatial organisation, small pieces of DNA known as transposons need to be kept inactive and our cells have several machines that are designed to keep the activity of these transposons in check. Failure to inactivate transposons can cause chaotic consequences for the spatial wiring of our genome and result in changes to cellular identity. We recently identified a new component of these machines known as ZMYM2 which plays an important role in our cells, allowing them to maintain their identity. Disruption of ZMYM2 function leads to genetically inherited kidney disorders and can also lead to cancer when combined with a different protein. Little is known about how this protein functions at the molecular level and here we will fill this knowledge gap. Specifically we will study how ZMYM2 affects the folding of the genome and the recruitment of machines that function to silence retrotransposons. We will also study the phenomenon of "phase separation" in ZMYM2 function. Phase separation relates to when molecules become associated in a liquid-like state that helps with compartmentalisation of cellular processes. Our findings will be important for understanding how cell states are maintained through the suppression of retrotransposon activity.

The mammalian nucleus is a highly ordered entity, where chromatin folding ultimately determines the gene expression profiles. It is therefore vitally important that looping interactions between enhancers and silencers to the correct promoter regions are maintained. Disruption of retrotransposon regulation can disturb this ordered 3D environment by rewiring connections between distal regulatory elements and coding genes. Several repressive complexes have therefore evolved to suppress the transcription and activity of the multitude of retrotransposable elements in our genomes. We and others recently identified the zinc finger protein ZMYM2 as a component of these repressive complexes. ZMYM2 is an important player in maintaining cell fate and has been shown to operate in the control of many different stem cell transitions. Heterozygous loss occurs in congenital anomalies of the kidney and urinary tract (CAKUT) and fusions to FGFR1 drive myeloproliferative disease. In this project we will provide mechanistic insights into the role of ZMYM2 in repressive complexes in the context of suppression of transcription of retrotransposable elements of the non-coding genome. Moreover, our work will uncover the role of phase separation in ZMYM2 activity with a focus on compartmentalisation and potential links to the correct 3D wiring of the genome and the concentration of repressive factors. Our findings will therefore have broader impacts on our understanding of the role of phase separation in transcriptional repression and therefore have the potential to impact more widely across multiple biological systems. Finally, our studies will be done in the context of embryonic stem cell differentiation systems and will examine whether phase separation and its impact on transcriptional repression plays a role in the transitions between and maintenance of cell states.