Research Valeriya Malysheva

Abstract

Isoform expression is highly cell type-specific, drives cell fate trajectories, profoundly influences drug responses and its dysregulation is a cause of disease. Despite research traditionally focusing on alternative splicing, the use of alternative transcription start sites (TSSs) and termination sites (TTSs) accounts for the majority of transcriptional diversity in humans. Yet little is known about what governs alternative TSS and TTS isoform choice. Our preliminary data show chromatin organisation, via 3D isoform-enhancer interactions, likely plays a crucial role, but no in-depth research has been done. We hypothesise that chromatin organisation is a central coordinator of isoform choice. As the brain contains the widest isoform diversity it is ideal for addressing this question. I will use experimental methods including the chromatin organisation technology patented by Prof. Malysheva, which is the only method capable of detecting isoform-level 3D chromatin organisation interactions in rare cell populations at high resolution, as well as computational methods for integrative regulatory network inference to identify the drivers of isoform choice in the major cell types of the human frontal cortex. This project will reveal the ground rules of isoform choice, which, in the long run, will be a game-changer for understanding the role of isoforms in health and disease and shift the regulatory paradigm from gene-centric to isoform-centric.

Researcher(s)

• Promoter: Malysheva Valeriya
• Fellow: De Broeck Noémie

Research team(s)

• VIB CMN - Computational Neurobiology

Project type(s)

• Research Project

Abstract

Over the last decade, organoids emerged as an attractive middle ground between 2D cell cultures, which do not fully recapitulate the 3D environment and animal models, which pose technical and ethical limits. In particular, cerebral organoids are emerging as the next step in patient-derived in vitro models for both neurodevelopmental as well as neurodegenerative diseases. However, cerebral organoids have mostly been based on neuronal cells alone, while evidence increases that the role of non-neuronal types (microglia, astrocytes, endothelial cells) is critical in these conditions. Integration of these cell types will more closely mimic the in vivo cellular environment in health and disease and constitutes the major challenge of this project. The established neuroimmune organoid technology will find a wide range of applications as models for studying fundamental mechanisms underlying cellular biology and genetic pathophysiology as well as for efficient drug screening.

Researcher(s)

• Promoter: Sleegers Kristel
• Co-promoter: Jordanova Albena
• Co-promoter: Malysheva Valeriya
• Co-promoter: Mancuso Renzo
• Co-promoter: Weckhuysen Sarah

Research team(s)

• VIB CMN - Genetics of Alzheimer’s Disease

Project type(s)

• Research Project