QBI Seminar: 'Epigenetic Determination of Biological Robustness: Perfecting Hindgut-to-Motor Neuron Transdifferentiation'
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- Dr Steven Zuryn, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Strasbourg
Title: 'Epigenetic Determination of Biological Robustness: Perfecting Hindgut-to-Motor Neuron Transdifferentiation'
Abstract:
'Life is constantly faced with variation, be it genetic, stochastic, or environmental. Despite this, developmental patterning systems and cellular functions can operate with astonishing precision and reproducibility. The property of generating invariant outcomes, despite external or internal noise, is called robustness. Interest in this property has increased not only because of its importance in understanding system behaviour and evolution, but also because of its implications in complex human disease. By studying an extremely robust neurogenesis event in Caenorhabditis elegans – the transdifferentiation (Td) of a hindgut cell (called Y) into a motor neuron (called PDA) – we found that dynamic regulation of histone methylation states determines this precision. The postmitotic Y cell forms a section of the rectal tube that stereotypically disengages and changes into PDA 100% of the time (n > 2, 209 animals). Through powerful and unbiased forward genetic screens, we uncovered that jmjd-3.1 (Jmjd3/KDM6B), a conserved histone H3 lysine 27 (H3K27) demethylase, as well as the Set1 complex (H3K4 methyltransferase), acted cell-autonomously to reinforce progression through different phases of Td. This is elicited through sequential and partitioned epigenetic activities mediated by active degradation and phase-specific interactions with transcription factors. Importantly, these epigenetic activities are especially critical for a precise outcome under stressful conditions, as demonstrated through exposure to a diverse range of environmental insults. Together, this work has raised the intriguing possibility that epigenome health, set by active enzymatic regulation, protects biological output from variation. I will discuss how I intend to uncover key epigenetic pathways that insulate neural physiology from genetic stochasticity, environmental stress, and perhaps most intriguingly, endogenous stress caused by the types of cellular dysfunction that are associated with aging and neurodegenerative diseases.'
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