Neuroepigenetics

During the development of the mammalian brain, immature neurons undergo a series of complex morphological and functional transitions to become mature neurons integrated into brain circuitry. These processes take place during embryogenesis and early postnatal life, and once neurons have matured, they are typically not replaced over the course of an organism’s lifetime. The chromatin landscape undergoes dramatic changes during neuronal maturation, including dynamic changes in chromatin 3D architecture and epigenetic modifications that control developmental gene expression programs. My laboratory studies how epigenetic mechanisms control neuronal identity and function throughout life: from setting the pace of the developmental progression during maturation to the maintenance of neuronal gene expression and function in adulthood and ageing. Specifically, we focus on two projects: 1. Histone bivalency in developing and adult neurons. We recently showed that histone bivalency, the colocalization of activating and repressive histone modifications, regulates the timing of gene expression programs during neuronal maturation. Our studies on the cerebellum revealed that if bivalency is perturbed, developing neurons skip glial-guided migration, an essential step in cerebellar cortex formation, and instead undergo premature maturation. As the next step, we are identifying novel bivalency regulators and exploring how bivalency is regulated in mouse and human neurons. 2. Chromatin dynamics in developing and ageing neurons. Changes in the epigenetic landscape and chromatin interactions that occur during neuronal maturation establish the transcriptional programs that regulate neuronal function. Our unpublished work has revealed a striking redistribution of the repressive histone modification H3K27me3 during neuronal maturation. We are currently studying how global and local changes in H3K27me3 control chromatin interactions, gene expression, and neuronal identity during neuronal maturation, adulthood, and ageing. These studies are expected to yield insight into the fundamental mechanisms that regulate chromatin architecture and gene expression in the developing, adult, and ageing brain.

This project aims to investigate how epigenetic mechanisms, specifically histone modifications, control gene expression during neuronal development and maturation. We recently discovered that histone bivalency, the simultaneous presence of two histone modifications with opposing functions, controls the timing of gene expression during the maturation of cerebellar neurons. In the proposed studies, we will examine the mechanisms and function of histone bivalency in the adult brain, as well as the species-specific differences in bivalency during mouse and human neuronal development. The research also aims to uncover the molecular mechanisms underlying neurodevelopmental diseases associated with mutations in EZH1, a key enzyme involved in the regulation of bivalent domains. This project will provide fundamental insights into the chromatin mechanisms of brain development and function, with potential implications for understanding and treating neurodevelopmental disorders.

How do neurons maintain their function throughout life? Neurons are born early in development and are not regenerated during an individual’s lifetime. Therefore, after maturation, our neurons must remain functional throughout life, which in humans can be up to a hundred years of more. The goal of my ERC Starting Grant 2024 proposal EpiNeuroLife was to uncover how the formation of the epigenetic landscape during neuronal maturation contributes to the maintenance of neuronal gene expression and function during adulthood and ageing. My preliminary studies show that developing neurons in the mouse cerebellum accumulate extremely high levels of the repressive histone modification H3K27me3 during maturation, which I hypothesise is critical for regulating chromatin compaction and neuronal gene expression later in life. In MOB3ERC113, I will generate supporting data for my ERC application to uncover the mechanisms of H3K27me3 deposition in neurons.