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11 janvier 2019: 1 événement

  • Département Biologie des Génomes

    Vendredi 11 janvier 11:00-12:00 - Pierre Therizols - Institut Jean-Bernard – Hôpital St. Louis

    Dual role of the histone variant H3.3 in embryonic stem cells

    Résumé : The 3D organisation of the chromatin has emerged as an important contributor to genome regulation. Nuclear periphery and pericentromeric centromeric clusters are essential landmarks that contribute to the compartmentalisation of heterochromatin and directly regulates important processes such as transcription or DNA repair.
    Several epigenetic transitions occur during early embryogenesis. Between the morula and blastula stages, parental DNA methylation is erased. This hypomethylated phase leads to a massive reorganisation of DNA repeat-associated heterochromatin. Later, upon embryo implantation, nuclear periphery associated heterochromatin is reorganised, 1,600 genes gain or lose association with the nuclear envelope upon transcriptional activation or repression.
    In this presentation, we identify the histone variant H3.3 as an important factor for the nuclear organisation in embryonic stem cells (ESCs). H3.3 is a histone H3 variant playing a dual role by regulating both euchromatin and heterochromatin. H3.3 is essential for early development, but its exact role remains elusive.
    In the first part, we show that H3.3 is an important factor for heterochromatin reorganisation in ground-state ESCs. Upon DNA demethylation, we observe a clustering of pericentromeric heterochromatin. This clustering correlates with the recruitment of H3.3 and its chaperone Daxx and we demonstrate that their recruitment to major-satellite is sufficient to mediate pericentric heterochromatin clustering. Interestingly, in Daxx knock-out cell lines pericentromeric heterochromatin fails to cluster properly and peripheral heterochromatin is lost. These heterochromatin defects lead to severe growth defect after few days. Altogether, our results suggest Daxx and H3.3 maintain heterochromatin homeostasis in absence of DNA methylation.
    In the second part, we highlight another role for H3.3 during ESCs differentiation. We find a strong correlation between lamina-associated domains repositioning and H3.3 deposition or depletion. By using TALE mediated epigenome editing, we observe that H3.3 chaperone recruitment is sufficient to decondense the Nrp1 gene and to relocate it away from the nuclear periphery.
    Contact : Daan Noordermeer <daan.noordermeer>

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    En savoir plus : Département Biologie des Génomes