Justine Renauld

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

ABSTRACT Genetic loss-of-function studies on development, cancer and somatic cell reprogramming have suggested that the group of macroH2A histone variants might function through stabilizing the differentiated state by a yet unknown mechanism. Here, we present results demonstrating that macroH2A variants have a major function in maintaining nuclear organization and heterochromatin architecture. Specifically, we find that a substantial amount of macroH2A is associated with heterochromatic repeat sequences. We further identify macroH2A on sites of interstitial heterochromatin decorated by histone H3 trimethylated on K9 (H3K9me3). Loss of macroH2A leads to major defects in nuclear organization, including reduced nuclear circularity, disruption of nucleoli and a global loss of dense heterochromatin. Domains formed by DNA repeat sequences are disorganized, expanded and fragmented, and mildly re-expressed when depleted of macroH2A. At the molecular level, we find that macroH2A is required for the interaction of repeat sequences with the nucleostructural protein lamin B1. Taken together, our results argue that a major function of macroH2A histone variants is to link nucleosome composition to higher-order chromatin architecture. Highlighted Article: MacroH2A links nucleosome composition to higher-order chromatin architecture, in part by mediating the interaction of heterochromatin repeats with the nuclear lamina.

MicroRNA-124 Regulates Cell Specification in the Cochlea through Modulation of Sfrp4/5.

The organ of Corti, the auditory organ of the mammalian inner ear, contains sensory hair cells and supporting cells that arise from a common sensory progenitor. The molecular bases allowing the specification of these progenitors remain elusive. In the present study, by combining microarray analyses with conditional deletion of Dicer in the developing inner ear, we identified that miR-124 controls cell fate in the developing organ of Corti. By targeting secreted frizzled-related protein 4 (Sfrp4) and Sfrp5, two inhibitors of the Wnt pathway, we showed that miR-124 controls the β-catenin-dependent and also the PCP-related non-canonical Wnt pathways that contribute to HC differentiation and polarization in the organ of Corti. Thus, our work emphasizes the importance of miR-124 as an epigenetic safeguard that fine-tunes the expression of genes critical for cell patterning during cochlear differentiation.

Spatio-temporal dynamics of β-tubulin isotypes during the development of the sensory auditory organ in rat.

Abstract There are different β-tubulin isoforms in microtubules of vertebrate tissues. However, their functional significance is still largely unknown. In the present study, we investigated the localization of five β-tubulin isotypes (β1–5) within the hearing organ during development in rat. By using confocal microscopy, we showed that with the exception of the β3-tubulin isoform that was specific to nerve fibres, all the different β-tubulin isoforms were mainly present in the supporting cells. Contrary to β1–4-tubulins, we also found that the β5-tubulin isoform appeared only at a key stage of the post-natal development in specific cell types (pillar cells and Deiters’ cells). By using transmission electron microscopy, we revealed further that this developmental stage coincided with the formation of two separate bundles of microtubules from a unique one in these supporting cells. Together, these results suggest that the β5-tubulin isoform might be involved in the generation of new microtubule bundles from a pre-existing one.