Réorganisation de l'épigénome associé à la spermiogénèse

Each spermatozoon not only transmits the paternal genome, but also epigenetic information, closely related to the genome structural organization, or “epigenome”. Despite its crucial involvement in embryonic development, epigenome reprogramming during germ cells post-meiotic differentiation, or spermiogenesis, is a very poorly known process. It involves a global chromatin restructuration, characterized by extraction of most histones and their replacement by sperm-specific proteins. Based on the study of post meiotic cells, this work shows an original dialogue between post-translational histone modifications, and the presence of new histone variants associated with pericentric heterochromatin. Epigenetic reprogramming of imprinting control regions is also analyzed. Moreover, new functions have been attributed to several chaperones, mainly HSP70.2, Npm3 and NAP1L4, which are involved in chromatin incorporation of histone variants and basic proteins during the late steps of spermiogenesis.Altogether, a coordinated action of several chromatin reorganization pathways leads to the setting of a new epigenome, which will be transmitted to the zygote.Chaque spermatozoïde transmet non seulement le génome paternel, mais également une information épigénétique, portée par l'organisation structurale du génome, ou épigénome. Malgré son importance lors du développement embryonnaire, peu de données décrivent l'épigénome transmis par le gamète mâle. Ce travail étudie la reprogrammation de l'épigénome lors de la différenciation post-méiotique des cellules germinales males, ou spermiogenèse. Ce processus implique une restructuration globale de la chromatine caractérisée par l'enlèvement de la majorité des histones, associées à l'ADN dans les cellules somatiques, et leur remplacement par des protéines nucléaires spécifiques du gamète male. Ce travail met en évidence dans les cellules post-méiotiques, un dialogue original entre les modifications post-traductionnelles des histones et la présence de nouveaux variants d'histones associés à l'hétérochromatine péricentrique. La reprogrammation épigénétique des régions de contrôle de l'empreinte parentale a également été analysée. De plus, de nouvelles fonctions ont été mises en évidence pour plusieurs protéines chaperones, notamment HSP70.2, Npm3 et NAP1L4, qui seraient impliquées dans l'incorporation de variants d'histones ou de protéines basiques spécifiques lors des étapes tardives de la spermiogenèse.Ainsi, l'action coordonnée de plusieurs voies de réorganisation de la chromatine participe à la mise en place de l'épigénome transmis par les spermatozoïdes

Histone deacetylases and their inhibition in Candida species

Fungi are generally benign members of the human mucosal flora or live as saprophytes in the environment. However, they can become pathogenic, leading to invasive and life threatening infections in vulnerable patients. These invasive fungal infections are regarded as a major public health problem on a similar scale to tuberculosis or malaria. Current treatment for these infections is based on only four available drug classes. This limited therapeutic arsenal and the emergence of drug-resistant strains are a matter of concern due to the growing number of patients to be treated, and new therapeutic strategies are urgently needed. Adaptation of fungi to drug pressure involves transcriptional regulation, in which chromatin dynamics and histone modifications play a major role. Histone deacetylases (HDACs) remove acetyl groups from histones and actively participate in controlling stress responses. HDAC inhibition has been shown to limit fungal development, virulence, biofilm formation and dissemination in the infected host, while also improving the efficacy of existing antifungal drugs towards Candida spp. In this article, we review the functional roles of HDACs and the biological effects of HDAC inhibitors on Candida spp., highlighting the correlations between their pathogenic effects in vitro and in vivo. We focus on how HDAC inhibitors could be used to treat invasive candidiasis while also reviewing recent developments in their clinical evaluation

Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis

Sporulation in Saccharomyces cerevisiae is a highly regulated process wherein a diploid cell gives rise to four haploid gametes. In this study we show that histone H4 Ser1 is phosphorylated (H4 S1ph) during sporulation, starting from mid-sporulation and persisting to germination, and is temporally distinct from earlier meiosis-linked H3 S10ph involved in chromosome condensation. A histone H4 S1A substitution mutant forms aberrant spores and has reduced sporulation efficiency. Deletion of sporulation-specific yeast Sps1, a member of the Ste20 family of kinases, nearly abolishes the sporulation-associated H4 S1ph modification. H4 S1ph may promote chromatin compaction, since deletion of SPS1 increases accessibility to antibody immunoprecipitation; furthermore, either deletion of Sps1 or an H4 S1A substitution results in increased DNA volume in nuclei within spores. We find H4 S1ph present during Drosophila melanogaster and mouse spermatogenesis, and similar to yeast, this modification extends late into sperm differentiation relative to H3 S10ph. Thus, H4 S1ph may be an evolutionarily ancient histone modification to mark the genome for gamete-associated packaging