Biomedical research institute
     
    You are here: Home / Institute / News / Sperm chromatin reorganization is controlled by SLY

    Sperm chromatin reorganization is controlled by SLY

    •  
    A study by Julie Cocquet and colleagues, Daniel Vaiman team

    FigureSperm differentiation requires a specific genetic and epigenetic program at the end of which the vast majority of histones (the proteins associated with DNA) is replaced by another type of proteins responsible for the extreme compaction of spermatozoa DNA and nucleus, the protamines. The reorganization of the spermatozoa chromatin facilitates their movements and preserve the integrity of their genome until fecundation; it is also expected to have an impact on the programming of the future embryo. The study, led by Julie Cocquet (Genomics, Epigenetics and Reproductive Pathophysiology team) recently published in Cell Death & Differentiation, shows that SLY plays a key role in the reorganization of sperm chromatin during their differentiation.

    SLY is a protein specifically expressed in mouse spermatids; its absence leads to the deregulation of hundreds of genes during spermiogenesis, resulting in abnormal morphology, motility and nucleus compaction of the spermatozoa, and a male infertility. The underlying mechanism remained, to date, unknown. In a study published in the journal Cell Death & Differentiation, the team has demonstrated, by chromatin immunoprecipitation, that SLY binds to the promoter of numerous genes, many of which are involved in chromatin structure or remodeling, such as genes coding for histone H2A variants, or for the histone H3K79 methyl transferase DOT1L. In absence of SLY, DOT1L and the level of methylated H3K79 are decreased in spermatids; this leads to other changes in the histone ‘code’ of spermatids, such as a decrease in histone H4 acetylation, and an abnormal chromatin remodeling in spermatids characterized by a less efficient removal and replacement of nucleosomes. The spermatozoa resulting from this abnormal spermiogenesis present a higher proportion of histones, are abnormally shaped, their nucleus and DNA is less compact, and present a higher susceptibility to DNA damage. Finally, the team has shown that SLY interacts with the Ncor/SMRT complex, a known regulator gene expression, which could be at the basis of SLY effect. This work, via the characterization of SLY protein partners and gene targets, has led to the identification of novel actors of gene regulation and chromatin remodeling during mouse and potentially human sperm differentiation.

    photoIn addition to causing male infertility, abnormal chromatin remodeling and compaction could affect the development of the future embryo, when male infertility is overcome by assisted reproductive techniques such as In vitro fertilization (IVF) or intra-nuclear sperm injection (ICSI). It is therefore essential to identify and characterize the proteins involved in chromatin reorganization during spermiogenesis.

     

    Reference

    Moretti C, Serrentino ME, Ialy-Radio C, Delessard M, Soboleva TA, Tores F, Leduc M, Nitschké P, Drevet JR, Tremethick DJ, Vaiman D, Kocer A, Cocquet J. SLY regulates genes involved in chromatin remodeling and interacts with TBL1XR1 during sperm differentiation. Cell Death Differ. 2017 Jun;24(6):1029-1044. doi: 10.1038/cdd.2017.32. PMID:28475176

     

    Contact researcher

     

    Legends

    Figure: From Moretti et al. 2017. Model presenting the mechanism by which SLY controls gene expression and chromatin remodeling during sperm differentiation.
    In WT round spermatids (left panel), SLY (in blue) interacts with the SMRT/N-CoR complex and is located at the start of genes involved in gene regulation, chromatin regulation and the ubiquitin pathway. In particular, SLY directly controls the expression of genes coding for H2.A variants and of the H3K79 methyltransferase DOT1L. In elongating spermatids, there is a wave of H3K79 dimethylation (orange circles) and of histone H4 acetylation (green circles); those modifications are expected to be a prerequisite to the efficient removal of nucleosomes (light pink oval) and replacement by protamines (purple oval), a process which is required to achieve optimal compaction of the spermatozoa nucleus.
    When SLY is absent (right panel), X-encoded H2.A variants are upregulated and more incorporated in the spermatid chromatin, while DOT1L is downregulated. DOT1L downregulation leads to a decrease in dimethylated H3K79 and acetylated histone H4 in elongating spermatids. Alterations in the spermatid chromatin structure affect the replacement of nucleosomes by protamines and lead to a higher proportion of nucleosomes and a decreased proportion of protamines. As a result, Sly-deficient spermatozoa are abnormally shaped, less compact and present a higher susceptibility to DNA damage than WT spermatozoa.

    Cover: Immunodetection of DOT1L (in pink) at different stages of spermiogenesis. DAPI (in blue) stains the nucleus.