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    • br Acknowledgments The breast cancer laboratory is supported

    2022-06-13


    Acknowledgments The breast cancer laboratory is supported by the Australian National Health and Medical Research Council (NHMRC) grants no. 1016701, no. 1024852, no. 1086727; NHMRC IRIISS; the Victorian State Government through VCA funding of the Victorian Breast Cancer Research Consortium and Operational Infrastructure Support; and the Australian Cancer Research Foundation. E.M.M. is supported by a National Breast Cancer Foundation Career Development Fellowship and J.E.V. by a NHMRC Australia Fellowship. We thank K. Hogg for critical reading of the manuscript and P. Maltezos for assistance with preparation of figures.
    Introduction T lymphocytes protect vertebrates against a wide variety of endogenous and exogenous dangers. Their efficacy comes at least in part from their ability to adapt their phenotype and function to the threat detected by the what he said of the innate immune system. Depending on the nature and strength of the signals delivered by these cells and the surrounding tissues, T lymphocytes mobilize different networks of transcription factors to induce distinct developmental programs that coordinate the acquisition of lineage-specific and danger-adapted phenotypes and functions (O’Shea and Paul, 2010, Wilson et al., 2009). This plasticity is best illustrated by naive CD4+ T cells, which are able to differentiate into multiple distinct effector populations. The transcription factors mobilized in response to environmental signals orchestrate a massive remodeling of the epigenetic landscape of T cells (Kanno et al., 2012, Wilson et al., 2009). These dynamic changes in chromatin composition and compaction are necessary for setting up and stabilizing gene expression programs and allowing their faithful transmission to the progeny. Indeed, interfering with the post-translational modifications of histones or with DNA methylation critically affects the differentiation and stability of effector and memory T cells (Allan et al., 2012, Wilson et al., 2009, Xiao et al., 2016, Young et al., 1994). In CD4+ T lymphocytes, epigenetic remodeling is largely coordinated by STAT proteins and by the master regulators specific to each lineage, such as T-bet and GATA-3 for, respectively, Th1 and Th2 cells (Kanno et al., 2012, O’Shea et al., 2011). These transcriptional regulators fine-tune the balance between T helper cell determination and plasticity by directing the deposition of permissive epigenetic marks at lineage-specific cis-regulatory elements and by targeting repressive epigenetic pathways to the loci associated with alternative fates (Kanno et al., 2012, O’Shea et al., 2011, Vahedi et al., 2012, Wilson et al., 2009). Trimethylation of histone H3 on lysine 9 (H3K9me3) has varied roles in the control of genome functions (Mozzetta et al., 2015). This epigenetic mark was first implicated in the scaffolding and function of constitutive heterochromatin (Lachner et al., 2001, Peters et al., 2001). H3K9me3 deposition at promoters of genes that encode developmental regulators is necessary to repress these loci and maintain embryonic stem cell pluripotency (Bilodeau et al., 2009). In adult cells, H3K9me3-dependent repression of gene expression in euchromatin and facultative heterochromatin is also important for defining and maintaining cell identity (Allan et al., 2012, Liu et al., 2015). However, the repertoires of loci and genomic elements that are targeted, as well as the molecular mechanisms at work, remain poorly characterized. H3K9me3 also accumulates on the body of active genes, where it might affect transcription elongation and alternative splicing (Saint-André et al., 2011, Vakoc et al., 2005). H3K9me3 is thus a versatile chromatin mark that has multiple, and at times potentially opposing, functions. Several lysine methyltransferases trimethylate H3K9. These include SUV39H1, SUV39H2, and SETDB1, all of which belong to the SUV39H family (Mozzetta et al., 2015). SUV39H1 and SUV39H2 were first identified as key components of constitutive heterochromatin (Peters et al., 2001, Peters et al., 2002), whereas SETDB1 was initially found to be involved in the dynamic repression of gene transcription at euchromatin and facultative heterochromatin (Schultz et al., 2002). SUV39H1 can also repress euchromatic gene expression through H3K9me3 deposition at promoters (Allan et al., 2012, Liu et al., 2015), whereas the maintenance of H3K9me3 at pericentromeric heterochromatin during DNA replication might depend on a stepwise process involving H3K9 mono- and trimethylation by SETDB1 and SUV39H1, respectively (Loyola et al., 2009). In embryonic stem cells, these two enzymes also collaborate to repress endogenous retroviruses (ERVs) (Bulut-Karslioglu et al., 2014). Because various cell types use these repeat elements as cis-regulatory modules to shape and control gene networks (Chuong et al., 2017), SETDB1 and SUV39H1 might therefore also control cell integrity through deposition of H3K9me3 at ERVs.