The methyltransferase Suv39h1 links the SUMO pathway to HP1a marking at pericentric heterochromatin

International audienceThe trimethylation of histone H3 on lysine 9 (H3K9me3) – a mark recognized by HP1 that depends on the Suv39h lysine methyltransferases (KMTs) – has provided a basis for the reader/writer model to explain HP1 accumulation at pericentric heterochromatin in mammals. Here, we identify the Suv39h1 paralog, as a unique enhancer of HP1a sumoylation both in vitro and in vivo. The region responsible for promoting HP1a sumoylation (aa1–167) is distinct from the KMT catalytic domain and mediates binding to Ubc9. Tethering the 1–167 domain of Suv39h1 to pericentric heterochromatin, but not mutants unable to bind Ubc9, accelerates the de novo targeting of HP1a to these domains. Our results establish an unexpected feature of Suv39h1, distinct from the KMT activity, with a major role for heterochromatin formation. We discuss how linking Suv39h1 to the SUMO pathway provides conceptual implications for our general view on nuclear domain organization and physiological functions

An epigenetic silencing pathway controlling T helper 2 cell lineage commitment

During immune responses, naive CD4 T cells differentiate into several T helper (T ) cell subsets under the control of lineage-specifying genes. These subsets (T 1, T 2 and T 17 cells and regulatory T cells) secrete distinct cytokines and are involved in protection against different types of infection. Epigenetic mechanisms are involved in the regulation of these developmental programs, and correlations have been drawn between the levels of particular epigenetic marks and the activity or silencing of specifying genes during differentiation. Nevertheless, the functional relevance of the epigenetic pathways involved in T cell subset differentiation and commitment is still unclear. Here we explore the role of the SUV39H1-H3K9me3-HP1α silencing pathway in the control of T 2 lineage stability. This pathway involves the histone methylase SUV39H1, which participates in the trimethylation of histone H3 on lysine 9 (H3K9me3), a modification that provides binding sites for heterochromatin protein 1α (HP1α) and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. We now propose that the SUV39H1-H3K9me3-HP1α pathway participates in maintaining the silencing of T 1 loci, ensuring T 2 lineage stability. In T 2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1α at the promoters of silenced T 1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient T 2 cells and HP1α-deficient T 2 cells, in contrast to wild-type cells, expressed T 1 genes when recultured under conditions that drive differentiation into T 1 cells. In a mouse model of T 2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards T 1 responses and decreased the lung pathology. These results establish a link between the SUV39H1-H3K9me3- HP1α pathway and the stability of T 2 cells, and they identify potential targets for therapeutic intervention in T 2-cell-mediated inflammatory diseases

HP1α guides neuronal fate by timing E2F-targeted genes silencing during terminal differentiation

A critical step of neuronal terminal differentiation is the permanent withdrawal from the cell cycle that requires the silencing of genes that drive mitosis. Here, we describe that the α isoform of the heterochromatin protein 1 (HP1) protein family exerts such silencing on several E2F-targeted genes. Among the different isoforms, HP1α levels progressively increase throughout differentiation and take over HP1γ binding on E2F sites in mature neurons. When overexpressed, only HP1α is able to ensure a timed repression of E2F genes. Specific inhibition of HP1α expression drives neuronal progenitors either towards death or cell cycle progression, yet preventing the expression of the neuronal marker microtubule-associated protein 2. Furthermore, we provide evidence that this mechanism occurs in cerebellar granule neurons in vivo, during the postnatal development of the cerebellum. Finally, our results suggest that E2F-targeted genes are packaged into higher-order chromatin structures in mature neurons relative to neuroblasts, likely reflecting a transition from a ‘repressed' versus ‘silenced' status of these genes. Together, these data present new epigenetic regulations orchestrated by HP1 isoforms, critical for permanent cell cycle exit during neuronal differentiation