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The epigenetic states and associated chromatin dynamics underlying the initiation and maintenance of memory and effector CD8 + T cells are poorly understood. Pace et al. found that mice lacking the histone H3 lysine 9 methyltransferase Suv39h1 had markedly reduced antigen-specific effector CD8 + T cell responses to Listeria monocytogenes infection (see the Perspective by Henning et al. ). Instead, CD8 + T cells in these mice were enriched for genes associated with naïve and memory signatures and showed enhanced memory potential and increased survival capacity. Thus, Suv39h1 marks chromatin through H3K9me3 deposition and silences memory and stem cell programs during the terminal differentiation of effector CD8 + T cells. Science , this issue p. 177 ; see also p. 163 Suv39h1 silences stem/memory gene expression during effector CD8 + T cell differentiation. After priming, naïve CD8 + T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expression programs. We explored the role of gene silencing by the histone methyltransferase Suv39h1. In murine CD8 + T cells activated after Listeria monocytogenes infection, Suv39h1-dependent trimethylation of histone H3 lysine 9 controls the expression of a set of stem cell–related memory genes. Single-cell RNA sequencing revealed a defect in silencing of stem/memory genes selectively in Suv39h1 -defective T cell effectors. As a result, Suv39h1 -defective CD8 + T cells show sustained survival and increased long-term memory reprogramming capacity. Thus, Suv39h1 plays a critical role in marking chromatin to silence stem/memory genes during CD8 + T effector terminal differentiation.

The eukaryotic genome is replicated according to a specific spatio‐temporal programme. However, little is known about both its molecular control and biological significance. Here, we identify mouse Rif1 as a key player in the regulation of DNA replication timing. We show that Rif1 deficiency in primary cells results in an unprecedented global alteration of the temporal order of replication. This effect takes place already in the first S‐phase after Rif1 deletion and is neither accompanied by alterations in the transcriptional landscape nor by major changes in the biochemical identity of constitutive heterochromatin. In addition, Rif1 deficiency leads to both defective G1/S transition and chromatin re‐organization after DNA replication. Together, these data offer a novel insight into the global regulation and biological significance of the replication‐timing programme in mammalian cells. Rif1 deficiency profoundly alters the spatio‐temporal organization of replication in mouse cells, identifying Rif1 as the first global regulator of the mammalian replication‐timing programme.

Chromatin states and 3D architecture have been used as proxy to identify replication initiation zones (IZs) in mammalian cells, yet their functional interconnections remain a puzzle. Here, to dissect these relationships, we focus on the histone H3.3 chaperone HIRA recently implicated in early initiation zone (IZ) definition. We monitor 3D organisation, chromatin accessibility and histone post-translational modifications (PTMs) in wild-type and HIRA knock-out cells in parallel with early replication initiation. In the absence of HIRA, compartment A loses H3.3 enrichment and gains accessibility without changes in associated histone post-translational modifications (PTMs). Furthermore, impaired early firing at HIRA-dependent IZs does not correspond to changes in chromatin accessibility or patterns of histone H3 PTMs. Additionally, a small subset of early IZs initially in compartment A switch to B and lose early initiation in the absence of HIRA. Critically, HIRA complementation restores these early IZ, and H3.3 variant enrichment, without substantial compartment reversal. Thus, while HIRA contributes to compartment A features, its role in regulating early replication initiation can be uncoupled from accessibility, histone marks and compartment organisation. Karagyozova at al. reveal that the histone H3.3 chaperone HIRA impacts higher-order spatial arrangement of chromatin, independently from its role in regulating early replication, providing a model to disentangle long-standing correlations between early replication, accessibility, typical histone marks and A compartment.

DNA replication is a challenge for the faithful transmission of parental information to daughter cells, as both DNA and chromatin organization must be duplicated. Replication stress further complicates the safeguard of epigenome integrity. Here, we investigate the transmission of the histone variants H3.3 and H3.1 during replication. We follow their distribution relative to replication timing, first in the genome and, second, in 3D using super-resolution microscopy. We find that H3.3 and H3.1 mark early- and late-replicating chromatin, respectively. In the nucleus, H3.3 forms domains, which decrease in density throughout replication, while H3.1 domains increase in density. Hydroxyurea impairs local recycling of parental histones at replication sites. Similarly, depleting the histone chaperone ASF1 affects recycling, leading to an impaired histone variant landscape. We discuss how faithful transmission of histone variants involves ASF1 and can be impacted by replication stress, with ensuing consequences for cell fate and tumorigenesis. Epigenetic modifications are a key contributor to cell identity, and their propagation is crucial for proper development. Here the authors use a super-resolution microscopy approach to reveal how histone variants are faithfully transmitted during genome duplication, and reveal an important role for the histone chaperone ASF1 in the redistribution of parental histones.

Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity. Understanding CD8 + T cell response to immune checkpoint blockade at the molecular level is important for the design of more efficient cancer immune therapies. Authors show here that the histone lysine methyltransferase Suv39h1 controls the transcriptional programs that determine the functionality of CD8 + T cells and Suv39h1 inhibition may potentiate anti-PD-1 therapy of melanomas.

In mammals, CENP-A, a histone H3 variant found in the centromeric chromatin, is critical for faithful chromosome segregation and genome integrity maintenance through cell divisions. Specifically, it has dual functions, enabling to define epigenetically the centromere position and providing the foundation for building up the kinetochore. Regulation of its dynamics of synthesis and deposition ensures to propagate proper centromeres on each chromosome across mitosis and meiosis. However, CENP-A overexpression is a feature identified in many cancers. Importantly, high levels of CENP-A lead to its mislocalization outside the centromere. Recent studies in mammals have begun to uncover how CENP-A overexpression can affect genome integrity, reprogram cell fate and impact 3D nuclear organization in cancer. Here, we summarize the mechanisms that orchestrate CENP-A regulation. Then we review how, beyond its centromeric function, CENP-A overexpression is linked to cancer state in mammalian cells, with a focus on the perturbations that ensue at the level of chromatin organization. Finally, we review the clinical interest for CENP-A in cancer treatment.

The 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 HP1α sumoylation both in vitro and in vivo . The region responsible for promoting HP1α 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 HP1α 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. The Suv39h histone methyltransferases promote trimethylation of histone H3 on lysine 9 (H3K9me3). Here, in the Suv39h1 paralog, the authors identify an enhancer of HP1a sumoylation activity that impacts heterochromatin.

During development and throughout life, a variety of specialized cells must be generated to ensure the proper function of each tissue and organ. Chromatin plays a key role in determining cellular state, whether totipotent, pluripotent, multipotent, or differentiated. We highlight chromatin dynamics involved in the generation of pluripotent stem cells as well as their influence on cell fate decision and reprogramming. We focus on the capacity of histone variants, chaperones, modifications, and heterochromatin factors to influence cell identity and its plasticity. Recent technological advances have provided tools to elucidate the underlying chromatin dynamics for a better understanding of normal development and pathological conditions, with avenues for potential therapeutic application.

Genome and epigenome integrity in eukaryotes depends on the proper coupling of histone deposition with DNA synthesis. This process relies on the evolutionary conserved histone chaperone CAF-1 for which the links between structure and functions are still a puzzle. While studies of the Saccharomyces cerevisiae CAF-1 complex enabled to propose a model for the histone deposition mechanism, we still lack a framework to demonstrate its generality and in particular, how its interaction with the polymerase accessory factor PCNA is operating. Here, we reconstituted a complete Sp CAF-1 from fission yeast. We characterized its dynamic structure using NMR, SAXS and molecular modeling together with in vitro and in vivo functional studies on rationally designed interaction mutants. Importantly, we identify the unfolded nature of the acidic domain which folds up when binding to histones. We also show how the long KER helix mediates DNA binding and stimulates Sp CAF-1 association with PCNA. Our study highlights how the organization of CAF-1 comprising both disordered regions and folded modules enables the dynamics of multiple interactions to promote synthesis-coupled histone deposition essential for its DNA replication, heterochromatin maintenance, and genome stability functions.

SUMOylation targets HP1α to pericentric heterochromatin, but the enzyme responsible for removing the SUMO molecule from HP1α has not been determined. SENP7 is now identified as the factor that deconjugates SUMO, promoting retention of HP1α at these domains. SUMOylation promotes targeting of HP1α to pericentric heterochromatin. Here we identify the SUMO-specific protease SENP7 in mouse as a maintenance factor for HP1α accumulation at this location. SENP7 interacts directly with HP1α, localizes at HP1-enriched pericentric domains and can deconjugate SUMOylated HP1α in vivo . Depletion of SENP7 delocalizes HP1α from pericentric heterochromatin without affecting H3K9me3 levels. We propose that following targeting of HP1α, a subsequent deSUMOylation event enables HP1α retention at these domains.