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Recent studies have elucidated cell-lineage-specific three-dimensional genome organization; however, how such specific architecture is established or maintained is unclear. We hypothesized that lineage-defining transcription factors maintain cell identity via global control of genome organization. These factors bind many genomic sites outside of the genes that they directly regulate and thus are potentially implicated in three-dimensional genome organization. Using chromosome-conformation-capture techniques, we show that the transcription factor Paired box 5 (Pax5) is critical for the establishment and maintenance of the global lineage-specific architecture of B cells. Pax5 was found to supervise genome architecture throughout B cell differentiation, until the plasmablast stage, in which Pax5 is naturally silenced and B cell–specific genome structure is lost. Crucially, Pax5 did not rely on ongoing transcription to organize the genome. These results implicate sequence-specific DNA-binding proteins in global genome organization to establish and maintain lineage fidelity. The transcription factor Pax5 enforces B cell identity. Nutt, Allan and colleagues show that Pax5 is needed to establish and maintain the three-dimensional genome organization of B cells throughout their lineage development.

The functions of individual dendritic cell subsets in the skin are unclear. Heath and colleagues now show that langerin-positive CD103 + dermal dendritic cells are the main migratory subtype able to cross-present antigen. Skin-derived dendritic cells (DCs) include Langerhans cells, classical dermal DCs and a langerin-positive CD103 + dermal subset. We examined their involvement in the presentation of skin-associated viral and self antigens. Only the CD103 + subset efficiently presented antigens of herpes simplex virus type 1 to naive CD8 + T cells, although all subsets presented these antigens to CD4 + T cells. This showed that CD103 + DCs were the migratory subset most efficient at processing viral antigens into the major histocompatibility complex class I pathway, potentially through cross-presentation. This was supported by data showing only CD103 + DCs efficiently cross-presented skin-derived self antigens. This indicates CD103 + DCs are the main migratory subtype able to cross-present viral and self antigens, which identifies another level of specialization for skin DCs.

Each type of cell in the immune system performs critical functions to protect the body and maintain health. In order to fulfil these roles some immune cells rely on unique processes, including antigen receptor loci recombination, clonal expansion or the contortion of their nuclei. In turn, each of these processes relies on, or poses unique challenges to, a genome organized in three dimensions. Here, we explore the current understanding of the importance of 3D genome organization in the function and development of a healthy immune system.Some immune cells undergo processes that pose unique challenges to the 3D organization of their genomes. These include antigen receptor rearrangement, clonal expansion and the contortion of their nuclei. Here, Allan and colleagues discuss the latest insights into these processes from a structural genomics perspective.

Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of dCas9-based activation systems. To counter this, we create an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). We show that TETact demethylation-coupled activation is able to induce transcription of suppressed genes, both individually and simultaneously in cells, and has utility across a number of cell types. Furthermore, we show that TETact can effectively reactivate embryonic haemoglobin genes in non-erythroid cells. We anticipate that TETact will expand the existing CRISPR toolbox and be valuable for functional studies, genetic screens and potential therapeutics. Stably silenced genes with methylated CpG at the promoter are refractory to current CRISPR activation systems. Here the authors create a more robust activation system, TETact that recruits DNA-demethylating TET1 with transcriptional activators.

Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in chromatin architecture orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analyzed chromatin accessibility, chromosome conformation and gene expression in activated human T cells. T cell activation was characterized by widespread changes in chromatin accessibility and interactions that were shared between activated CD4 + and CD8 + T cells, and with the formation of active regulatory regions associated with transcription factors relevant to T cell biology. Chromatin interactions that increased and decreased were coupled, respectively, with up- and down-regulation of corresponding target genes. Furthermore, activation was associated with disruption of long-range chromatin interactions and with partitioning of topologically associating domains (TADs) and remodelling of their TAD boundaries. Newly formed/strengthened TAD boundaries were associated with higher nucleosome occupancy and lower accessibility, linking changes in lower and higher order chromatin architecture. T cell activation exemplifies coordinate multi-level remodelling of chromatin underlying gene transcription.

During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, although it has been proposed to occur during DNA synthesis or after mitosis. Here, we elucidate the chromosome conformational changes in B lymphocytes as they differentiate and expand from a naive, quiescent state into antibody secreting plasma cells. We find gene-regulatory chromosome reorganization in late G1 phase before the first division, and that this configuration is remarkably stable as the cells massively and rapidly clonally expand. A second wave of conformational change occurs as cells terminally differentiate into plasma cells, coincident with increased time in G1 phase. These results provide further explanation for how lymphocyte fate is imprinted prior to the first division. They also suggest that chromosome reconfiguration occurs prior to DNA replication and mitosis, and is linked to a gene expression program that controls the differentiation process required for the generation of immunity. During differentiation, chromosome conformation is remodelled to support lineage-specific transcriptional programs. Here, the authors characterise chromosome conformational changes in B lymphocytes as they differentiate into plasma cells, and provide evidence that chromosome reconfiguration occurs prior to DNA replication and mitosis and guides gene expression that controls differentiation.

In the two decades since the invention of laser-based super resolution microscopy this family of technologies has revolutionised the way life is viewed and understood. Its unparalleled resolution, speed, and accessibility makes super resolution imaging particularly useful in examining the highly complex and dynamic immune system. Here we introduce the super resolution technologies and studies that have already fundamentally changed our understanding of a number of central immunological processes and highlight other immunological puzzles only addressable in super resolution.

The Microrchidia (MORC) family of chromatin-remodelling ATPases is pivotal in forming higher-order chromatin structures that suppress transcription. The exact mechanisms of MORC-induced chromatin remodelling have been elusive. Here, we report an in vitro reconstitution of full-length MORC2, the most commonly mutated MORC member, linked to various cancers and neurological disorders. MORC2 possesses multiple DNA-binding sites that undergo structural rearrangement upon DNA binding. MORC2 locks onto the DNA using its C-terminal domain (CTD) and acts as a clamp. A conserved phosphate-interacting motif within the CTD was found to regulate ATP hydrolysis and cooperative DNA binding. Importantly, MORC2 mediates chromatin remodelling via ATP hydrolysis-dependent DNA compaction in vitro, regulated by the phosphorylation state of its CTD. These findings position MORC2 CTD phosphorylation as a critical regulator of chromatin remodelling and a promising therapeutic target. MORC2, a chromatin remodeler involved in epigenetic silencing and DNA repair, is linked to cancer and neurological disorders when dysregulated. Here, the authors show that MORC2 binds DNA at multiple sites, clamps onto it, and induces compaction, a process regulated by its phosphorylation.

It has been proposed that interactions between mammalian chromosomes, or transchromosomal interactions (also known as kissing chromosomes), regulate gene expression and cell fate determination. Here we aimed to identify novel transchromosomal interactions in immune cells by high-resolution genome-wide chromosome conformation capture. Although we readily identified stable interactions in cis, and also between centromeres and telomeres on different chromosomes, surprisingly we identified no gene regulatory transchromosomal interactions in either mouse or human cells, including previously described interactions. We suggest that advances in the chromosome conformation capture technique and the unbiased nature of this approach allow more reliable capture of interactions between chromosomes than previous methods. Overall our findings suggest that stable transchromosomal interactions that regulate gene expression are not present in mammalian immune cells and that lineage identity is governed by cis, not trans chromosomal interactions.

Aging inevitably leads to reduced immune function, leaving the elderly more susceptible to infections, less able to respond to pathogen challenges, and less responsive to preventative vaccinations. No cell type is exempt from the ravages of age, and extensive studies have found age‐related alterations in the frequencies and functions of both stem and progenitor cells, as well as effector cells of both the innate and adaptive immune systems. The intrinsic functional reduction in immune competence is also associated with low‐grade chronic inflammation, termed “inflamm‐aging,” which further perpetuates immune dysfunction. While many of these age‐related cellular changes are well characterized, understanding the molecular changes that underpin the functional decline has proven more difficult. Changes in chromatin are increasingly appreciated as a causative mechanism of cellular and organismal aging across species. These changes include increased genomic instability through loss of heterochromatin and increased DNA damage, telomere attrition, and epigenetic alterations. In this review, we discuss the connections between chromatin, immunocompetence, and the loss of function associated with mammalian immune aging. Through understanding the molecular events which underpin the phenotypic changes observed in the aged immune system, it is hoped that the aged immune system can be restored to provide youthful immunity once more.