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Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis -acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis -acting variants generally exhibit additive inheritance, while those linked to trans -acting variants are most often dominantly inherited. Cis -acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states. “Variation in the noncoding regulatory sequences in the genome plays important roles in human disease and evolution. Here, the authors use F1 mouse hybrids to shed light on the regulatory mechanisms mediating transcription factor binding, chromatin state and gene expression in mammalian cells.”

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcγRIIb is an inhibitory Fc receptor with a critical role in immune regulation. Mouse data suggest that FcγRIIb deficiency increases susceptibility to autoimmune disease but protects against infection. We show that a SNP in human FCGR2B that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians. The minor allele of this SNP is more common in Southeast Asians and Africans, populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56; P = 7.1 x 10⁻⁵). This protective effect against malaria may contribute to the higher frequency of this SNP and hence, SLE in Africans and Southeast Asians.

Objective To optimise a strategy for identifying gene expression signatures differentiating systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis that provide insight into disease pathogenesis and identify biomarkers. Methods 44 vasculitis patients, 13 SLE patients and 25 age and sex-matched controls were enrolled. CD4 and CD8 T cells, B cells, monocytes and neutrophils were isolated from each patient and, together with unseparated peripheral blood mononuclear cells (PBMC), were hybridised to spotted oligonucleotide microarrays. Results Using expression data obtained from purified cells a substantial number of differentially expressed genes were identified that were not detectable in the analysis of PBMC. Analysis of purified T cells identified a SLE-associated, CD4 T-cell signature consistent with type 1 interferon signalling driving the generation and survival of tissue homing T cells and thereby contributing to disease pathogenesis. Moreover, hierarchical clustering using expression data from purified monocytes provided significantly improved discrimination between the patient groups than that obtained using PBMC data, presumably because the differentially expressed genes reflect genuine differences in processes underlying disease pathogenesis. Conclusion Analysis of leucocyte subsets enabled the identification of gene signatures of both pathogenic relevance and with better disease discrimination than those identified in PBMC. This approach thus provides substantial advantages in the search for diagnostic and prognostic biomarkers in autoimmune disease.

Follicular helper T (T FH ) cells provide survival and selection signals to germinal center B cells. Here, Carola Vinuesa and colleagues describe a regulatory T cell subset that co-opts the differentiation program of T FH cells and limits their numbers in vivo . Ablation of these T FH -like, T regulatory cells alters the number of antigen-specific B cells suggesting regulatory T cells modulate germinal center responses. Follicular helper (T FH ) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T FH numbers maintains self tolerance. We describe a population of Foxp3 + Blimp-1 + CD4 + T cells constituting 10–25% of the CXCR5 high PD-1 high CD4 + T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T FR ) cells share phenotypic characteristics with T FH and conventional Foxp3 + regulatory T (T reg ) cells yet are distinct from both. Similar to T FH cells, T FR cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T FR cells originate from thymic-derived Foxp3 + precursors, not naive or T FH cells. T FR cells are suppressive in vitro and limit T FH cell and germinal center B cell numbers in vivo . In the absence of T FR cells, an outgrowth of non–antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T FH differentiation pathway is co-opted by T reg cells to control the germinal center response.

This study confirms the presence of a genetic component of the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis and genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis. Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a systemic small-vessel vasculitis comprising three clinical syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), 1 microscopic polyangiitis, and the Churg–Strauss syndrome. 2 ANCA-associated vasculitis commonly causes life-threatening kidney failure or pulmonary hemorrhage, has a fatality rate of 28% at 5 years, and causes substantial long-term morbidity in survivors. 3 Granulomatosis with polyangiitis and microscopic polyangiitis are the major clinical syndromes, both often featuring a pauci-immune necrotizing glomerulonephritis. Granulomatosis with polyangiitis is characterized by granulomatous inflammation of the respiratory tract and by autoantibodies against the neutrophil granule serine protease proteinase 3 in 66% of patients (considered . . .

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.

DNA base damage is a major source of oncogenic mutations 1 . Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation 2 . Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication 3 , 4 , we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts 5 . The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution. How strand-asymmetric processes such as replication and transcription interact with DNA damage to drive mechanisms of repair and mutagenesis is explored.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion 1 , 2 . Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes. Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity.

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous [CD8.sup.+] T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation--pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with [CD4.sup.+] T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.

Follicular helper ([T.sub.FH]) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of [T.sub.FH] numbers maintains self tolerance. We describe a population of [Foxp3.sup.+] [Blimp-1.sup.+] [CD4.sup.+] T cells constituting 10-25% of the CXCR5 high [PD-1.sup.high] [CD4.sup.+] T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T ([T.sub.FR]) cells share phenotypic characteristics with [T.sub.FH] and conventional [Foxp3.sup.+] regulatory T ([T.sub.reg]) cells yet are distinct from both. Similar to [T.sub.FH] cells, [T.sub.FR] cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, [T.sub.FR] cells originate from thymic-derived [Foxp3.sup.+] precursors, not naive or [T.sub.FH] cells. [T.sub.FR] cells are suppressive in vitro and limit [T.sub.FH] cell and germinal center B cell numbers in vivo. In the absence of [T.sub.FR] cells, an outgrowth of non--antigen-specific B cells in germinal centers leads to fewer antigen- specific cells. Thus, the [T.sub.FH] differentiation pathway is co-opted by [T.sub.reg] cells to control the germinal center response.