While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by ...tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene
knockout (KO) mutant
unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR
) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of
,
, and
genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Lymphopoiesis requires the activation of lineage-specific genes embedded in naive, inaccessible chromatin or in primed, accessible chromatin. The mechanisms responsible for de novo gain of chromatin ...accessibility, known as “pioneer” function, remain poorly defined. Here, we showed that the EBF1 C-terminal domain (CTD) is required for the regulation of a specific gene set involved in B cell fate decision and differentiation, independently of activation and repression functions. Using genome-wide analysis of DNaseI hypersensitivity and DNA methylation in multipotent Ebf1−/− progenitors and derivative EBF1wt- or EBF1ΔC-expressing cells, we found that the CTD promoted chromatin accessibility and DNA demethylation in previously naive chromatin. The CTD allowed EBF1 to bind at inaccessible genomic regions that offer limited co-occupancy by other transcription factors, whereas the CTD was dispensable for EBF1 binding at regions that are occupied by multiple transcription factors. Thus, the CTD enables EBF1 to confer permissive lineage-specific changes in progenitor chromatin landscape.
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•EBF1 induces chromatin accessibility and DNA demethylation in naive chromatin•C-terminal domain (CTD) of EBF1 is required for the regulation of a specific gene set•CTD-dependent genes are involved in B cell fate decision and differentiation•CTD enables EBF1 to access progenitor chromatin at sites with low TF co-occupancy
EBF1 is a key transcription factor for B cell programming in hematopoietic progenitors. Boller et al. show that EBF1 induces lineage-specific accessibility in progenitor chromatin. EBF1 requires its C-terminal domain to access naive chromatin at sites that lack co-occupancy with multiple transcription factors, thereby conferring “pioneer function” upon EBF1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The transcription factors EBF1 and Pax5 have been linked to activation of the B cell lineage program and irreversible loss of alternative lineage potential (commitment), respectively. Here we ...conditionally deleted Ebf1 in committed pro-B cells after transfer into alymphoid mice. We found that those cells converted into innate lymphoid cells (ILCs) and T cells with variable-diversity-joining (VDJ) rearrangements of loci encoding both B cell and T cell antigen receptors. As intermediates in lineage conversion, Ebf1-deficient CD19(+) cells expressing Pax5 and transcriptional regulators of the ILC and T cell fates were detectable. In particular, genes encoding the transcription factors Id2 and TCF-1 were bound and repressed by EBF1. Thus, both EBF1 and Pax5 are required for B lineage commitment by repressing distinct and common determinants of alternative cell fates.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Immune cells combating chronic infection express numerous ‘check point’ receptors in human patients.•Inhibition of these receptors restores the function of exhausted T cells in chronically infected ...humans and animals.•Initial case reports in humans suggest targeting checkpoint inhibitors in HBV, HCV, and HIV could repress viral loads.•Newly identified inhibitory receptors may synergize to induce exhaustion, and therefore multiple pathways could be targeted to facilitate immunity.
The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection. Blockade of these pathways influences more than simply T cell responses, and may provide new therapeutic options for chronically infected patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into the functions of Ebf1 at distinct stages of differentiation, we conditionally inactivated ...Ebf1. We found that Ebf1 is required for the proliferation, survival, and signaling of pro-B cells and peripheral B-cell subsets, including B1 cells and marginal zone B cells. The proliferation defect of Ebf1-deficient pro-B cells and the impaired expression of multiple cell cycle regulators are overcome by transformation with v-Abl. The survival defect of transformed Ebf1(fl/fl) pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-x(L). In mature B cells, Ebf1 deficiency interferes with signaling via the B-cell-activating factor receptor (BAFF-R)- and B-cell receptor (BCR)-dependent Akt pathways. Moreover, Ebf1 is required for germinal center formation and class switch recombination. Genome-wide analyses of Ebf1-mediated gene expression and chromatin binding indicate that Ebf1 regulates both common and distinct sets of genes in early and late stage B cells. By regulating important components of transcription factor and signaling networks, Ebf1 appears to be involved in the coordination of cell proliferation, survival, and differentiation at multiple stages of B lymphopoiesis.
Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that ...Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.
Satb1 and the closely related Satb2 proteins regulate gene expression and higher-order chromatin structure of multigene clusters in vivo. In examining the role of Satb proteins in murine embryonic ...stem (ES) cells, we find that Satb1(-/-) cells display an impaired differentiation potential and augmented expression of the pluripotency determinants Nanog, Klf4, and Tbx3. Metastable states of self-renewal and differentiation competence have been attributed to heterogeneity of ES cells in the expression of Nanog. Satb1(-/-) cultures have a higher proportion of Nanog(high) cells, and an increased potential to reprogram human B lymphocytes in cell fusion experiments. Moreover, Satb1-deficient ES cells show an increased expression of Satb2, and we find that forced Satb2 expression in wild-type ES cells antagonizes differentiation-associated silencing of Nanog and enhances the induction of NANOG in cell fusions with human B lymphocytes. An antagonistic function of Satb1 and Satb2 is also supported by the almost normal differentiation potential of Satb1(-/-)Satb2(-/-) ES cells. Taken together with the finding that both Satb1 and Satb2 bind the Nanog locus in vivo, our data suggest that the balance of Satb1 and Satb2 contributes to the plasticity of Nanog expression and ES cell pluripotency.
Satb1 and Satb2 have been recently described as regulators of embryonic stem (ES) cell pluripotency and as silencing factors in X chromosome inactivation. The influence of the pluripotency machinery ...on X chromosome inactivation and the lack of an X chromosome inactivation defect in Satb1−/− and Satb2−/− mice raise the question of whether or not Satb proteins are directly and/or redundantly involved in this process. Here, we analyzed X chromosome inactivation in fibroblastic cells that were derived from female Satb1−/−Satb2−/− embryos. By fluorescence in situ hybridization to visualize Xist RNA and by immunohistochemistry to detect H3K27me3 histone modifications, we found that female Satb1−/−Satb2−/− fibroblastic cells contain proper Barr bodies. Moreover, we did not detect an upregulation of X-linked genes, suggesting that Satb proteins are dispensable for X chromosome inactivation in mice.
► Satb1/Satb2 double deficiency is compatible with normal early embryonic development ► Female mice lacking Satb proteins undergo proper dosage compensation ► Female Satb1/Satb2-deficient somatic cells contain a silenced X chromosome ► Satb1/Satb2 expression does not correlate with competence for X inactivation
Agrelo et al. previously proposed that Satb family DNA-binding factors allow Xist RNA to initiate X inactivation. Nechanitzky et al. now find that Satb factors are not required for X inactivation and that their expression does not strictly correlate with cellular competence to initiate X inactivation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Resident macrophages orchestrate homeostatic, inflammatory, and reparative activities. It is appreciated that different tissues instruct specialized macrophage functions. However, individual tissues ...contain heterogeneous subpopulations, and how these subpopulations are related is unclear. We asked whether common transcriptional and functional elements could reveal an underlying framework across tissues. Using single-cell RNA sequencing and random forest modeling, we observed that four genes could predict three macrophage subsets that were present in murine heart, liver, lung, kidney, and brain. Parabiotic and genetic fate mapping studies revealed that these core markers predicted three unique life cycles across 17 tissues. TLF
(expressing TIMD4 and/or LYVE1 and/or FOLR2) macrophages were maintained through self-renewal with minimal monocyte input; CCR2
(TIMD4
LYVE1
FOLR2
) macrophages were almost entirely replaced by monocytes, and MHC-II
macrophages (TIMD4
LYVE1
FOLR2
CCR2
), while receiving modest monocyte contribution, were not continually replaced. Rather, monocyte-derived macrophages contributed to the resident macrophage population until they reached a defined upper limit after which they did not outcompete pre-existing resident macrophages. Developmentally, TLF
macrophages were first to emerge in the yolk sac and early fetal organs. Fate mapping studies in the mouse and human single-cell RNA sequencing indicated that TLF
macrophages originated from both yolk sac and fetal monocyte precursors. Furthermore, TLF
macrophages were the most transcriptionally conserved subset across mouse tissues and between mice and humans, despite organ- and species-specific transcriptional differences. Here, we define the existence of three murine macrophage subpopulations based on common life cycle properties and core gene signatures and provide a common starting point to understand tissue macrophage heterogeneity.
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