Allergic asthma is an inflammatory disease characterized by lung eosinophilia controlled by type 2 cytokines. Cysteine proteases are potent triggers of allergic inflammation by causing barrier ...disruption in lung epithelial cells inducing the elevation of interleukin-5 (IL-5) and IL-13 from natural helper (NH) cells, a member of ILC2s, which leads to lung eosinophilia. In this study, we found that basophils play a crucial role in NH cell-mediated eosinophilic inflammation induced by protease allergens. Conditional deletion of basophils caused a resolution of the papain-induced eosinophilia and mucus production. Resolution of eosinophilia was also observed in mice lacking IL-4 specifically in basophils, indicating that basophil-derived IL-4 enhanced expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in NH cells, thus attracting eosinophils. These results demonstrate that IL-4 from basophils has an important role in the NH-derived cytokine and chemokine expression, subsequently leading to protease allergen-induced airway inflammation.
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•Basophils are essential for protease allergen-induced airway responses•Basophil-derived IL-4 controls ILC2-mediated eosinophilic inflammation•IL-4 is necessary for the expression of CCL11, IL-9, and IL-13 from NH cells•Interaction of basophils and ILC2 controls the IL-33 mediated allergic responses
The Polycomb-group (PcG) repressive complex-1 (PRC1) forms microscopically visible clusters in nuclei; however, the impact of this cluster formation on transcriptional regulation and the underlying ...mechanisms that regulate this process remain obscure. Here, we report that the sterile alpha motif (SAM) domain of a PRC1 core component Phc2 plays an essential role for PRC1 clustering through head-to-tail macromolecular polymerization, which is associated with stable target binding of PRC1/PRC2 and robust gene silencing activity. We propose a role for SAM domain polymerization in this repression by two distinct mechanisms: first, through capturing and/or retaining PRC1 at the PcG targets, and second, by strengthening the interactions between PRC1 and PRC2 to stabilize transcriptional repression. Our findings reveal a regulatory mechanism mediated by SAM domain polymerization for PcG-mediated repression of developmental loci that enables a robust yet reversible gene repression program during development.
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•PRC1 forms visible subnuclear clusters at its target loci in mouse primary cells•The polymerization of the Phc2 SAM domain is required for PRC1 clustering•Clustering of PRC1 links to chromatin condensation and gene silencing•PRC1 clustering associates with stable binding of PRC1/PRC2 at its target loci
Gene silencing by the Polycomb-repressive complex-1 (PRC1) is crucial for embryogenesis. Isono et al. show that subnuclear PRC1 clustering at its target genes is mediated by the polymerization capacity of the Phc2 SAM domain and associates with stable PRC1/PRC2 binding, trimethylation of histone H3 Lys27, and robust gene silencing.
Precise cell division control is critical for developmental patterning. For the differentiation of a functional stoma, a cellular valve for efficient gas exchange, the single symmetric division of an ...immediate precursor is absolutely essential. Yet, the mechanism governing this event remains unclear. Here we report comprehensive inventories of gene expression by the Arabidopsis bHLH protein MUTE, a potent inducer of stomatal differentiation. MUTE switches the gene expression program initiated by SPEECHLESS. MUTE directly induces a suite of cell-cycle genes, including CYCD5;1, in which introduced expression triggers the symmetric divisions of arrested precursor cells in mute, and their transcriptional repressors, FAMA and FOUR LIPS. The regulatory network initiated by MUTE represents an incoherent type 1 feed-forward loop. Our mathematical modeling and experimental perturbations support a notion that MUTE orchestrates a transcriptional cascade leading to a tightly restricted pulse of cell-cycle gene expression, thereby ensuring the single cell division to create functional stomata.
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•Comprehensive inventories of gene expression in stomatal differentiation reported•MUTE switches stomatal patterning program initiated by its sister bHLH, SPEECHLESS•MUTE directly induces cell-cycle genes and their direct transcriptional repressors•Incoherent feed-forward loop by MUTE ensures stomata composed of paired guard cells
Stomata, small valves on the plant epidermis, are made of two guard cells surrounding a pore. Han et al. show that the transcription factor MUTE orchestrates gene regulatory circuits to switch cells to a differentiation state, then ensures that only a single symmetric division occurs to create a functional stoma.
During neocortical development, neural precursor cells (NPCs, or neural stem cells) produce neurons first and astrocytes later. Although the timing of the fate switch from neurogenic to astrogenic is ...critical for determining the number of neurons, the mechanisms are not fully understood. Here, we show that the polycomb group complex (PcG) restricts neurogenic competence of NPCs and promotes the transition of NPC fate from neurogenic to astrogenic. Inactivation of PcG by knockout of the Ring1B or Ezh2 gene or Eed knockdown prolonged the neurogenic phase of NPCs and delayed the onset of the astrogenic phase. Moreover, PcG was found to repress the promoter of the proneural gene neurogenin1 in a developmental-stage-dependent manner. These results demonstrate a role of PcG: the temporal regulation of NPC fate.
Polycomb-group (PcG) proteins mediate repression of developmental regulators in a reversible manner, contributing to their spatiotemporally regulated expression. However, it is poorly understood how ...PcG-repressed genes are activated by developmental cues. Here, we used the mouse Meis2 gene as a model to identify a role of a tissue-specific enhancer in removing PcG from the promoter. Meis2 repression in early development depends on binding of RING1B, an essential E3 component of PcG, to its promoter, coupled with its association with another RING1B-binding site (RBS) at the 3′ end of the Meis2 gene. During early midbrain development, a midbrain-specific enhancer (MBE) transiently associates with the promoter-RBS, forming a promoter-MBE-RBS tripartite interaction in a RING1-dependent manner. Subsequently, RING1B-bound RBS dissociates from the tripartite complex, leaving promoter-MBE engagement to activate Meis2 expression. This study therefore demonstrates that PcG and/or related factors play a role in Meis2 activation by regulating the topological transition of cis-regulatory elements.
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•Strong Meis2 expression in forebrain and midbrain is lost in Ring1 mutants•DNA-DNA associations alter during development and transcription status•RING1 contributes to the DNA-DNA associations•Meis2 promoter and midbrain enhancer association is mediated by RING1
Polycomb group (PcG) proteins contribute to transcriptional regulation of developmental genes. By examining Meis2 gene regulation in midbrain development, Kondo et al. show that the PcG component Ring1 is required for promoter-tissue-specific enhancer associations not only for initial gene repression but also for interactions that later mediate Meis2 activation.
Repression of endogenous retroviruses (ERVs) in mammals involves several epigenetic mechanisms. Acute loss of the maintenance methyltransferase Dnmt1 induces widespread DNA demethylation and ...transcriptional activation of ERVs, including CpG-rich IAP (intracisternal A particle) proviruses. Here, we show that this effect is not due simply to a loss of DNA methylation. Conditional deletions reveal that both Dnmt1 and Np95 are essential for maintenance DNA methylation. However, while IAPs are derepressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these ERVs remain silenced when Np95 is deleted alone or in combination with Dnmt1. This paradoxical phenotype results from an ectopic interaction between NP95 and the H3K9 methyltransferase SETDB1. Normally, SETDB1 maintains silencing of IAPs, but in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA transiently disrupts SETDB1-dependent H3K9me3 deposition. Thus, our observations reveal an unexpected antagonistic interplay between two repressive pathways involved in retroviral silencing in mammalian cells.
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•Acute depletion of Dnmt1, but not Np95, leads to activation of IAP proviral sequences•Global DNA demethylation occurs to a similar extent following deletions of Np95 or Dnmt1•Hemimethylated DNA accumulation after Dnmt1 deletion prolongs NP95 binding•Prolonged NP95 binding disrupts SETDB1 recruitment and inhibits IAP repression
Sharif et al. show that transient derepression of proviral loci following acute depletion of Dnmt1 in ESCs is not dependent on loss of DNA methylation per se. Rather, elevated levels of hemimethylated DNA promote prolonged binding of NP95, which in turn disrupts SETDB1-dependent deposition of the repressive histone mark H3K9me3.
Two distinct Polycomb complexes, PRC1 and PRC2, collaborate to maintain epigenetic repression of key developmental loci in embryonic stem cells (ESCs). PRC1 and PRC2 have histone modifying ...activities, catalyzing mono-ubiquitination of histone H2A (H2AK119u1) and trimethylation of H3 lysine 27 (H3K27me3), respectively. Compared to H3K27me3, localization and the role of H2AK119u1 are not fully understood in ESCs. Here we present genome-wide H2AK119u1 maps in ESCs and identify a group of genes at which H2AK119u1 is deposited in a Ring1-dependent manner. These genes are a distinctive subset of genes with H3K27me3 enrichment and are the central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2A ubiquitination activity of PRC1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate PRC1-dependent repression of genes that are crucial for the maintenance of ESC identity. Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During neocortical development, the neuroepithelial or neural precursor cells that commit to neuronal fate need to delaminate and start migration toward the pial surface. However, the mechanism that ...couples neuronal fate commitment to detachment from the neuroepithelium remains largely unknown. Here we show that Scratch1 and Scratch2, members of the Snail superfamily of transcription factors, are expressed upon neuronal fate commitment under the control of proneural genes and promote apical process detachment and radial migration in the developing mouse neocortex. Scratch-induced delamination from the apical surface was mediated by transcriptional repression of the adhesion molecule E-cadherin. These findings suggest that Scratch proteins constitute a molecular link between neuronal fate commitment and the onset of neuronal migration. On the basis of their similarity to proteins involved in the epithelial-mesenchymal transition (EMT), we propose that Scratch proteins mediate the conversion of neuroepithelial cells to migrating neurons or intermediate neuronal progenitors through an EMT-related mechanism.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The histone acetyltransferases (HATs) of the MYST family include TIP60, HBO1, MOZ/MORF, and MOF and function in multisubunit protein complexes. Bromodomain-containing protein 1 (BRD1), also known as ...BRPF2, has been considered a subunit of the MOZ/MORF H3 HAT complex based on analogy with BRPF1 and BRPF3. However, its physiologic function remains obscure. Here we show that BRD1 forms a novel HAT complex with HBO1 and regulates erythropoiesis. Brd1-deficient embryos showed severe anemia because of impaired fetal liver erythropoiesis. Biochemical analyses revealed that BRD1 bridges HBO1 and its activator protein, ING4. Genome-wide mapping in erythroblasts demonstrated that BRD1 and HBO1 largely colocalize in the genome and target key developmental regulator genes. Of note, levels of global acetylation of histone H3 at lysine 14 (H3K14) were profoundly decreased in Brd1-deficient erythroblasts and depletion of Hbo1 similarly affected H3K14 acetylation. Impaired erythropoiesis in the absence of Brd1 accompanied reduced expression of key erythroid regulator genes, including Gata1, and was partially restored by forced expression of Gata1. Our findings suggest that the Hbo1-Brd1 complex is the major H3K14 HAT required for transcriptional activation of erythroid developmental regulator genes.
Molecular mechanisms for the establishment of transcriptional memory are poorly understood. 5,6-dichloro-1-D-ribofuranosyl-benzimidazole (DRB) is a P-TEFb kinase inhibitor that artificially induces ...the poised RNA polymerase II (RNAPII), thereby manifesting intermediate steps for the establishment of transcriptional activation. Here, using genetics and DRB, we show that mammalian Absent, small, or homeotic discs 1-like (Ash1l), a member of the trithorax group proteins, methylates Lys36 of histone H3 to promote the establishment of Hox gene expression by counteracting Polycomb silencing. Importantly, we found that Ash1l-dependent Lys36 di-, tri-methylation of histone H3 in a coding region and exclusion of Polycomb group proteins occur independently of transcriptional elongation in embryonic stem (ES) cells, although both were previously thought to be consequences of transcription. Genome-wide analyses of histone H3 Lys36 methylation under DRB treatment have suggested that binding of the retinoic acid receptor (RAR) to a certain genomic region promotes trimethylation in the RAR-associated gene independent of its ongoing transcription. Moreover, DRB treatment unveils a parallel response between Lys36 methylation of histone H3 and occupancy of either Tip60 or Mof in a region-dependent manner. We also found that Brg1 is another key player involved in the response. Our results uncover a novel regulatory cascade orchestrated by Ash1l with RAR and provide insights into mechanisms underlying the establishment of the transcriptional activation that counteracts Polycomb silencing.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK