Similar Datasets
Project description:Type-2 immune responses are critical in tissue homeostasis, anti-helminth immunity and allergy. Th2 cells produce interleukin (IL)-4, IL-5 and IL-13 from the type-2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand this system we performed CRISPR-Cas9 screens targeting 1131 TFs during Th2 cell differentiation. We discovered that ADNP is indispensable for immune reactions to allergen. Mechanistically, ADNP performs a previously unappreciated role in gene activation forming a critical bridge in the transition from pioneer TFs to chromatin remodelling by recruiting CHD4 and BRG1. Although GATA3 and AP-1 bound the type-2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type-2 cytokine expression. Similar ADNP-dependent regulation was observed for the Maf and Il4ra genes which are known regulators of Th2 differentiation. Our results demonstrate an important role for ADNP in promoting immune cell specialization.
2023-06-06 | GSE218014 | GEO
Project description:Type-2 immune responses are critical in tissue homeostasis, anti-helminth immunity and allergy. Th2 cells produce interleukin (IL)-4, IL-5 and IL-13 from the type-2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand this system we performed CRISPR-Cas9 screens targeting 1131 TFs during Th2 cell differentiation. We discovered that ADNP is indispensable for immune reactions to allergen. Mechanistically, ADNP performs a previously unappreciated role in gene activation forming a critical bridge in the transition from pioneer TFs to chromatin remodelling by recruiting CHD4 and BRG1. Although GATA3 and AP-1 bound the type-2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type-2 cytokine expression. Similar ADNP-dependent regulation was observed for the Maf and Il4ra genes which are known regulators of Th2 differentiation. Our results demonstrate an important role for ADNP in promoting immune cell specialization.
2023-06-06 | GSE231522 | GEO
Project description:Type-2 immune responses are critical in tissue homeostasis, anti-helminth immunity and allergy. Th2 cells produce interleukin (IL)-4, IL-5 and IL-13 from the type-2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand this system we performed CRISPR-Cas9 screens targeting 1131 TFs during Th2 cell differentiation. We discovered that ADNP is indispensable for immune reactions to allergen. Mechanistically, ADNP performs a previously unappreciated role in gene activation forming a critical bridge in the transition from pioneer TFs to chromatin remodelling by recruiting CHD4 and BRG1. Although GATA3 and AP-1 bound the type-2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type-2 cytokine expression. Similar ADNP-dependent regulation was observed for the Maf and Il4ra genes which are known regulators of Th2 differentiation. Our results demonstrate an important role for ADNP in promoting immune cell specialization.
2023-06-06 | GSE218016 | GEO
Project description:Type-2 immune responses are critical in tissue homeostasis, anti-helminth immunity and allergy. Th2 cells produce interleukin (IL)-4, IL-5 and IL-13 from the type-2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand this system we performed CRISPR-Cas9 screens targeting 1131 TFs during Th2 cell differentiation. We discovered that ADNP is indispensable for immune reactions to allergen. Mechanistically, ADNP performs a previously unappreciated role in gene activation forming a critical bridge in the transition from pioneer TFs to chromatin remodelling by recruiting CHD4 and BRG1. Although GATA3 and AP-1 bound the type-2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type-2 cytokine expression. Similar ADNP-dependent regulation was observed for the Maf and Il4ra genes which are known regulators of Th2 differentiation. Our results demonstrate an important role for ADNP in promoting immune cell specialization.
2023-06-06 | GSE218015 | GEO
Project description:BackgroundADNP is vital for embryonic development. Is this function conserved for the homologous protein ADNP2?ResultsDown-regulation/silencing of ADNP or ADNP2 in zebrafish embryos or mouse erythroleukemia cells inhibited erythroid maturation, with ADNP directly associating with the ?-globin locus control region.ConclusionADNPs are novel molecular regulators of erythropoiesis.SignificanceNew regulators of globin synthesis are suggested. Activity-dependent neuroprotective protein (ADNP) and its homologue ADNP2 belong to a homeodomain, the zinc finger-containing protein family. ADNP is essential for mouse embryonic brain formation. ADNP2 is associated with cell survival, but its role in embryogenesis has not been evaluated. Here, we describe the use of the zebrafish model to elucidate the developmental roles of ADNP and ADNP2. Although we expected brain defects, we were astonished to discover that the knockdown zebrafish embryos were actually lacking blood and suffered from defective hemoglobin production. Evolutionary conservation was established using mouse erythroleukemia (MEL) cells, a well studied erythropoiesis model, in which silencing of ADNP or ADNP2 produced similar results as in zebrafish. Exogenous RNA encoding ADNP/ADNP2 rescued the MEL cell undifferentiated state, demonstrating phenotype specificity. Brg1, an ADNP-interacting chromatin-remodeling protein involved in erythropoiesis through regulation of the globin locus, was shown here to interact also with ADNP2. Furthermore, chromatin immunoprecipitation revealed recruitment of ADNP, similar to Brg1, to the mouse ?-globin locus control region in MEL cells. This recruitment was apparently diminished upon dimethyl sulfoxide (DMSO)-induced erythrocyte differentiation compared with the nondifferentiated state. Importantly, exogenous RNA encoding ADNP/ADNP2 significantly increased ?-globin expression in MEL cells in the absence of any other differentiation factors. Taken together, our results reveal an ancestral role for the ADNP protein family in maturation and differentiation of the erythroid lineage, associated with direct regulation of ?-globin expression.
| S-EPMC3504731 | biostudies-literature
Project description:Neuroadaptations in the brain reward system caused by excessive alcohol intake, lead to drinking escalation and alcohol use disorder phenotypes. Activity-dependent neuroprotective protein (ADNP) is crucial for brain development, and is implicated in neural plasticity in adulthood. Here, we discovered that alcohol exposure regulates Adnp expression in the mesolimbic system, and that Adnp keeps alcohol drinking in moderation, in a sex-dependent manner. Specifically, Sub-chronic alcohol treatment (2.5?g/kg/day for 7 days) increased Adnp mRNA levels in the dorsal hippocampus in both sexes, and in the nucleus accumbens of female mice, 24?h after the last alcohol injection. Long-term voluntary consumption of excessive alcohol quantities (~10-15?g/kg/24?h, 5 weeks) increased Adnp mRNA in the hippocampus of male mice immediately after an alcohol-drinking session, but the level returned to baseline after 24?h of withdrawal. In contrast, excessive alcohol consumption in females led to long-lasting reduction in hippocampal Adnp expression. We further tested the regulatory role of Adnp in alcohol consumption, using the Adnp haploinsufficient mouse model. We found that Adnp haploinsufficient female mice showed higher alcohol consumption and preference, compared to Adnp intact females, whereas no genotype difference was observed in males. Importantly, daily intranasal administration of the ADNP-snippet drug candidate NAP normalized alcohol consumption in Adnp haploinsufficient females. Finally, female Adnp haploinsufficient mice showed a sharp increase in alcohol intake after abstinence, suggesting that Adnp protects against relapse in females. The current data suggest that ADNP is a potential novel biomarker and negative regulator of alcohol-drinking behaviors.
| S-EPMC6300527 | biostudies-literature
Project description:Histone biogenesis is tightly controlled at multiple steps to maintain the balance between the amounts of DNA and histone protein during the cell cycle. In particular, translation and degradation of replication-dependent histone mRNAs are coordinately regulated. However, the underlying molecular mechanisms remain elusive. Here, we investigate remodeling of stem-loop binding protein (SLBP)-containing histone mRNPs occurring during the switch from the actively translating mode to the degradation mode. The interaction between a CBP80/20-dependent translation initiation factor (CTIF) and SLBP, which is important for efficient histone mRNA translation, is disrupted upon the inhibition of DNA replication or at the end of S phase. This disruption is mediated by competition between CTIF and UPF1 for SLBP binding. Further characterizations reveal hyperphosphorylation of UPF1 by activated ATR and DNA-dependent protein kinase upon the inhibition of DNA replication interacts with SLBP more strongly, promoting the release of CTIF and eIF3 from SLBP-containing histone mRNP. In addition, hyperphosphorylated UPF1 recruits PNRC2 and SMG5, triggering decapping followed by 5'-to-3' degradation of histone mRNAs. The collective observations suggest that both inhibition of translation and recruitment of mRNA degradation machinery during histone mRNA degradation are tightly coupled and coordinately regulated by UPF1 phosphorylation.
| S-EPMC4132728 | biostudies-literature
Project description:Cancer cells frequently exhibit deregulation of coregulatory molecules to drive the process of growth and metastasis. One such group of ubiquitously expressed coregulators is the metastasis-associated protein (MTA) family, a critical component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA1 occupies a special place in cancer biology because of its dual corepressor or coactivator nature and widespread overexpression in human cancers. Here, we highlight recent advances in our understanding of the vital roles of MTA1 on transformation, epithelial-mesenchymal transition, and the functions of key cancer-relevant molecules such as a nexus of multiple oncogenes and tumor suppressors. In addition to its paramount role in oncogenesis, we reveal several new physiologic functions of MTA1 related to DNA damage, inflammatory responses, and infection, in which MTA1 functions as a permissive "gate keeper" for cancer-causing parasites. Further, these discoveries unraveled the versatile multidimensional modes of action of MTA1, which are independent of the NuRD complex and/or transcription. Given the emerging roles of MTA1 in DNA repair, inflammation, and parasitism, we discuss the possibility of MTA1-targeted therapy for use not only in combating cancer but also in other inflammation and pathogen-driven pathologic conditions.
| S-EPMC3261506 | biostudies-literature
Project description:The neural cell adhesion molecule (NCAM) regulates synapse formation and synaptic strength via mechanisms that have remained unknown. We show that NCAM associates with the postsynaptic spectrin-based scaffold, cross-linking NCAM with the N-methyl-d-aspartate (NMDA) receptor and Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIalpha) in a manner not firmly or directly linked to PSD95 and alpha-actinin. Clustering of NCAM promotes formation of detergent-insoluble complexes enriched in postsynaptic proteins and resembling postsynaptic densities. Disruption of the NCAM-spectrin complex decreases the size of postsynaptic densities and reduces synaptic targeting of NCAM-spectrin-associated postsynaptic proteins, including spectrin, NMDA receptors, and CaMKIIalpha. Degeneration of the spectrin scaffold in NCAM-deficient neurons results in an inability to recruit CaMKIIalpha to synapses after NMDA receptor activation, which is a critical process in NMDA receptor-dependent long-term potentiation. The combined observations indicate that NCAM promotes assembly of the spectrin-based postsynaptic signaling complex, which is required for activity-associated, long-lasting changes in synaptic strength. Its abnormal function may contribute to the etiology of neuropsychiatric disorders associated with mutations in or abnormal expression of NCAM.
| S-EPMC2064397 | biostudies-literature
Project description:ADNP (Activity Dependent Neuroprotective Protein) is a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome (also called the ADNP syndrome). However, its role in neural development and pathology remains unclear. Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize ?-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. Loss of ADNP promotes the formation of the degradation complex and ?-Catenin degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. In addition, adnp gene disruption in zebrafish leads to defective neurogenesis and reduced Wnt signaling. Our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP gene mutation.
| S-EPMC7293280 | biostudies-literature