P63 Maintains the Proliferative Potential of Salivary Gland Stem/Progenitor Cells by Regulating Follistatin, a Key Mediator of TGF-b/Activin Signaling [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145266 | GEO | 2020/09/23
REPOSITORIES: GEO
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Project description:Np63+ve cells are multipotent and maintain all epithelial cell lineages of the embryonic and adult salivary gland (SG). However, the molecular mechanisms by which Np63 regulates stem/progenitor (SP) cell populations in the SG remains elusive. To better understand Np63 s role in directing cell fate choices, here we have utilized Np63-null adult mice and primary salivary cell cultures to probe alterations in SP cell differentiation and function. Specifically, we have generated bulk RNA-seq and scRNA-seq data from Np63-null adult mice and p63 and H3K27Ac ChIP-seq data from primary salivary cell cultures. These genomic and epigenomic data sets were leveraged to interrogate altered SG cellular identities and differentiation states resulting from the loss of Np63. Our studies reveal that ablation of Np63 results in a loss of the SP cell population and skewed SG differentiation that is modulated by dysregulated TGF- /Activin signaling. Our findings offer new molecular revelations into the SP cell gene regulatory networks that are likely to be relevant for normal or diseased SG states.
2020-09-23 | GSE145267 | GEO
Project description:Np63+ve cells are multipotent and maintain all epithelial cell lineages of the embryonic and adult salivary gland (SG). However, the molecular mechanisms by which Np63 regulates stem/progenitor (SP) cell populations in the SG remains elusive. To better understand Np63 s role in directing cell fate choices, here we have utilized Np63-null adult mice and primary salivary cell cultures to probe alterations in SP cell differentiation and function. Specifically, we have generated bulk RNA-seq and scRNA-seq data from Np63-null adult mice and p63 and H3K27Ac ChIP-seq data from primary salivary cell cultures. These genomic and epigenomic data sets were leveraged to interrogate altered SG cellular identities and differentiation states resulting from the loss of Np63. Our studies reveal that ablation of Np63 results in a loss of the SP cell population and skewed SG differentiation that is modulated by dysregulated TGF- /Activin signaling. Our findings offer new molecular revelations into the SP cell gene regulatory networks that are likely to be relevant for normal or diseased SG states.
2020-09-23 | GSE145264 | GEO
Project description:Although the salivary transcriptome of adult mosquitoes has been thoroughly described in several recent papers, very little information exists regarding the biological role of larval salivary glands in the Culicidae. We used whole-transcriptome Affymetrix® chips to compare the transcriptional profiles of Anopheles gambiae larval (L4) salivary glands and whole larvae. We identified a total of 277 transcripts as being significantly enriched in the salivary glands. Based on available annotation for the known or predicted protein sequences encoded by these transcripts, 41 were identified as corresponding to secreted proteins, 233 as corresponding to non-secreted (housekeeping) proteins, and 3 as encoding proteins of unknown function. Based on functional annotation of the putatively secreted gene products, we propose that larval salivary secretions have roles in nutrient digestion, detoxification, immunity, and mouthpart lubrication. Interestingly, several components of the larval saliva (e.g. apyrase and serine proteases) have also been reported to exist in adult female saliva, where they are though to help regulate a vertebrate hostâs immune response to bloodfeeding. In conclusion, our results suggest that the salivary glands are important components of both the digestive and immune systems of larval mosquitoes, and that their study might provide clues about the evolution of adaptations to bloodfeeding observed in adults. Experiment Overall Design: We attempted to identify transcripts that are both present and significantly enriched in the salivary glands (SG) of the 4th instar Anopheles gambiae larva. Transcripts were considered as present in the SG if the built-in Affymetrix detection call scored them as such in all three biological replicates of the experiment. Expression values (i.e. signal intensities) of transcripts from the salivary glands were compared to those of a matching group of whole 4th instar larvae using a t-test. Transcripts showing an expression value two-fold or higher (p < 0.01; false discovery rate=1%) in the SG as compared to whole larvae were considered to be significantly enriched.
2008-11-06 | E-GEOD-9642 | biostudies-arrayexpress
Project description:Salivary gland squamous cell carcinomas (SG-SCCs) are a rare type of head and neck cancers which are linked to poor prognosis. Due to their low frequencies, the molecular mechanisms responsible for their aggressiveness are poorly understood. In this work we studied the function of the phosphatase DUSP1, a negative regulator of MAPK activity, in controlling the progression of SG-SCCs. We generated DUSP1 KO clones in A253 human cells. These clones showed a reduced ability to grow in 2D, self-renew in ECM matrices and grow tumors in immunodeficient mice. This was caused by an overactivation of the stress and apoptosis kinase JNK1/2 in DUSP1-KO clones. Interestingly, RNAseq analysis revealed that the expression of SOX2, a well know self-renewal gene was decreased at the mRNA and protein level. Unexpectedly, CRISPR-KO of SOX2 did not recapitulate DUSP1-KO phenotype, and SOX2-null cells had an enhanced ability to self-renew and grow tumors in mice. Gene expression analysis demonstrated that SOX2-null cells have a decreased squamous differentiation profile -losing TP63 expression- and an increased migratory phenotype, with an enhanced epithelial to mesenchymal transition signature. In summary, our data indicates that DUSP1 and SOX2 have opposite functions in SG-SCC, being DUSP1 necessary for tumor growth and SOX2 dispensable, and with a tumor suppressor function. Our data will suggest that the expression SOX2 and DUSP1 could be a useful biomarker to predict the progression of patients with SG-SCCs.
2024-05-01 | GSE253468 | GEO
Project description:Transcription factors, which regulate the spatiotemporal patterns of gene expression during organogenesis, often regulate multiple aspects of tissue morphogenesis, including cell-type specification, cell proliferation, cell death, cell polarity, cell shape, cell arrangement and cell migration. In this work, we describe a distinct role for Ribbon (Rib) in controlling cell shape changes during elongation of the Drosophila salivary gland (SG). Notably, the morphogenetic changes in rib mutants occurred without effects on general SG cell attributes such as specification, proliferation and apoptosis. Moreover, the abnormal cell/organ shape in rib mutants occurred without compromising epithelial-specific morphological attributes such as apicobasal polarity and junctional integrity. To identify the genes regulated by Rib that control cell and organ shape, we performed ChIP-seq analysis in embryos driving rib expression specifically in the SGs. To learn if the Rib binding sites identified in the ChIP-seq analysis were linked to changes in gene expression through transcriptional activation, repression, or both, we performed microarray analysis comparing RNA samples from age-matched wild-type and rib null embryos. From the superposed ChIP-seq and microarray gene expression data, we identified 60 genomic sites of bound Rib most likely to regulate SG-specific gene expression. We confirmed several of the identified Rib targets by qRT-pCR and/or in situ hybridization. Our results indicate that Rib regulates cell shape change in the Drosophila salivary gland via a diverse array of targets through both transcriptional activation and repression. Furthermore, our results suggest that a critical component of the SG morphogenetic gene network involving Rib is its autoregulation.
2015-12-21 | GSE72598 | GEO
Project description:Transcription factors, which regulate the spatiotemporal patterns of gene expression during organogenesis, often regulate multiple aspects of tissue morphogenesis, including cell-type specification, cell proliferation, cell death, cell polarity, cell shape, cell arrangement and cell migration. In this work, we describe a distinct role for Ribbon (Rib) in controlling cell shape changes during elongation of the Drosophila salivary gland (SG). Notably, the morphogenetic changes in rib mutants occurred without effects on general SG cell attributes such as specification, proliferation and apoptosis. Moreover, the abnormal cell/organ shape in rib mutants occurred without compromising epithelial-specific morphological attributes such as apicobasal polarity and junctional integrity. To identify the genes regulated by Rib that control cell and organ shape, we performed ChIP-seq analysis in embryos driving rib expression specifically in the SGs. To learn if the Rib binding sites identified in the ChIP-seq analysis were linked to changes in gene expression through transcriptional activation, repression, or both, we performed microarray analysis comparing RNA samples from age-matched wild-type and rib null embryos. From the superposed ChIP-seq and microarray gene expression data, we identified 60 genomic sites of bound Rib most likely to regulate SG-specific gene expression. We confirmed several of the identified Rib targets by qRT-pCR and/or in situ hybridization. Our results indicate that Rib regulates cell shape change in the Drosophila salivary gland via a diverse array of targets through both transcriptional activation and repression. Furthermore, our results suggest that a critical component of the SG morphogenetic gene network involving Rib is its autoregulation.
2015-12-21 | GSE73780 | GEO
Project description:Transcription factors, which regulate the spatiotemporal patterns of gene expression during organogenesis, often regulate multiple aspects of tissue morphogenesis, including cell-type specification, cell proliferation, cell death, cell polarity, cell shape, cell arrangement and cell migration. In this work, we describe a distinct role for Ribbon (Rib) in controlling cell shape changes during elongation of the Drosophila salivary gland (SG). Notably, the morphogenetic changes in rib mutants occurred without effects on general SG cell attributes such as specification, proliferation and apoptosis. Moreover, the abnormal cell/organ shape in rib mutants occurred without compromising epithelial-specific morphological attributes such as apicobasal polarity and junctional integrity. To identify the genes regulated by Rib that control cell and organ shape, we performed ChIP-seq analysis in embryos driving rib expression specifically in the SGs. To learn if the Rib binding sites identified in the ChIP-seq analysis were linked to changes in gene expression through transcriptional activation, repression, or both, we performed microarray analysis comparing RNA samples from age-matched wild-type and rib null embryos. From the superposed ChIP-seq and microarray gene expression data, we identified 60 genomic sites of bound Rib most likely to regulate SG-specific gene expression. We confirmed several of the identified Rib targets by qRT-pCR and/or in situ hybridization. Our results indicate that Rib regulates cell shape change in the Drosophila salivary gland via a diverse array of targets through both transcriptional activation and repression. Furthermore, our results suggest that a critical component of the SG morphogenetic gene network involving Rib is its autoregulation. Three independent collections of stage 11 â 16 rib1/ribP7 embryos and three of wild-type embryos were used for hybridization to Drosophila Genome 2.0 Chips. Scanned intensity values were normalized using RMA (Partek software) and statistical analysis analyses were performed using the Spotfire software package (TIBCO). Target genes were identified as those that were upregulated/downregulated (1.5-fold change cutoff, P < 0.05) in rib1/ribP7 embryos when compared with Oregon R controls.
2015-12-21 | E-GEOD-72598 | biostudies-arrayexpress
Project description:The differentiation of pluripotent stem cells has been broadly used in studying the disease mechanism and development process. We previously described a method for differentiating human pluripotent stem cells (hPSCs) into salivary gland epithelial progenitors (SGEPs). Here, to investigate whether the hPSCs-derived SGEPs are capable of modeling the characteristics of cystic fibrosis (CF), a disease impact SG function caused by mutation of cystic fibrosis transmembrane conductance regulator (CFTR) gene, the CFTR knockout hPSCs were differentiated into CF-SGEPs using the same protocol. Firstly, we successfully generated CFTR knockout hPSCs with reduced CFTR protein expression using the CRISPR-Cas9 system. After 16-day of differentiation, the protein expression of CFTR was also decreased in SGEPs generated from CFTR knockout hPSCs. RNA-sequencing shows that multiple genes modulating SG development, function and were down-regulated and positive regulators of inflammation were up-regulated in CF-SGEPs, which was correlated with salivary phenotype in CF patients. These results demonstrated that suppression of CFTR disrupted the differentiation of hPSCs-derived SGEPs, which modeled the SG development of patients with CF. In summary, this study not only provided the proof that the hPSCs-derived SGEPs could serve as manipulatable and easily accessible models to study the SG developmental diseases, but also provided new avenues for the study of the CF mechanism.
2023-12-06 | GSE224547 | GEO
Project description:There are multiple stem cells in adult mammalian epidermis, but the mechanisms controlling lineage specification are poorly understood. To identify gene expression signatures of the three major epidermal differentiation compartments we micro-dissected individual SG, IFE and HF from adult epidermis. The RNA was isolated from age and sex matched wild-type mice and performed transcriptome analysis with Affymetrix Exon microarrays We micro-dissected individual interfollicular epidermis (IFE), hair follicle (HF) and sebaceous gland (SG) from adult tail epidermis. The RNA was isolated from age and sex matched wild-type mice. Three biological replicates for each epidermal differentiation compartment were analyzed.
2017-05-16 | E-GEOD-62604 | biostudies-arrayexpress
Project description:p63, especially its dominant isoform ∆Np63⍺, plays essential roles in squamous cell carcinomas (SCCs); yet the mechanisms controlling its nuclear transport remain unknown. Nucleoporins (NUPs) are a family of proteins building nuclear pore complex (NPC) and mediating nuclear transport across the nuclear envelope. Recent evidence suggests a cell-type-specific function for certain NUPs; however, the significance of NUPs in SCC biology remains unknown. In this study, we report that nucleoporin 62 (NUP62) is highly expressed in stratified squamous epithelia, which is further elevated in SCCs. Depletion of NUP62 inhibited the proliferation ability and augmented differentiation characteristics of SCC cells. This loss of dedifferentiation status was associated with defects in ∆Np63⍺ nuclear transport. We further found that differentiation inducible Rho kinase reduced an interaction between NUP62 and ∆Np63a by phosphorylation of phenylalanine-glycine regions of NUP62, resulting in attenuated ∆Np63⍺ nuclear import. Our results characterize NUP62 as a key gatekeeper for ∆Np63⍺ and uncover its significant function to control ∆Np63⍺ nuclear transport in SCC.
2017-11-16 | GSE103991 | GEO