Exploring personalized treatment for cardiac graft rejection based on a four-archetype analysis model and bioinformatics analysis.

Heart transplantation is the gold standard for treating patients with advanced heart failure. Although improvements in immunosuppressive therapies have significantly reduced the frequency of cardiac graft rejection, the incidences of T cell-mediated rejection (TCMR) and antibody-mediated rejection remain almost unchanged. A four-archetype analysis (4AA) model, developed by Philip F. Halloran, illustrated this problem well. It provided a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. However, this model was based on the invasive method of endocardial biopsy, which undoubtedly increased the postoperative risk of heart transplant patients. Currently, little is known regarding the associated genes and specific functions of the different phenotypes. We performed bioinformatics analysis (using machine-learning methods and the WGCNA algorithm) to screen for hub-specific genes related to different phenotypes, based Gene Expression Omnibus accession number GSE124897. More immune cell infiltration was observed with the ABMR, TCMR, and injury phenotypes than with the stable phenotype. Hub-specific genes for each of the four archetypes were verified successfully using an external test set (accession number GSE2596). Logistic-regression models based on TCMR-specific hub genes and common hub genes were constructed with accurate diagnostic utility (area under the curve > 0.95). RELA, NFKB1, and SOX14 were identified as transcription factors important for TCMR/injury phenotypes and common genes, respectively. Additionally, 11 Food and Drug Administration-approved drugs were chosen from the DrugBank Database for each four-archetype model. Tyrosine kinase inhibitors may be a promising new option for transplant rejection treatment. KRAS signaling in cardiac transplant rejection is worth further investigation. Our results showed that heart transplant rejection subtypes can be accurately diagnosed by detecting expression of the corresponding specific genes, thereby enabling precise treatment or medication.

Joint analysis of WES and RNA-Seq identify signature genes related to metastasis in prostate cancer.

Prostate cancer (PCa) has a certain degree of heritability, and metastasis occurs as cancer progresses. However, its underlying mechanism remains largely unknown. We sequenced four cases of cancer without metastasis, four metastatic cancer, and four benign hyperplasia tissues as controls. A total of 1839 damaging mutations were identified. Pathway analysis, gene clustering, and weighted gene co-expression network analysis were employed to find characteristics associated with metastasis. Chr19 had the most mutation density and 1p36 had the highest mutation frequency across the genome. These mutations occurred in 1630 genes, including the most frequently mutated genes TTN and PLEC, and dozens of metastasis-related genes, such as FOXA1, NCOA1, CD34, and BRCA2. Ras signalling and arachidonic acid metabolism were uniquely enriched in metastatic cancer. Gene programmes 10 and 11 showed the signatures indicating the occurrence of metastasis better. A module (135 genes) was specifically associated with metastasis. Of them, 67.41% reoccurred in program 10, with 26 genes further retained as the signature genes related to PCa metastasis, including AGR3, RAPH1, SOX14, DPEP1, and UBL4A. Our study provides new molecular perspectives on PCa metastasis. The signature genes and pathways could be served as potential therapeutic targets for metastasis or cancer progression.

Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma.

Circadian rhythm genes were reported to be strongly associated with the development and prognosis of circadian rhythm disorders related to stomach adenocarcinoma (STAD), which is one of the most prevalent cancers. This study aimed to identify a circadian rhythm-related gene signature that could help predict STAD outcome. Using bioinformatics analysis approaches, 105 genes were examined in 350 patients with STAD. Overall, six hub-type circadian rhythm-associated genes (GNA11, PER1, SOX14, EZH2, MAGED1, and NR1D1) were identified using univariate and multivariate Cox regression analyses. These genes were then used to build a genetic predictive model, which was further validated using a publicly available dataset (GSE26899). Overall, genes associated with the circadian rhythm were found to be substantially correlated with the characteristics of the STAD patients (grade, sex, and M stage). In addition, the circadian rhythm-related gene signature was significantly associated with the MAPK and Notch signaling pathways, which are known risk factors for poorer STAD outcome. Taken together, these findings suggest that the herein proposed prognostic model based on six circadian rhythm-associated genes may have predictive value and potential application for clinical decision-making and for personalized treatment of STAD.

Novel Candidate Regulators and Developmental Trajectory of Pituitary Thyrotropes.

The pituitary gland regulates growth, metabolism, reproduction, the stress response, uterine contractions, lactation, and water retention. It secretes hormones in response to hypothalamic input, end organ feedback, and diurnal cues. The mechanisms by which pituitary stem cells are recruited to proliferate, maintain quiescence, or differentiate into specific cell types, especially thyrotropes, are not well understood. We used single-cell RNA sequencing in juvenile P7 mouse pituitary cells to identify novel factors in pituitary cell populations, with a focus on thyrotropes and rare subtypes. We first observed cells coexpressing markers of both thyrotropes and gonadotropes, such as Pou1f1 and Nr5a1. This was validated in vivo by both immunohistochemistry and lineage tracing of thyrotropes derived from Nr5a1-Cre; mTmG mice and demonstrates that Nr5a1-progenitors give rise to a proportion of thyrotropes during development. Our data set also identifies novel factors expressed in pars distalis and pars tuberalis thyrotropes, including the Shox2b isoform in all thyrotropes and Sox14 specifically in Pou1f1-negative pars tuberalis thyrotropes. We have therefore used single-cell transcriptomics to determine a novel developmental trajectory for thyrotropes and potential novel regulators of thyrotrope populations.

Distinct roles for SOX2 and SOX21 in differentiation, distribution and maturation of pulmonary neuroendocrine cells.

Pulmonary neuroendocrine (NE) cells represent a small population in the airway epithelium, but despite this, hyperplasia of NE cells is associated with several lung diseases, such as congenital diaphragmatic hernia and bronchopulmonary dysplasia. The molecular mechanisms causing the development of NE cell hyperplasia remains poorly understood. Previously, we showed that the SOX21 modulates the SOX2-initiated differentiation of epithelial cells in the airways. Here, we show that precursor NE cells start to develop in the SOX2 + SOX21 + airway region and that SOX21 suppresses the differentiation of airway progenitors to precursor NE cells. During development, clusters of NE cells start to form and NE cells mature by expressing neuropeptide proteins, such as CGRP. Deficiency in SOX2 resulted in decreased clustering, while deficiency in SOX21 increased both the numbers of NE ASCL1 + precursor cells early in development, and the number of mature cell clusters at E18.5. In addition, at the end of gestation (E18.5), a number of NE cells in Sox2 heterozygous mice, did not yet express CGRP suggesting a delay in maturation. In conclusion, SOX2 and SOX21 function in the initiation, migration and maturation of NE cells.

Co-Expression Analysis of Airway Epithelial Transcriptome in Asthma Patients with Eosinophilic vs. Non-Eosinophilic Airway Infiltration.

Asthma heterogeneity complicates the search for targeted treatment against airway inflammation and remodeling. We sought to investigate relations between eosinophilic inflammation, a phenotypic feature frequent in severe asthma, bronchial epithelial transcriptome, and functional and structural measures of airway remodeling. We compared epithelial gene expression, spirometry, airway cross-sectional geometry (computed tomography), reticular basement membrane thickness (histology), and blood and bronchoalveolar lavage (BAL) cytokines of n = 40 moderate to severe eosinophilic (EA) and non-eosinophilic asthma (NEA) patients distinguished by BAL eosinophilia. EA patients showed a similar extent of airway remodeling as NEA but had an increased expression of genes involved in the immune response and inflammation (e.g., KIR3DS1), reactive oxygen species generation (GYS2, ATPIF1), cell activation and proliferation (ANK3), cargo transporting (RAB4B, CPLX2), and tissue remodeling (FBLN1, SOX14, GSN), and a lower expression of genes involved in epithelial integrity (e.g., GJB1) and histone acetylation (SIN3A). Genes co-expressed in EA were involved in antiviral responses (e.g., ATP1B1), cell migration (EPS8L1, STOML3), cell adhesion (RAPH1), epithelial-mesenchymal transition (ASB3), and airway hyperreactivity and remodeling (FBN3, RECK), and several were linked to asthma in genome- (e.g., MRPL14, ASB3) or epigenome-wide association studies (CLC, GPI, SSCRB4, STRN4). Signaling pathways inferred from the co-expression pattern were associated with airway remodeling (e.g., TGF-ß/Smad2/3, E2F/Rb, and Wnt/ß-catenin).

Evolutionary Landscape of SOX Genes to Inform Genotype-to-Phenotype Relationships.

The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype-phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 gnomAD, 485 ClinVar, 1174 Geno2MP, and 4313 COSMIC human variants. We identified, within the HMG (High Mobility Group)- box, twenty-seven amino acids with changes in multiple SOX proteins annotated to clinical pathologies. These sites were screened through Geno2MP medical phenotypes, revealing novel SOX15 R104G associated with musculature abnormality and SOX8 R159G with intellectual disability. Within gnomAD, SOX18 E137K (rs201931544), found within the HMG box of ~0.8% of Latinx individuals, is associated with seizures and neurological complications, potentially through blood-brain barrier alterations. A total of 56 highly conserved variants were found at sites outside the HMG-box, including several within the SOX2 HMG-box-flanking region with neurological associations, several in the SOX9 dimerization region associated with Campomelic Dysplasia, SOX14 K88R (rs199932938) flanking the HMG box associated with cardiovascular complications within European populations, and SOX7 A379V (rs143587868) within an SOXF conserved far C-terminal domain heterozygous in 0.716% of African individuals with associated eye phenotypes. This SOX data compilation builds a robust genotype-to-phenotype association for a gene family through more robust ortholog data integration.

A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma.

Background: Gastric cancer (GC) represents a major global clinical problem with very limited therapeutic options and poor prognosis. Necroptosis, a recently discovered inflammatory form of cell death, has been implicated in carcinogenesis and inducing necroptosis has also been considered as a therapeutic strategy. Objective: We aim to evaluate the role of this pathway in gastric cancer development, prognosis and immune aspects of its tumor microenvironment. Methods and results: In this study, we evaluated the gene expression of 55 necroptosis-related genes (NRGs) that were identified via carrying out a comprehensive review of the medical literature. Necroptosis pathway was deregulated in gastric cancer samples (n=375) as compared to adjacent normal tissues (n=32) obtained from the "The Cancer Genome Atlas (TCGA)". Based on the expression of these NRGs, two molecular subtypes were obtained through consensus clustering that also showed significant prognostic difference. Differentially expressed genes between these two clusters were retrieved and subjected to prognostic evaluation via univariate cox regression analysis and LASSO cox regression analysis. A 13-gene risk signature, termed as necroptosis-related genes prognostic index (NRGPI), was constructed that comprehensively differentiated the gastric cancer patients into high- and low-risk subgroups. The prognostic significance of NRGPI was validated in the GEO cohort (GSE84437: n=408). The NRGPI-high subgroup was characterized by upregulation of 10 genes (CYTL1, PLCL1, CGB5, CNTN1, GRP, APOD, CST6, GPX3, FCN1, SERPINE1) and downregulation of 3 genes (EFNA3, E2F2, SOX14). Further dissection of these two risk groups by differential gene expression analysis indicated involvement of signaling pathways associated with cancer cell progression and immune suppression such as WNT and TGF-ß signaling pathway. Para-inflammation and type-II interferon pathways were activated in NRGPI-high patients with an increased infiltration of Tregs and M2 macrophage indicating an exhausted immune phenotype of the tumor microenvironment. These molecular characteristics were mainly driven by the eight NRGPI oncogenes (CYTL1, PLCL1, CNTN1, GRP, APOD, GPX3, FCN1, SERPINE1) as validated in the gastric cancer cell lines and clinical samples. NRGPI-high patients showed sensitivity to a number of targeted agents, in particular, the tyrosine kinase inhibitors. Conclusions: Necroptosis appears to play a critical role in the development of gastric cancer, prognosis and shaping of its tumor immune microenvironment. NRGPI can be used as a promising prognostic biomarker to identify gastric cancer patients with a cold tumor immune microenvironment and poor prognosis who may response to selected molecular targeted therapy.

A four immune-related long noncoding RNAs signature as predictors for cervical cancer.

The progression, metastasis, and prognosis of cervical cancer (CC) is influenced by the tumor immune microenvironment. Studies proved that long non-coding RNAs (lncRNAs) to engage in cervical cancer development, especially immune-related lncRNAs, have emerged crucial in the tumor immune process. This study was set out to identify an immune-related lncRNA signature. In total, 13,838 lncRNA expression profiles and 328 immune genes were acquired from the clnical data of 306 CC tissues and 3 non-CC tissues. From the 433 identified immune-related lncRNAs, 4 candidate immune-related lncRNAs (SOX21-AS1, AC005332.4, NCK1-DT, LINC01871) were considered independent indicators of cervical cancer prognosis through the univariate and multivariate Cox regression analysis, and they were used to construct a prognostic and survival lncRNA signature model followed by the bootstrap method for further verification. Kaplan-Meier curves illustrated that cervical cancer patients could be divided into high-risk and low-risk groups with significant differences (P = 2.052e - 05), and the discrepancy of immune profiles between these two risk groups was illustrated by principal components analysis. Taken together, the novel survival predictive model created by the four immune-related lncRNAs showed promising clinical prediction value in cervical cancer.

Sox14 is essential for initiation of neuronal differentiation in the chick spinal cord.

BACKGROUND: The neural tube comprises several different types of progenitors and postmitotic neurons that co-ordinately act with each other to play integrated functions. Its development consists of two phases: proliferation of progenitor cells and differentiation into postmitotic neurons. How progenitor cells differentiate into each corresponding neuron is an important question for understanding the mechanisms of neuronal development. RESULTS: Here we introduce one of the Sox transcription factors, Sox14, which plays an essential role in the promotion of neuronal differentiation. Sox14 belongs to the SoxB2 subclass and its expression starts in the progenitor regions before neuronal differentiation is initiated at the trunk level of the neural tube. After neuronal differentiation is initiated, Sox14 expression gradually becomes confined to the V2a region of the neural tube, where Chx10 is co-expressed. Overexpression of Sox14 restricts progenitor cell proliferation. Conversely, the blockade of Sox14 expression by the RNAi strategy inhibits V2a neuron differentiation and causes expansion of the progenitor domain. We further found that Sox14 acted as a transcriptional activator. CONCLUSIONS: Sox14 acts as a modulator of cell proliferation and is essential for initiation of neuronal differentiation in the chick neural tube.

SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways.

SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium, SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.

SOX14 hypermethylation as a tumour biomarker in cervical cancer.

BACKGROUND: The association between SOX14 and cancer has been reported. The aim of this study was to identify and validate the potential value of SOX14 methylation in the early detection of cervical cancer. METHODS: First, we extracted the data for SOX14 methylation and expression within cervical cancer from The Cancer Genome Atlas (TCGA) database and analysed them via UALCAN, Wanderer, MEXPRESS and LinkedOmics. Subsequently, according to the bioinformatics findings, primers and probes were designed for the most significantly differentiated methylation CpG site and synthesized for methylation-specific PCR (MSP) and quantitative methylation-specific PCR (QMSP) to verify SOX14 methylation in both cervical tissuses and liquid-based cell samples. Eventually, the clinical diagnostic efficacy of SOX14 methylation in the normal, cervical intraepithelial neoplasia, and cancer groups was analysed by ROCAUC. RESULTS: Pooled analysis demonstrated that SOX14 methylation levels were significantly increased in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) compared to normal tissues (P < 0.001). Both the verification and validation cohorts indicated that the methylation level and the positive rate of SOX14 gradually increased with increasing severity from normal to cancer samples (P < 0.01). When the cut-off value was set as 128.45, the sensitivity and specificity of SOX14 hypermethylation in the diagnosis of cervical cancer were 94.12 and 86.46%, respectively. When taken as a screening biomarker (>CINII), the sensitivity was 74.42% and the specificity was 81.48%, with a cut-off value of 10.37. CONCLUSION: SOX14 hypermethylation is associated with cervical cancer and has the potential to be a molecular biomarker for the screening and early diagnosis of cervical cancer.

Identification of Three Loci Associated with Achilles Tendon Injury Risk from a Genome-wide Association Study.

PURPOSE: This study aimed to screen the entire genome for genetic markers associated with risk for Achilles tendon injury. METHODS: A genome-wide association analysis was performed using data from the Kaiser Permanente Research Board and the UK Biobank. Achilles tendon injury cases were identified based on electronic health records from the Kaiser Permanente Research Board databank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for Achilles tendon injury using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms (SNP). Previously identified genes within the literature were also tested for association with Achilles tendon injury. RESULTS: There were a total of 12,354 cases of Achilles tendon injury and 483,080 controls within the two combined cohorts, with 67 SNP in three chromosomal loci demonstrating a genome-wide significant association with Achilles tendon injury. The first locus contains a single SNP (rs183364169) near the CDCP1 and TMEM158 genes on chromosome 3. The second locus contains 65 SNP in three independently segregating sets near the MPP7 gene on chromosome 10. The last locus contains a single SNP (rs4454832) near the SOX21 and GPR180 genes on chromosome 13. The current data were used to test 14 candidate genes previously reported to show an association with Achilles tendon injury, but none showed a significant association (all P > 0.05). CONCLUSION: Three loci were identified as potential risk factors for Achilles tendon injury and deserve further validation and investigation of molecular mechanisms.

Quantitative detection of SRY-Box 21 (SOX21) gene promoter methylation as a stool-based noninvasive biomarker for early diagnosis of colorectal cancer by MethyLight method.

BACKGROUND: In recent years, the study of potential epigenetic biomarkers in feces has been an attractive research approach for the noninvasive diagnosis of colorectal cancer (CRC). The aim of this study was to evaluate the stool-based DNA methylation potential of SRY-Box 21 (SOX21) gene promoter as an appropriate candidate biomarker for differentiating CRC patients and healthy individuals for the first time. METHODS: The MethyLight method was performed to analyze the methylation status of SOX21 gene promoter in fecal samples from 40 patients with CRC and 40 healthy controls. In addition, the diagnostic efficiency of measuring the hypermethylated SOX21 gene in the feces to the fecal occult blood test (FOBT) was compared. RESULTS: The percentage of methylated reference (PMR) values in the stool of CRC patients (median 1.44) was higher than those of healthy individuals (median 0.00) (P < 0.001). A sensitivity of 72.5% and specificity of 100% were obtained for SOX21 gene promoter methylation status and 29 of the patients were considered as positive in methylation status. There was no significant association between PMR values and demographic/clinicopathological features (P > 0.05). CONCLUSION: The results of the present study demonstrated that the stool-based assay of SOX21 gene promoter methylation has a relatively high sensitivity and specificity and it may serve as a noninvasive biomarker for early detection of CRC. However, more studies with a wide range of samples are required to further confirm the role of hypermethylation of SOX21 in the early CRC diagnosis.

Molecular Fingerprint and Developmental Regulation of the Tegmental GABAergic and Glutamatergic Neurons Derived from the Anterior Hindbrain.

Tegmental nuclei in the ventral midbrain and anterior hindbrain control motivated behavior, mood, memory, and movement. These nuclei contain inhibitory GABAergic and excitatory glutamatergic neurons, whose molecular diversity and development remain largely unraveled. Many tegmental neurons originate in the embryonic ventral rhombomere 1 (r1), where GABAergic fate is regulated by the transcription factor (TF) Tal1. We used single-cell mRNA sequencing of the mouse ventral r1 to characterize the Tal1-dependent and independent neuronal precursors. We describe gene expression dynamics during bifurcation of the GABAergic and glutamatergic lineages and show how active Notch signaling promotes GABAergic fate selection in post-mitotic precursors. We identify GABAergic precursor subtypes that give rise to distinct tegmental nuclei and demonstrate that Sox14 and Zfpm2, two TFs downstream of Tal1, are necessary for the differentiation of specific tegmental GABAergic neurons. Our results provide a framework for understanding the development of cellular diversity in the tegmental nuclei.

Silencing of long non-coding RNA SOX21-AS1 inhibits lung adenocarcinoma invasion and migration by impairing TSPAN8 via transcription factor GATA6.

Here, we revealed the novel role of long non-coding RNAs (lncRNAs) SOX21 antisense RNA 1 (SOX21-AS1)/TSPAN8/GATA6 in progression of lung adenocarcinoma. SOX21-AS1 expression was quantified in lung adenocarcinoma tissues and cells by RT-qPCR. Then, gain- and loss-of-function experiments were conducted in lung adenocarcinoma cells. Expression of GATA6, TSPAN8 and extracellular signal-regulated kinase (ERK) signaling pathway-related genes was determined in lung adenocarcinoma cells by western blot analysis. The interaction and relationship among SOX21-AS1, GATA6 and TSPAN8 were predicted and verified respectively by RNA pull down, RIP, ChIP, and dual-luciferase reporter assays. Next, lung adenocarcinoma cell proliferation, colony formation, invasion and migration were assessed by 5-ethynyl-2'-deoxyuridine staining, colony formation assay and Transwell assay. Xenograft tumors were established in nude mice and the tumor growth was observed and recorded. SOX21-AS1 was observed to be highly expressed in lung adenocarcinoma tissues. The overexpression of SOX21-AS1, GATA6 or TSPAN8 obviously enhanced cell biological functions in lung adenocarcinoma. Meanwhile, SOX21-AS1 interacted with GATA6 which bound to TSPAN8 promoter and promoted TSPAN8 expression, which further enhanced cell colony formation, proliferation and invasion, and also activated ERK signaling pathway. Silencing of SOX21-AS1 and inhibiting its binding to GATA6 downregulate TSPAN8 and thereby exert anti-oncogenic effects in lung adenocarcinoma.

Peroxisome Elevation Induces Stem Cell Differentiation and Intestinal Epithelial Repair.

Epithelial-repair-dependent mucosal healing (MH) is associated with a more favorable prognosis for patients with inflammatory bowel disease (IBD). MH is accomplished via repair and regeneration of the intestinal epithelium. However, the mechanism underlying MH is ill defined. We found a striking upregulation of peroxisomes in the injured crypts of IBD patients. By increasing peroxisome levels in Drosophila midguts, we found that peroxisome elevation enhanced RAB7-dependent late endosome maturation, which then promoted stem and/or progenitor-cell differentiation via modulation of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)-SOX21A signaling. This in turn enhanced ISC-mediated regeneration. Importantly, RAB7 and SOX21 were upregulated in the crypts of IBD patients. Moreover, administration of drugs that increased peroxisome levels reversed the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. This study demonstrates a peroxisome-mediated epithelial repair mechanism, which opens a therapeutic avenue for the enhancement of MH in IBD patients.

Knockdown of long non-coding RNA SOX21-AS1 attenuates amyloid-ß-induced neuronal damage by sponging miR-107.

BACKGROUND: Alzheimer's disease (AD), which has no effective drugs to delay or prevent its progression, is a multifactorial complex neurodegenerative disease. Long non-coding RNA SOX21 antisense RNA1 (SOX21-AS1) is associated with the development of AD, but the underlying molecular mechanism of SOX21-AS1 in AD is still largely unclear. METHODS: To construct the AD model, SH-SY5Y and SK-N-SH cells were treated with amyloid-ß1-42 (Aß1-42). Quantitative real-time polymerase chain reaction (qRT-PCR) was executed to detect the expression of SOX21-AS1 and miRNA-107. Western blot analysis was utilized to assess the levels of phosphorylated Tau (p-Tau). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or flow cytometry assay was employed to determine the viability and apoptosis of SH-SY5Y and SK-N-SH cells. The relationship between SOX21-AS1 and miRNA-107 was verified with the dual-luciferase reporter assay. RESULTS: SOX21-AS1 expression was augmented while miR-107 expression was decreased in Aß1-42-treated SH-SY5Y and SK-N-SH cells. Moreover, Aß1-42 elevated the levels of p-Tau and impeded viability and induced apoptosis of SH-SY5Y and SK-N-SH cells. Also, SOX21-AS1 silencing attenuated Aß1-42 mediated the levels of p-Tau, viability, and apoptosis of SH-SY5Y and SK-N-SH cells. Importantly, SOX21-AS1 acted as a sponge for miR-107 in SH-SY5Y and SK-N-SH cells. Furthermore, the increase in p-Tau levels and apoptosis and the repression of viability of Aß1-42-treated SH-SY5Y and SK-N-SH cells mediated by miR-107 inhibition were partly recovered by SOX21-AS1 depletion. CONCLUSION: SOX21-AS1 silencing could attenuate Aß1-42-induced neuronal damage by sponging miR-107, which provided a possible strategy for the treatment of AD.

Characterization of gonad differentially expressed SoxB2 genes in mud crab Scylla paramamosain.

Members of sox gene family play critical roles in development, and some of them have crucial functions in sexual dimorphism. To understand the role of two SoxB2 genes, Sox14b and Sox21 of mud crab Scylla paramamosain, the full-length 1939 bp SpSox14b cDNA sequence and 861 bp SpSox21 cDNA sequence were obtained from the crab's transcriptome database, which encode 397 and 259 amino acids respectively. The results of sq-PCR showed that SpSox14b was expressed in all tissues, while SpSox21 was only expressed in the testis and brain. qRT-PCR showed that the expression level of SpSox14b in ovary was significantly higher than that of testis, and during the gonad development its expression was the highest in O2 (previtellogenesis) stage. The expression level of SpSox21 in testis was much higher than in brain, and was significantly higher in T3 (the mature sperm stage) than in other stages of testis development. Meanwhile, in different stages of larval development, SpSox21 was low expressed in zoea, then increased significantly in megalopa. Therefore we speculated that SpSox14b and SpSox21 may play different roles in the gonad development of mud crab, especially SpSox21 may be involved in the development and maintenance of testis. The expression level of SpSox14b and SpSox21 during the eye-pigment formation was significantly higher than that in other embryonic development stages, the results of whole-mount in situ hybridization showed that SpSox14b and SpSox21 were mainly located near the head and the compound eyes in eye-pigment formation stage and hatching. It suggested that they may be involved in the formation of brain nerves and are related to the regulation of body segments, and play different roles in sexual dimorphism.

Sox100B Regulates Progenitor-Specific Gene Expression and Cell Differentiation in the Adult Drosophila Intestine.

Robust production of terminally differentiated cells from self-renewing resident stem cells is essential to maintain proper tissue architecture and physiological functions, especially in high-turnover tissues. However, the transcriptional networks that precisely regulate cell transition and differentiation are poorly understood in most tissues. Here, we identified Sox100B, a Drosophila Sox E family transcription factor, as a critical regulator of adult intestinal stem cell differentiation. Sox100B is expressed in stem and progenitor cells and required for differentiation of enteroblast progenitors into absorptive enterocytes. Mechanistically, Sox100B regulates the expression of another critical stem cell differentiation factor, Sox21a. Supporting a direct control of Sox21a by Sox100B, we identified a Sox21a intronic enhancer that is active in all intestinal progenitors and directly regulated by Sox100B. Taken together, our results demonstrate that the activity and regulation of two Sox transcription factors are essential to coordinate stem cell differentiation and proliferation and maintain intestinal tissue homeostasis.