Microglial ASD-related genes are involved in oligodendrocyte differentiation

Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.

Downregulating lncRNA NEAT1 induces proliferation and represses apoptosis of ovarian granulosa cells in polycystic ovary syndrome via microRNA-381/IGF1 axis

Objective Researchers have revealed the combined functions of long noncoding RNAs (lncRNAs) and microRNA (miRNAs) in polycystic ovary syndrome (PCOS). This study aimed to understand the role of nuclear-enriched abundant transcript 1 (NEAT1) and miR-381 involving insulin-like growth factor 1 (IGF1) in PCOS. Methods PCOS rat model was established by dehydroepiandrosterone induction. NEAT1, miR-381 and IGF1 expression in ovarian granulosa cells of PCOS patients and ovarian tissues of PCOS rats were tested. Bioinformatics website and dual luciferase reporter gene assay were utilized to verify the relationship between NEAT1 and miR-381 and that between miR-381 and IGF1. Levels of sex hormone, pathological changes and ovarian granulosa cell apoptosis in ovarian tissues of PCOS rats were detected. Ovarian granulosa cell proliferation and apoptosis were analyzed in vitro. Results NEAT1 and IGF1 expression increased while miR-381 expression decreased in the ovarian granulosa cells of patients with PCOS and the ovarian tissues of PCOS rats. In in vivo experiments, interference with NEAT1 improved the levels of sex hormones, alleviated pathological changes and suppressed ovarian granulosa cell apoptosis in the ovarian tissues of PCOS rats. In in vitro cell experiments, interference with NEAT1 suppressed apoptosis and enhanced cell proliferation of ovarian granulosa cells. NEAT1 interference-mediated effect would be reversed by up-regulating miR-381. NEAT1 acted as a ceRNA to adsorb miR-381 to target IGF1. Overexpression of IGF1 reversed the inhibitory effect of miR-381 on ovarian granulosa cell apoptosis. Conclusion Interference with NEAT1 increases miR-381 and reduces IGF1 levels, effectively improving the levels of sex hormones and reducing the pathological damage of ovarian tissue in rats with PCOS.

MiR-186-3p attenuates tumorigenesis of cervical cancer by targeting IGF1

Background Mounting evidence in the cancer literature suggests that microRNAs (miRNAs) influence the progression of human cancer cells by targeting protein-coding genes. How insulin-like growth factor 1(IGF1) and miR-186-3p contribute to the development of cervical cancer (CC) remains unclear. This study examined the regulatory roles of miR-186-3p and IGF1 in CC development. Methods Gene expression levels were determined by qRT-PCR. Proliferation, migration, and apoptosis of CC and normal cells were determined by MTT, Transwell, and caspase-3 activity assays, respectively. Dual-luciferase reporter activity and RNA pull-down assays were performed to identify the target gene of miR-186-3p. Results IGF1 was the target of miR-186-3p. The expression of miR-186-3p inhibited cell proliferation and migration abilities of CC cell lines, but induced the apoptosis rate of CC cells. IGF1 could restore the inhibitory effects of miR-186-3p on the proliferation, migration, and apoptosis abilities of CC cells. Experimental results revealed that miR-186-3p could inhibit IGF1 expression, thereby reducing the viability of CC cells. Conclusions The data suggest that targeting of IGF1 by miR-186-3p could be crucial in regulating the progression of CC.

Unraveling Stage-Dependent Expression Patterns of Circular RNAs and Their Related ceRNA Modulation in Ovine Postnatal Testis Development

Circular RNAs (circRNAs) have been shown to function in the reproductive systems including testis. However, their expression, as well as function in testicular development of sheep remain undefined. Herein, we performed RNA sequencing to reveal circRNA temporal expression patterns in testes of Tibetan sheep from different stages of maturation (3M, 3-month-old; 1Y, 1-year-old; 3Y, 3-year-old). A total of 3,982, 414, and 4,060 differentially expressed (DE) circRNAs were uncovered from 3M vs 1Y, 1Y vs 3Y, and 3M vs 3Y, respectively. Functional enrichment assessment indicated that the source genes of DE circRNAs were primarily engaged in spermatogenesis and testicular immune privilege including blood–testis barrier (BTB). We subsequently constructed the core circRNA–miRNA–mRNA interaction network for genes related to testicular function, such as spermatogenesis, germ cell development, BTB, and cell cycle/meiosis. Furthermore, we validated the target associations between either circ_024949, circ_026259 or IGF1, and oar-miR-29b in this network, and revealed their similar expression signatures in developmental testes that they were extensively expressed in germ cells, Leydig cells, and Sertoli cells, thus suggesting their broad functions in the functional maintenance of Leydig cells and Sertoli cells, as well as the development and maturation of male germ cells. Meanwhile, circ_026259 was shown to promote IGF1 expression through inhibition of oar-miR-29b in sheep Sertoli cells. This work gives the first global view for the expression and regulation of circRNAs in sheep testis, which will be helpful for providing new insights into the molecular mechanism of ovine testis function.

Early Dietary Exposures Epigenetically Program Mammary Cancer Susceptibility through IGF1-mediated Expansion of Mammary Stem Cells

Dietary exposures at early developmental stages have been shown to program lifetime breast cancer susceptibility. We previously reported that manipulation of gestational and postweaning diets leads to different mammary tumor outcomes in carcinogen-treated mice. The high tumor incidence (HT) groups (average 61.5% tumor incidence) received a low-fat, low-sugar, mildly restricted (12%v/v) (DR) diet during gestation, followed by a high-fat, high-sugar (HF) diet postweaning. Conversely, the low tumor incidence (LT) groups (average 20% tumor incidence) received the HF diet during gestation, followed by the DR diet postweaning. Herein, we extended these findings by demonstrating that HT animals had an expanded mammary stem cell (MaSC) population compared to LT animals before puberty, and this expansion persisted into adulthood. IGF1 expression was increased in mammary stromal cells from HT animals, which promoted the self-renewal capacity of MaSCs in a paracrine fashion. This increased IGF1 expression was programmed prepubertally through DNA hypomethylation of the IGF1 promoter 1, mediated by decreased DNMT3b levels. IGFBP5 mRNA and protein levels were also reduced in mammary tissues from HT animals, indicating an increased bioavailability of tissue IGF1. In association with these changes, mammary tissues from carcinogen-treated HT animals developed an increased proportion of mammary adenosquamous carcinomas compared to carcinogen-treated LT animals. This study provides novel mechanistic insights into how early dietary exposures program mammary cancer risk and tumor phenotypes by increasing IGF1 expression through epigenetic alterations, thereby expanding the MaSC population, resulting in a higher number of carcinogen targets susceptible to transformation in adulthood.SignificanceEarly high-fat dietary exposure programs lifetime mammary cancer susceptibility before puberty through epigenetic alterations of IGF1 promoters and IGF1-mediated paracrine regulation of mammary stem cell homeostasis.

MN1 overexpression with varying tumor grade is a promising predictor of survival of glioma patients

Gliomas have substantial mortality to incidence rate ratio and a dismal clinical course. Newer molecular insights, therefore, are imperative to refine glioma diagnosis, prognosis and therapy. Meningioma 1 (MN1) gene is a transcriptional co-regulator implicated in other malignancies, albeit its significance in glioma pathology remains to be explored. IGFBP5 is regulated transcriptionally by MN1 and IGF1, and is associated with higher glioma grade and shorter survival time, prompting us to ascertain their correlation in these tumors. We quantified MN1, IGFBP5 and IGF1 expression in 40 glioma samples and examined their interrelatedness. MN1 mRNA-protein inter-correlation and gene’s copy number were evaluated in these tumors. Publicly available TCGA datasets were used to examine the association of MN1 expression levels with patient survival and for validating our findings. We observed MN1 overexpression correlated with low grade (LGGs) and not high grade gliomas (HGGs), and is not determined by copy number alteration of the gene. Notably, gliomas with upregulated MN1 have better overall and progression-free survival. IGFBP5 expression inversely associated with MN1 expression levels in gliomas but correlated positively with IGF1 expression in only LGGs. This suggests a potential grade-specific interplay between repressive and activating roles of MN1 and IGF1, respectively in the regulation of IGFBP5. Thus, MN1 overexpression, a promising predictor of overall and progression-free survival in gliomas, may serve as a prognostic biomarker in clinical practice to categorize patients with survival advantage.

IGF1 Knockdown Hinders Myocardial Development through Energy Metabolism Dysfunction Caused by ROS-Dependent FOXO Activation in the Chicken Heart

Insulin-like growth factor 1 (IGF1) is a multifunctional cellular regulatory factor that can regulate cell growth and development by mediating growth hormone stimulation. However, the mechanism of IGF1 dysfunction in cardiomyocyte development is seldom reported. To study this, we employed the models of IGF1 knockdown in chicken embryo in vivo and in cardiomyocytes in vitro. We detected the antioxidant capacity, PI3K/Akt pathway, energy metabolism-related genes, and myocardial development-related genes. Our results revealed that the low expression of IGF1 can significantly suppress the antioxidant capacity and increase the ROS (P<0.05) levels, activating the AMPK and PI3K pathway by inhibiting the expression of IRS1. We also found that myocardial energy metabolism is blocked through IGF1, GLUT, and IGFBP inhibition, further inducing myocardial developmental disorder by inhibiting Mesp1, GATA, Nkx2.5, and MyoD expression. Altogether, we conclude that low IGF1 expression can hinder myocardial development through the dysfunction of energy metabolism caused by ROS-dependent FOXO activation.

lncRNA H19 promotes matrix mineralization through up-regulating IGF1 by sponging miR-185-5p in osteoblasts

Background Matrix mineralization is a key stage in bone formation involving in many bone-specific genes and signaling pathways. Emerging evidence indicate that long non-coding RNA (lncRNA) and microRNAs (miRNAs) play crucial roles in regulating the mineralization process of osteoblasts. This study aims to characterize the function and mechanism of lncRNA H19/miR-185-5p/IGF1 axis in modulating matrix mineralization of osteoblasts. Results H19 and IGF1 were highly expressed while miR-185-5p was lowly expressed in mineralized cells. Knocking down H19 inhibited matrix mineralization of osteoblasts, yet miR-185-5p had opposite effects. Moreover, H19 directly targeted miR-185-5p, whereas miR-185-5p repressed IGF1 expression. Meanwhile, miR-185-5p inhibition compensated the suppression of the matrix mineralization in osteoblasts by H19 knockdown. Conclusions The findings of this study showed that lncRNA H19 was upregulated in mineralized osteoblasts and promoted matrix mineralization through miR-185-5p/IGF1 axis in osteoblasts for the first time. This study may provide a new perspective for the diagnosis and treatment of diseases related to bone metabolism.