Faculty Opinions recommendation of Unwrapping glial biology: Gcm target genes regulating glial development, diversification, and function.

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

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Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability during Supplementation

Antioxidants ◽

10.3390/antiox10020173 ◽

2021 ◽

Vol 10 (2) ◽

pp. 173

Author(s):

Desirée Bartolini ◽

Rita Marinelli ◽

Danilo Giusepponi ◽

Roberta Galarini ◽

Carolina Barola ◽

...

Keyword(s):

Vitamin E ◽

Target Genes ◽

Interindividual Variability ◽

Pregnane X Receptor ◽

Alpha Tocopherol ◽

Therapeutic Interventions ◽

Intrinsic Variability ◽

Blood Leukocytes ◽

Definition Of ◽

And Function

The metabolism of α-tocopherol (α-TOH, vitamin E) shows marked interindividual variability, which may influence the response to nutritional and therapeutic interventions with this vitamin. Recently, new metabolomics protocols have fostered the possibility to explore such variability for the different metabolites of α-TOH so far identified in human blood, i.e., the “vitamin E metabolome”, some of which have been reported to promote important biological functions. Such advances prompt the definition of reference values and degree of interindividual variability for these metabolites at different levels of α-TOH intake. To this end, a one-week oral administration protocol with 800 U RRR-α-TOH/day was performed in 17 healthy volunteers, and α-TOH metabolites were measured in plasma before and at the end of the intervention utilizing a recently validated LC-MS/MS procedure; the expression of two target genes of α-TOH with possible a role in the metabolism and function of this vitamin, namely pregnane X receptor (PXR) and the isoform 4F2 of cytochrome P450 (CYP4F2) was assessed by immunoblot in peripheral blood leukocytes. The levels of enzymatic metabolites showed marked interindividual variability that characteristically increased upon supplementation. With the exception of α-CEHC (carboxy-ethyl-hydroxychroman) and the long-chain metabolites M1 and α-13′OH, such variability was found to interfere with the possibility to utilize them as sensitive indicators of α-TOH intake. On the contrary, the free radical-derived metabolite α-tocopheryl quinone significantly correlated with the post-supplementation levels of α-TOH. The supplementation stimulated PXR, but not CYP4F2, expression of leucocytes, and significant correlations were observed between the baseline levels of α-TOH and both the baseline and post-supplementation levels of PXR. These findings provide original analytical and molecular information regarding the human metabolism of α-TOH and its intrinsic variability, which is worth considering in future nutrigenomics and interventions studies.

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NFATc3 regulates the transcription of genes involved in T-cell activation and angiogenesis

Blood ◽

10.1182/blood-2010-12-322701 ◽

2011 ◽

Vol 118 (3) ◽

pp. 795-803 ◽

Cited By ~ 31

Author(s):

Katia Urso ◽

Arantzazu Alfranca ◽

Sara Martínez-Martínez ◽

Amelia Escolano ◽

Inmaculada Ortega ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Target Genes ◽

Gene Knockout ◽

Activated T Cells ◽

Knock Down ◽

And Function

Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors plays important roles in many biologic processes, including the development and function of the immune and vascular systems. Cells usually express more than one NFAT member, raising the question of whether NFATs play overlapping roles or if each member has selective functions. Using mRNA knock-down, we show that NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in transformed and primary T cells and for T-cell proliferation. We also show that NFATc3 regulates COX2 in endothelial cells, where it is required for COX2, dependent migration and angiogenesis in vivo. These results indicate that individual NFAT members mediate specific functions through the differential regulation of the transcription of target genes. These effects, observed on short-term suppression by mRNA knock-down, are likely to have been masked by compensatory effects in gene-knockout studies.

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Steroidogenic Factor-1 (SF-1)-Driven Differentiation of Murine Embryonic Stem (ES) Cells into a Gonadal Lineage

Endocrinology ◽

10.1210/en.2011-0219 ◽

2011 ◽

Vol 152 (7) ◽

pp. 2870-2882 ◽

Cited By ~ 24

Author(s):

Unmesh Jadhav ◽

J. Larry Jameson

Keyword(s):

Target Genes ◽

De Novo ◽

Embryoid Body ◽

Es Cells ◽

Embryonic Stem ◽

Cell Lineage ◽

Culture Conditions ◽

Steroidogenic Factor 1 ◽

Lineage Differentiation ◽

And Function

Steroidogenic factor 1 (SF-1) is essential for the development and function of steroidogenic tissues. Stable incorporation of SF-1 into embryonic stem cells (SF-1-ES cells) has been shown to prime the cells for steroidogenesis. When provided with exogenous cholesterol substrate, and after treatment with retinoic acid and cAMP, SF-1-ES cells produce progesterone but do not produce other steroids such as cortisol, estradiol, or testosterone. In this study, we explored culture conditions that optimize SF-1-mediated differentiation of ES cells into defined steroidogenic lineages. When embryoid body formation was used to facilitate cell lineage differentiation, SF-1-ES cells were found to be restricted in their differentiation, with fewer cells entering neuronal pathways and a larger fraction entering the steroidogenic lineage. Among the differentiation protocols tested, leukemia inhibitory factor (LIF) removal, followed by prolonged cAMP treatment was most efficacious for inducing steroidogenesis in SF-1-ES cells. In this protocol, a subset of SF-1-ES cells survives after LIF withdrawal, undergoes morphologic differentiation, and recovers proliferative capacity. These cells are characterized by induction of steroidogenic enzyme genes, use of de novo cholesterol, and production of multiple steroids including estradiol and testosterone. Microarray studies identified additional pathways associated with SF-1 mediated differentiation. Using biotinylated SF-1 in chromatin immunoprecipitation assays, SF-1 was shown to bind directly to multiple target genes, with induction of binding to some targets after steroidogenic treatment. These studies indicate that SF-1 expression, followed by LIF removal and treatment with cAMP drives ES cells into a steroidogenic pathway characteristic of gonadal steroid-producing cells.

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Heterozygous Orthodenticle Homeobox 2 Mutations Are Associated with Variable Pituitary Phenotype

Endocrine Reviews ◽

10.1210/edrv.31.1.9987 ◽

2010 ◽

Vol 31 (1) ◽

pp. 133-133

Author(s):

Sumito Dateki ◽

Kitaro Kosaka ◽

Kosei Hasegawa ◽

Hiroyuki Tanaka ◽

Noriyuki Azuma ◽

...

Keyword(s):

Target Genes ◽

Japanese Patients ◽

Dominant Negative ◽

Pituitary Function ◽

Hormone Deficiency ◽

Dominant Negative Effect ◽

Pituitary Hormone ◽

Positive Role ◽

Negative Effect ◽

And Function

ABSTRACT Context Although recent studies have suggested a positive role of OTX2 in pituitary as well as ocular development and function, detailed pituitary phenotypes in OTX2 mutations and OTX2 target genes for pituitary function other than HESX1 and POU1F1 remain to be determined. Objective We aimed to examine such unresolved issues. Subjects We studied 94 Japanese patients with various ocular or pituitary abnormalities. Results We identified heterozygous p.K74fsX103 in case 1, p.A72fsX86 in case 2, p.G188X in two unrelated cases (3 and 4), and a 2,860,561-bp microdeletion involving OTX2 in case 5. Clinical studies revealed isolated GH deficiency in cases 1 and 5; combined pituitary hormone deficiency in case 3; abnormal pituitary structures in cases 1, 3, and 5; and apparently normal pituitary function in cases 2 and 4, together with ocular anomalies in cases 1-5. The wild-type Orthodenticle homeobox 2 (OTX2) protein transactivated the GNRH1 promoter as well as the HESX1, POU1F1, and IRBP (interstitial retinoid-binding protein) promoters, whereas the p.K74fsX103-OTX2 and p.A72fsX86-OTX2 proteins had no transactivation functions and the p.G188X-OTX2 protein had reduced (∼50%) transactivation functions for the four promoters, with no dominant-negative effect. cDNA screening identified positive OTX2 expression in the hypothalamus. Conclusions The results imply that OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations, and that OTX2 can transactivate GNRH1 as well as HESX1 and POU1F1.

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miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts

PeerJ ◽

10.7717/peerj.10502 ◽

2020 ◽

Vol 8 ◽

pp. e10502

Author(s):

Huan Guo ◽

Xinke Zhao ◽

Haixiang Su ◽

Chengxu Ma ◽

Kai Liu ◽

...

Keyword(s):

Myocardial Fibrosis ◽

Target Genes ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Differentially Expressed Gene ◽

Stem Loop ◽

Cardiac Morbidity ◽

Increased Risk ◽

And Function

Background Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. Methods We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. Results DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation—the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

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A class act: conservation of homeodomain protein functions

Development ◽

10.1242/dev.1994.supplement.61 ◽

1994 ◽

Vol 1994 (Supplement) ◽

pp. 61-77 ◽

Cited By ~ 2

Author(s):

J. Robert Manak ◽

Matthew P. Scott

Keyword(s):

Gene Function ◽

Target Genes ◽

Hox Genes ◽

Homeobox Gene ◽

Homeodomain Protein ◽

Animal Development ◽

Protein Functions ◽

Unified View ◽

Protein Classes ◽

And Function

Dramatic successes in identifying vertebrate homeobox genes closely related to their insect relatives have led to the recognition of classes within the homeodomain superfamily. To what extent are the homeodomain protein classes dedicated to specific functions during development? Although information on vertebrate gene functions is limited, existing evidence from mice and nematodes clearly supports conservation of function for the Hox genes. Less compelling, but still remarkable, is the conservation of other homeobox gene classes and of regulators of homeotic gene expression and function. It is too soon to say whether the cases of conservation are unique and exceptional, or the beginning of a profoundly unified view of gene regulation in animal development. In any case, new questions are raised by the data: how can the differences between mammals and insects be compatible with conservation of homeobox gene function? Did the evolution of animal form involve a proliferation of new homeodomain proteins, new modes of regulation of existing gene types, or new relationships with target genes, or is evolutionary change largely the province of other classes of genes? In this review, we summarize what is known about conservation of homeobox gene function.

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Analysis of MicroRNA Transcriptomes Insights into the miR-148a-3p Inducer of Rumen Development in Goats

10.21203/rs.3.rs-40834/v1 ◽

2020 ◽

Author(s):

Tao Zhong ◽

Cheng Wang ◽

Jiangtao Hu ◽

Xiaoyong Chen ◽

Lili Niu ◽

...

Keyword(s):

Signaling Pathway ◽

Target Genes ◽

Genetic Regulation ◽

Mapk Signaling ◽

Regulation Mechanism ◽

Ras Signaling ◽

Genome Wide ◽

A Genome ◽

Differentially Expressed Mirnas ◽

And Function

Abstract Background: Rumen is an important digestive organ of ruminant. From fetal to adult stage, the morphology, structure and function of rumen have changed significantly. But the intrinsic genetic regulation is still limited. We previously reported a genome-wide expression profile of miRNAs in prenatal goat rumens. In the present study, we rejoined analyzed the transcriptomes of rumen miRNAs during prenatal (E60 and E135) and postnatal (D30 and D150) stages.Results: A total of 66 differentially expressed miRNAs (DEMs) were identified in the rumen tissues from D30 and D150 goats. Of these, 17 DEMs were consistently highly expressed in the rumens at the preweaning stages (E60, E135 and D30), while down-regulated at D150. Noteworthy, annotation analysis revealed that the target genes regulated by the DEMs were mainly enriched in MAPK signaling pathway, Jak-STAT signaling pathway and Ras signaling pathway. Interestingly, the expression of miR-148a-3p was significantly high in the embryonic stage and down-regulated at D150. The potential binding sites between miR-148a-3p and QKI were predicted by the TargetScan and verified by the dual luciferase report assay. The co-localization of miR-148a-3p and QKI was observed not in intestinal tracts but in rumen tissues by in situ hybridization. Moreover, the expression of miR-148a-3p in the epithelium was significantly higher than that in the other layers, suggesting that miR-148a-3p involve in the development of rumen epithelial cells by targeting QKI. Subsequently, miR-148a-3p inhibitor was found to induce the proliferation of GES-1 cells.Conclusions: Taken together, these results identified the DEMs involved in the development of rumen and provided an insight into the regulation mechanism of goat rumens during development.

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The Roles of Long Noncoding RNAs HNF1α-AS1 and HNF4α-AS1 in Drug Metabolism and Human Diseases

Non-Coding RNA ◽

10.3390/ncrna6020024 ◽

2020 ◽

Vol 6 (2) ◽

pp. 24 ◽

Cited By ~ 1

Author(s):

Liming Chen ◽

Yifan Bao ◽

Suzhen Jiang ◽

Xiao-bo Zhong

Keyword(s):

Drug Metabolism ◽

Drug Toxicity ◽

Target Genes ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Future Directions ◽

Protein Coding ◽

Mirna Sponge ◽

Current Review ◽

And Function

Long noncoding RNAs (lncRNAs) are RNAs with a length of over 200 nucleotides that do not have protein-coding abilities. Recent studies suggest that lncRNAs are highly involved in physiological functions and diseases. lncRNAs HNF1α-AS1 and HNF4α-AS1 are transcripts of lncRNA genes HNF1α-AS1 and HNF4α-AS1, which are antisense lncRNA genes located in the neighborhood regions of the transcription factor (TF) genes HNF1α and HNF4α, respectively. HNF1α-AS1 and HNF4α-AS1 have been reported to be involved in several important functions in human physiological activities and diseases. In the liver, HNF1α-AS1 and HNF4α-AS1 regulate the expression and function of several drug-metabolizing cytochrome P450 (P450) enzymes, which also further impact P450-mediated drug metabolism and drug toxicity. In addition, HNF1α-AS1 and HNF4α-AS1 also play important roles in the tumorigenesis, progression, invasion, and treatment outcome of several cancers. Through interacting with different molecules, including miRNAs and proteins, HNF1α-AS1 and HNF4α-AS1 can regulate their target genes in several different mechanisms including miRNA sponge, decoy, or scaffold. The purpose of the current review is to summarize the identified functions and mechanisms of HNF1α-AS1 and HNF4α-AS1 and to discuss the future directions of research of these two lncRNAs.

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