Changes in Hypothalamic Expression of the Lin28/let-7 System and Related MicroRNAs During Postnatal Maturation and After Experimental Manipulations of Puberty

Lin28 and Lin28b are related RNA-binding proteins that inhibit the maturation of miRNAs of the let-7 family and participate in the control of cellular stemness and early embryonic development. Considerable interest has arisen recently concerning other physiological roles of the Lin28/let-7 axis, including its potential involvement in the control of puberty, as suggested by genome-wide association studies and functional genomics. We report herein the expression profiles of Lin28 and let-7 members in the rat hypothalamus during postnatal maturation and in selected models of altered puberty. The expression patterns of c-Myc (upstream positive regulator of Lin28), mir-145 (negative regulator of c-Myc), and mir-132 and mir-9 (putative miRNA repressors of Lin28, predicted by bioinformatic algorithms) were also explored. In male and female rats, Lin28, Lin28b, and c-Myc mRNAs displayed very high hypothalamic expression during the neonatal period, markedly decreased during the infantile-to-juvenile transition and reached minimal levels before/around puberty. A similar puberty-related decline was observed for Lin28b in monkey hypothalamus but not in the rat cortex, suggesting species conservation and tissue specificity. Conversely, let-7a, let-7b, mir-132, and mir-145, but not mir-9, showed opposite expression profiles. Perturbation of brain sex differentiation and puberty, by neonatal treatment with estrogen or androgen, altered the expression ratios of Lin28/let-7 at the time of puberty. Changes in the c-Myc/Lin28b/let-7 pathway were also detected in models of delayed puberty linked to early photoperiod manipulation and, to a lesser extent, postnatal underfeeding or chronic subnutrition. Altogether, our data are the first to document dramatic changes in the expression of the Lin28/let-7 axis in the rat hypothalamus during the postnatal maturation and after different manipulations that disturb puberty, thus suggesting the potential involvement of developmental changes in hypothalamic Lin28/let-7 expression in the mechanisms permitting/leading to puberty onset.

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The HaemAtlas: Characterising Gene Expression in Differentiated Human Blood Cells

Blood ◽

10.1182/blood.v112.11.2453.2453 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2453-2453

Author(s):

Nicholas A. Watkins ◽

Marloes R. Tijssen ◽

Arief Gusnanto ◽

Bernard de Bono ◽

Subhajyoti De ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Transcription Factors ◽

Cell Function ◽

Expression Profiles ◽

Association Studies ◽

Cytotoxic T Cells ◽

Expression Patterns ◽

Immunoglobulin Superfamily ◽

Genome Wide Association Studies

Abstract Haematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell surface receptors. In order to further understand haematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B-cells, cytotoxic and helper T-cells, Natural Killer cells, granulocytes and monocytes using whole genome microarrays. A bioinformatics analysis of this data was performed focusing on transcription factors, immunoglobulin superfamily members and lineage specific transcripts. We observed that the numbers of lineage specific genes varies by two orders of magnitude, ranging from five for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel co-expression patterns for key transcription factors involved in haematopoiesis (eg. GATA3–GFI1 and GATA2–KLF1). This study represents the most comprehensive analysis of gene expression in haematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which is freely accessible, will be invaluable for future studies on haematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.

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Distinct Expression Patterns Predict Differential Roles of the miRNA-Binding Proteins, Lin28 and Lin28b, in the Mouse Testis: Studies During Postnatal Development and in a Model of Hypogonadotropic Hypogonadism

Endocrinology ◽

10.1210/en.2012-1745 ◽

2013 ◽

Vol 154 (3) ◽

pp. 1321-1336 ◽

Cited By ~ 28

Author(s):

Francisco Gaytan ◽

Susana Sangiao-Alvarellos ◽

María Manfredi-Lozano ◽

David García-Galiano ◽

Francisco Ruiz-Pino ◽

...

Keyword(s):

Postnatal Development ◽

Binding Proteins ◽

Rna Binding ◽

Hypogonadotropic Hypogonadism ◽

Expression Patterns ◽

Mouse Testis ◽

Null Mouse ◽

Cellular Distribution ◽

Protein Distribution ◽

Postnatal Maturation

Abstract Lin28 (also termed Lin28a) and Lin28b are related RNA-binding proteins, involved in the control of microRNA synthesis, especially of the let-7 family, with putative functions in early (embryo) development. However, their roles during postnatal maturation remain ill defined. Despite the general assumption that Lin28 and Lin28b share similar targets and functions, conclusive demonstration of such redundancy is still missing. In addition, recent observations suggest a role of Lin28 proteins in mammalian reproduction, which is yet to be defined. We document herein the patterns of RNA expression and protein distribution of Lin28 and Lin28b in mouse testis during postnatal development and in a model of hypogonadotropic hypogonadism as a result of inactivation of the kisspeptin receptor, Gpr54. Lin28 and Lin28b mRNAs were expressed in mouse testis across postnatal maturation, but their levels disparately varied between neonatal and pubertal periods, with peak Lin28 levels in infantile testes and sustained elevation of Lin28b mRNA in young adult male gonads, where relative levels of let-7a and let-7b miRNAs were significantly suppressed. In addition, Lin28 peptides displayed totally different patterns of cellular distribution in mouse testis: Lin28 was located in undifferentiated and type-A1 spermatogonia, whereas Lin28b was confined to spermatids and interstitial Leydig cells. These profiles were perturbed in Gpr54 null mouse testis, which showed preserved but irregular Lin28 signal and absence of Lin28b peptide, which was rescued by administration of gonadotropins, mainly hCG (as super-agonist of LH). In addition, increased relative levels of Lin28, but not Lin28b, mRNA and of let-7a/let-7b miRNAs were observed in Gpr54 KO mouse testes. Altogether, our data are the first to document the divergent patterns of cellular distribution and mRNA expression of Lin28 and Lin28b in the mouse testis along postnatal maturation and their alteration in a model of congenital hypogonadotropic hypogonadism. Our findings suggest distinct functional roles of these two related, but not overlapping, miRNA-binding proteins in the male gonad.

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Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

Genes ◽

10.3390/genes12050615 ◽

2021 ◽

Vol 12 (5) ◽

pp. 615

Author(s):

Achala Fernando ◽

Chamikara Liyanage ◽

Afshin Moradi ◽

Panchadsaram Janaththani ◽

Jyotsna Batra

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Expression Profiles ◽

Association Studies ◽

Protein Isoforms ◽

The Cancer Genome Atlas ◽

Mass Spectrometry Analysis ◽

Functional Domains ◽

Homeodomain Protein ◽

Genome Wide Association Studies

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management.

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Genome-wide Identification and Expression Analysis of the YTH Domain-containing RNA-binding Protein Family in Citrus Sinensis

Journal of the American Society for Horticultural Science ◽

10.21273/jashs04567-18 ◽

2019 ◽

Vol 144 (2) ◽

pp. 79-91 ◽

Cited By ~ 1

Author(s):

Zhigang Ouyang ◽

Huihui Duan ◽

Lanfang Mi ◽

Wei Hu ◽

Jianmei Chen ◽

...

Keyword(s):

Stress Responses ◽

Messenger Rna ◽

Citrus Sinensis ◽

Rna Binding ◽

Developmental Stages ◽

Rna Binding Proteins ◽

Expression Profiles ◽

Expression Patterns ◽

Genome Wide ◽

Yth Domain

In eukaryotic systems, messenger RNA regulations, including splicing, 3′-end formation, editing, localization, and translation, are achieved by different RNA-binding proteins and noncoding RNAs. The YTH domain is a newly identified RNA-binding domain that was identified by comparing its sequence with that of splicing factor YT521-B. Previous study showed that the YTH gene plays an important role in plant resistance to abiotic and biotic stress. In this study, 211 YTH genes were identified in 26 species that represent four major plant lineages. Phylogenetic analysis revealed that these genes could be divided into eight subgroups. All of the YTH genes contain a YT521 domain and have different structures. Ten YTH genes were identified in navel orange (Citrus sinensis). The expression profiles of these CitYTH genes were analyzed in different tissues and at different fruit developmental stages, and CitYTH genes displayed distinct expression patterns under heat, cold, salt, and drought stress. Furthermore, expression of the CitYTH genes in response to exogenous hormones was measured. Nuclear localization was also confirmed for five of the proteins encoded by these genes after transient expression in Nicotiana benthamiana cells. This study provides valuable information on the role of CitYTHs in the signaling pathways involved in environmental stress responses in Citrus.

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RECENT RESEARCH ON THE GROWTH PLATE: Recent insights into the regulation of the growth plate

Journal of Molecular Endocrinology ◽

10.1530/jme-14-0022 ◽

2014 ◽

Vol 53 (1) ◽

pp. T1-T9 ◽

Cited By ~ 43

Author(s):

Julian C Lui ◽

Ola Nilsson ◽

Jeffrey Baron

Keyword(s):

Growth Plate ◽

Bone Morphogenetic Proteins ◽

Bone Growth ◽

Association Studies ◽

Expression Patterns ◽

Human Growth ◽

Cytokine Signaling ◽

Genome Wide Association Studies ◽

Paracrine Factors ◽

Large Numbers

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth.

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The Genetic Basis of Delayed Puberty

Neuroendocrinology ◽

10.1159/000481569 ◽

2017 ◽

Vol 106 (3) ◽

pp. 283-291 ◽

Cited By ~ 13

Author(s):

Sasha R. Howard ◽

Leo Dunkel

Keyword(s):

Genetic Control ◽

Large Scale ◽

Pubertal Timing ◽

Association Studies ◽

Genetic Regulation ◽

Psychosocial Health ◽

Delayed Puberty ◽

Genome Wide Association Studies ◽

Fetal Life ◽

Mineral Density

The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty “brake.” These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.

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Identification and characterization of SEC24D as a susceptibility gene for hepatitis B virus infection

Scientific Reports ◽

10.1038/s41598-019-49777-8 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Xianzhong Jiang ◽

Bin Zhang ◽

Junsheng Zhao ◽

Yi Xu ◽

Haijun Han ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Time Course ◽

Expression Profiles ◽

Association Studies ◽

Susceptibility Gene ◽

Hbv Infection ◽

Genome Wide Association Studies ◽

B Virus

Abstract Single nucleotide polymorphisms (SNPs) and genes associated with susceptibility to hepatitis B virus (HBV) infection that have been identified by genome-wide association studies explain only a limited portion of the known heritability, indicating more genetic variants remain to be discovered. In this study, we adopted a new research strategy to identify more susceptibility genes and variants for HBV infection. We first performed genetic association analysis of 300 sib-pairs and 3,087 case-control samples, which revealed that 36 SNPs located in 31 genes showed nominal associations with HBV infection in both samples. Of these genes, we selected SEC24D for further molecular analysis according to the following two main lines of evidence. First, a time course analysis of the expression profiles from HBV-infected primary human hepatocytes (PHH) demonstrated that SEC24D expression increased markedly as time passed after HBV infection (P = 4.0 × 10−4). Second, SNP rs76459466 in SEC24D was adversely associated with HBV risk (ORmeta = 0.82; Pmeta = 0.002), which again indicated that SEC24D represents a novel susceptibility gene for HBV infection. Moreover, SEC24D appeared to be protective against HBV infection in vitro. Consistently, we found that SEC24D expression was significantly enhanced in non-infected liver tissues (P = 0.002). We conclude that SEC24D is a novel candidate gene linked to susceptibility to HBV infection.

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Integrated genomics analysis highlights important SNPs and genes implicated in moderate-to-severe asthma based on GWAS and eQTL datasets

BMC Pulmonary Medicine ◽

10.1186/s12890-020-01303-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Zhouzhou Dong ◽

Yunlong Ma ◽

Hua Zhou ◽

Linhui Shi ◽

Gongjie Ye ◽

...

Keyword(s):

Bayesian Analysis ◽

Severe Asthma ◽

Antigen Processing ◽

Association Studies ◽

Expression Patterns ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Type I ◽

Genome Wide Association Studies ◽

Bioinformatics Analyses

Abstract Background Severe asthma is a chronic disease contributing to disproportionate disease morbidity and mortality. From the year of 2007, many genome-wide association studies (GWAS) have documented a large number of asthma-associated genetic variants and related genes. Nevertheless, the molecular mechanism of these identified variants involved in asthma or severe asthma risk remains largely unknown. Methods In the current study, we systematically integrated 3 independent expression quantitative trait loci (eQTL) data (N = 1977) and a large-scale GWAS summary data of moderate-to-severe asthma (N = 30,810) by using the Sherlock Bayesian analysis to identify whether expression-related variants contribute risk to severe asthma. Furthermore, we performed various bioinformatics analyses, including pathway enrichment analysis, PPI network enrichment analysis, in silico permutation analysis, DEG analysis and co-expression analysis, to prioritize important genes associated with severe asthma. Results In the discovery stage, we identified 1129 significant genes associated with moderate-to-severe asthma by using the Sherlock Bayesian analysis. Two hundred twenty-eight genes were prominently replicated by using MAGMA gene-based analysis. These 228 replicated genes were enriched in 17 biological pathways including antigen processing and presentation (Corrected P = 4.30 × 10− 6), type I diabetes mellitus (Corrected P = 7.09 × 10− 5), and asthma (Corrected P = 1.72 × 10− 3). With the use of a series of bioinformatics analyses, we highlighted 11 important genes such as GNGT2, TLR6, and TTC19 as authentic risk genes associated with moderate-to-severe/severe asthma. With respect to GNGT2, there were 3 eSNPs of rs17637472 (PeQTL = 2.98 × 10− 8 and PGWAS = 3.40 × 10− 8), rs11265180 (PeQTL = 6.0 × 10− 6 and PGWAS = 1.99 × 10− 3), and rs1867087 (PeQTL = 1.0 × 10− 4 and PGWAS = 1.84 × 10− 5) identified. In addition, GNGT2 is significantly expressed in severe asthma compared with mild-moderate asthma (P = 0.045), and Gngt2 shows significantly distinct expression patterns between vehicle and various glucocorticoids (Anova P = 1.55 × 10− 6). Conclusions Our current study provides multiple lines of evidence to support that these 11 identified genes as important candidates implicated in the pathogenesis of severe asthma.

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Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

Journal of Experimental Medicine ◽

10.1084/jem.20150218 ◽

2015 ◽

Vol 212 (8) ◽

pp. 1239-1254 ◽

Cited By ~ 28

Author(s):

Elisabeth K. Malle ◽

Nathan W. Zammit ◽

Stacey N. Walters ◽

Yen Chin Koay ◽

Jianmin Wu ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Association Studies ◽

Nuclear Factor Κb ◽

Negative Regulator ◽

Genome Wide Association Studies ◽

Nuclear Factor ◽

Pancreatic Β Cell ◽

Β Cell ◽

The Metabolic Syndrome

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB–inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell–intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.

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Posttranscriptional gene regulation by RNA-binding proteins during oxidative stress: implications for cellular senescence

Biological Chemistry ◽

10.1515/bc.2008.022 ◽

2008 ◽

Vol 389 (3) ◽

pp. 243-255 ◽

Cited By ~ 156

Author(s):

Kotb Abdelmohsen ◽

Yuki Kuwano ◽

Hyeon Ho Kim ◽

Myriam Gorospe

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Cellular Senescence ◽

Mammalian Cells ◽

Rna Binding ◽

Rna Binding Proteins ◽

Expression Profiles ◽

Expression Patterns ◽

Oxidant Damage ◽

Regulated Gene Expression

AbstractTo respond adequately to oxidative stress, mammalian cells elicit rapid and tightly controlled changes in gene expression patterns. Besides alterations in the subsets of transcribed genes, two posttranscriptional processes prominently influence the oxidant-triggered gene expression programs: mRNA turnover and translation. Here, we review recent progress in our knowledge of theturnover andtranslationregulatory (TTR) mRNA-bindingproteins (RBPs) that influence gene expression in response to oxidative damage. Specifically, we identify oxidant damage-regulated mRNAs that are targets of TTR-RBPs, we review the oxidant-triggered signaling pathways that govern TTR-RBP function, and we examine emerging evidence that TTR-RBP activity is altered with senescence and aging. Given the potent influence of TTR-RBPs upon oxidant-regulated gene expression profiles, we propose that the senescence-associated changes in TTR-RBPs directly contribute to the impaired responses to oxidant damage that characterize cellular senescence and advancing age.

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