scholarly journals Deletion of SREBF1, a Functional Bone-Muscle Pleiotropic Gene, Alters Bone Density and Lipid Signaling in Zebrafish

Endocrinology ◽  
2020 ◽  
Vol 162 (1) ◽  
Author(s):  
Chen Shochat ◽  
Zhiying Wang ◽  
Chenglin Mo ◽  
Sarah Nelson ◽  
Rajashekar Donaka ◽  
...  
Keyword(s):  
Acid Metabolism ◽  
Regulatory Element ◽  
Arachidonic Acid Metabolism ◽  
Lipid Signaling ◽  
Epoxyeicosatrienoic Acid ◽  
Mineral Density ◽  
Genome Wide ◽  
A Genome ◽  
Liquid Chromatography Tandem Mass ◽  
Quantitative Correlational Study

Abstract Through a genome-wide analysis of bone mineral density (BMD) and muscle mass, identification of a signaling pattern on 17p11.2 recognized the presence of sterol regulatory element-binding factor 1 (SREBF1), a gene responsible for the regulation of lipid homeostasis. In conjunction with lipid-based metabolic functions, SREBF1 also codes for the protein, SREBP-1, a transcription factor known for its role in adipocyte differentiation. We conducted a quantitative correlational study. We established a zebrafish (ZF) SREBF1 knockout (KO) model and used a targeted customized lipidomics approach to analyze the extent of SREBF1 capabilities. For lipidomics profiling, we isolated the dorsal muscles of wild type (WT) and KO fishes, and we performed liquid chromatography-tandem mass spectrometry screening assays of these samples. In our analysis, we profiled 48 lipid mediators (LMs) derived from various essential polyunsaturated fatty acids to determine potential targets regulated by SREBF1, and we found that the levels of 11,12 epoxyeicosatrienoic acid (11,12-EET) were negatively associated with the number of SREBF1 alleles (P = 0.006 for a linear model). We also compared gene expression between KO and WT ZF by genome-wide RNA-sequencing. Significantly enriched pathways included fatty acid elongation, linoleic acid metabolism, arachidonic acid metabolism, adipocytokine signaling, and DNA replication. We discovered trends indicating that BMD in adult fish was significantly lower in the KO than in the WT population (P < 0.03). These studies reinforce the importance of lipidomics investigation by detailing how the KO of SREBF1 affects both BMD and lipid-signaling mediators, thus confirming the importance of SREBF1 for musculoskeletal homeostasis.

scholarly journals Genome-Wide DNA Methylation in Mixed Ancestry Individuals with Diabetes and Prediabetes from South Africa

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Tandi E. Matsha ◽  
Carmen Pheiffer ◽  
Stephen E. Humphries ◽  
Junaid Gamieldien ◽  
Rajiv T. Erasmus ◽  
...  
Keyword(s):  
South Africa ◽  
Dna Methylation ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Mixed Ancestry ◽  
Kegg Pathways ◽  
Genome Wide ◽  
A Genome ◽  
Control Versus ◽  
And Control

Aims. To conduct a genome-wide DNA methylation in individuals with type 2 diabetes, individuals with prediabetes, and control mixed ancestry individuals from South Africa.Methods. We used peripheral blood to perform genome-wide DNA methylation analysis in 3 individuals with screen detected diabetes, 3 individuals with prediabetes, and 3 individuals with normoglycaemia from the Bellville South Community, Cape Town, South Africa, who were age-, gender-, body mass index-, and duration of residency-matched. Methylated DNA immunoprecipitation (MeDIP) was performed by Arraystar Inc. (Rockville, MD, USA).Results. Hypermethylated DMRs were 1160 (81.97%) and 124 (43.20%), respectively, in individuals with diabetes and prediabetes when both were compared to subjects with normoglycaemia. Our data shows that genes related to the immune system, signal transduction, glucose transport, and pancreas development have altered DNA methylation in subjects with prediabetes and diabetes. Pathway analysis based on the functional analysis mapping of genes to KEGG pathways suggested that the linoleic acid metabolism and arachidonic acid metabolism pathways are hypomethylated in prediabetes and diabetes.Conclusions. Our study suggests that epigenetic changes are likely to be an early process that occurs before the onset of overt diabetes. Detailed analysis of DMRs that shows gradual methylation differences from control versus prediabetes to prediabetes versus diabetes in a larger sample size is required to confirm these findings.

A genome-wide scan for loci linked to forearm bone mineral density

1999 ◽  
Vol 104 (3) ◽  
pp. 226-233 ◽  
Author(s):  
Tianhua Niu ◽  
Changzhong Chen ◽  
Heather Cordell ◽  
Jianhua Yang ◽  
Binyan Wang ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Mineral Density ◽  
Forearm Bone Mineral Density ◽  
Genome Wide ◽  
A Genome ◽  
Forearm Bone ◽  
Genome Wide Scan

scholarly journals Meta-Analysis of Genome-Wide Association Studies Identifies Novel Functional CpG-SNPs Associated with Bone Mineral Density at Lumbar Spine

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Chuan Qiu ◽  
Hui Shen ◽  
Xiaoying Fu ◽  
Chao Xu ◽  
Hongwen Deng
Keyword(s):  
Bone Mineral Density ◽  
Dna Methylation ◽  
Lumbar Spine ◽  
Bone Mineral ◽  
Meta Analysis ◽  
Mineral Density ◽  
Significance Level ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

Osteoporosis is a serious public health issue, which is mostly characterized by low bone mineral density (BMD). To search for additional genetic susceptibility loci underlying BMD variation, an effective strategy is to focus on testing of specific variants with high potential of functional effects. Single nucleotide polymorphisms (SNPs) that introduce or disrupt CpG dinucleotides (CpG-SNPs) may alter DNA methylation levels and thus represent strong candidate functional variants. Here, we performed a targeted GWAS for 63,627 potential functional CpG-SNPs that may affect DNA methylation in bone-related cells, in five independent cohorts (n=5905). By meta-analysis, 9 CpG-SNPs achieved a genome-wide significance level (p<7.86×10−7) for association with lumbar spine BMD and additional 15 CpG-SNPs showed suggestive significant (p<5.00×10−5) association, of which 2 novel SNPs rs7231498 (NFATC1) and rs7455028 (ESR1) also reached a genome-wide significance level in the joint analysis. Several identified CpG-SNPs were mapped to genes that have not been reported for association with BMD in previous GWAS, such as NEK3 and NFATC1 genes, highlighting the enhanced power of targeted association analysis for identification of novel associations that were missed by traditional GWAS. Interestingly, several genomic regions, such as NEK3 and LRP5 regions, contained multiple significant/suggestive CpG-SNPs for lumbar spine BMD, suggesting that multiple neighboring CpG-SNPs may synergistically mediate the DNA methylation level and gene expression pattern of target genes. Furthermore, functional annotation analyses suggested a strong regulatory potential of the identified BMD-associated CpG-SNPs and a significant enrichment in biological processes associated with protein localization and protein signal transduction. Our results provided novel insights into the genetic basis of BMD variation and highlighted the close connections between genetic and epigenetic mechanisms of complex disease.

scholarly journals Genome-Wide cis-Regulatory Element Based Discovery of Auxin-Responsive Genes in Higher Plant

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 24
Author(s):  
Jianfei Wu ◽  
Fan Gao ◽  
Tongtong Li ◽  
Haixia Guo ◽  
Li Zhang ◽  
...  
Keyword(s):  
Target Genes ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Auxin Response ◽  
Higher Plant ◽  
Response Factors ◽  
Auxin Response Factors ◽  
Genome Wide ◽  
A Genome ◽  
Almost All

Auxin has a profound impact on plant physiology and participates in almost all aspects of plant development processes. Auxin exerts profound pleiotropic effects on plant growth and differentiation by regulating the auxin response genes’ expressions. The classical auxin reaction is usually mediated by auxin response factors (ARFs), which bind to the auxin response element (AuxRE) in the promoter region of the target gene. Experiments have generated only a limited number of plant genes with well-characterized functions. It is still unknown how many genes respond to exogenous auxin treatment. An economical and effective method was proposed for the genome-wide discovery of genes responsive to auxin in a model plant, Arabidopsis thaliana (A. thaliana). Our method relies on cis-regulatory-element-based targeted gene finding across different promoters in a genome. We first exploit and analyze auxin-specific cis-regulatory elements for the transcription of the target genes, and then identify putative auxin responsive genes whose promoters contain the elements in the collection of over 25,800 promoters in the A. thaliana genome. Evaluating our result by comparing with a published database and the literature, we found that this method has an accuracy rate of 65.2% (309/474) for predicting candidate genes responsive to auxin. Chromosome distribution and annotation of the putative auxin-responsive genes predicted here were also mined. The results can markedly decrease the number of identified but merely potential auxin target genes and also provide useful clues for improving the annotation of gene that lack functional information.

scholarly journals The Arachidonic Acid Metabolism Mechanism Based on UPLC-MS/MS Metabolomics in Recurrent Spontaneous Abortion Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Meihe Li ◽  
Yang Haixia ◽  
Minchao Kang ◽  
Peng An ◽  
Xili Wu ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Spontaneous Abortion ◽  
Acid Metabolism ◽  
Ultra Performance Liquid Chromatography ◽  
Arachidonic Acid Metabolism ◽  
Recurrent Spontaneous Abortion ◽  
Metabolism Pathway ◽  
Liquid Chromatography Tandem Mass ◽  
Novel Biomarkers ◽  
Cox 1

Recurrent spontaneous abortion (RSA) remains a critical and challenging problem in reproduction. To discover novel biomarkers for RSA, ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) metabolomics approach was applied to detect RSA serum metabolic profiles and explore its possible pathogenesis and mechanism. The abortion rat model was established, and a metabolomics analysis was performed to evaluate the differentially expressed metabolites between the control and model groups. Immunohistochemistry (IHC), qRT-PCR, and Western blot further examined the expression of Arachidonic acid metabolism-related genes in uterus tissues. To identify arachidonic acid metabolism-related changes in RSA, ELISA’s potential mechanisms were further confirmed in serum. Ninety-one metabolites were significantly different between the two groups, as indicated by a VIP ≥1, fold change ≥1. The metabolic pathways involving arachidonic acid metabolism pathway (P = 0.00044) are related to RSA. Verification by experimental showed that compared with the control rats, the expression of the COX-1, COX-2, PTGFR, and TBXA2R genes associated with the arachidonic acid metabolism pathway has significantly increased the uterus and serum of RSA rats (P &lt; 0.05). Regulation of the arachidonic acid metabolism pathway might serve as a promising therapeutic strategy for relieving RSA women’s symptoms.

scholarly journals Mouse Genome-Wide Association and Systems Genetics Identifies Lhfp as a Regulator of Bone Mass

2018 ◽  
Author(s):  
Larry D. Mesner ◽  
Gina Calabrese ◽  
Basel Al-Barghouthi ◽  
Daniel M. Gatti ◽  
John P. Sundberg ◽  
...  
Keyword(s):  
Bone Mass ◽  
Genome Wide Association Study ◽  
Strong Predictor ◽  
Genome Wide Association ◽  
Systems Genetics ◽  
Fusion Partner ◽  
Mineral Density ◽  
Osteoblast Activity ◽  
Genome Wide ◽  
A Genome

ABSTRACTBone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P=3.1 x 10−12) BMD locus on Chromosome [email protected] Mbp that replicated in two seperate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes; Gm2447, Gm20750, Cog6, and Lhfp. Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts and its expression was regulated by local expression QTL (eQTL) in multiple tissues. A co-expression network analysis revealed that Lhfp was strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone, Lhfp deficient mice (Lhfp−/−) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) from Lhfp−/− displayed increased osteogenic differentiation. Lfhp−/− mice also had elevated BMD due to increased cortical bone mass. In conclusion, we used GWAS and systems genetics in mice to identify Lhfp as a regulator of osteoblast activity and bone mass.

scholarly journals Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

2021 ◽  
Author(s):  
Doris Skoric-Milosavljevic ◽  
Rafik Tadros ◽  
Fernanda M Bosada ◽  
Federico Tessadori ◽  
Jan Hendrik van Weerd ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Regulatory Element ◽  
Susceptibility Locus ◽  
Mouse Heart ◽  
Polygenic Risk Score ◽  
Polygenic Inheritance ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

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