scholarly journals The atlas of human cardiac promoters and enhancers reveals an important role for regulatory elements in heart failure

2021 ◽  
Author(s):  
Ruslan Deviatiiarov ◽  
Anna Gams ◽  
Roman Syunyaev ◽  
Tatiana Tatarinova ◽  
Ramesh Singh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Regulatory Network ◽  
Regulatory Elements ◽  
Nucleotide Polymorphisms ◽  
Alternative Promoters ◽  
Continuous Increase ◽  
Regulatory Changes ◽  
Cap Analysis ◽  
Failing States ◽  
Transcriptomic Changes

Abstract A continuous increase in the prevalence of heart failure and the lack of adequate therapy highlight poor understanding of the underlying genetic regulatory mechanisms involved in heart failure pathogenesis. Growing evidence has demonstrated a significant contribution of non-coding genome regulatory elements towards transcriptomic changes in heart disease. Thus, there is a pressing need for a comprehensive resource of the human cardiac regulatory network in healthy and failing states. We applied cap analysis of gene expression sequencing to directly measure the expression of RNA associated with enhancers and promoters. Based on this data, we constructed the atlas of transcribed cardiac regulatory elements from 21 healthy and 10 failing (ischemic and non-ischemic cardiomyopathy) human hearts. In total, we have sequenced 109 samples from the left and right atria and ventricles, identifying 17,668 promoters and 14,920 enhancers associated with 14,519 genes. Leveraging this atlas, we provide insights into functional and structural regulatory changes between healthy and failing hearts. Healthy atria and ventricles had distinct pathway enrichment and transcription factor binding patterns, significantly remodeled by heart failure. Using the advantages of deep sequencing that allow effective analysis of cis-regulatory elements-derived RNA, we found that heart failure is associated with the expression of transcripts derived from alternative promoters and a specific set of transcribed enhancers. Furthermore, we identified a high prevalence of single nucleotide polymorphisms associated with cardiovascular diseases within the regulatory regions highlighting their importance in disease pathogenesis. This open-source atlas will serve the cardiovascular community to improve understanding cardiac regulatory network and facilitate the development of novel therapeutics.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

Multiple cis-regulatory elements and the yeast sulphur regulatory network are required for the regulation of the yeast glutathione transporter, Hgt1p

2005 ◽  
Vol 47 (6) ◽  
pp. 345-358 ◽  
Author(s):  
Chittur V. Srikanth ◽  
Purva Vats ◽  
Andrée Bourbouloux ◽  
Serge Delrot ◽  
Anand K. Bachhawat
Keyword(s):  
Regulatory Network ◽  
Regulatory Elements

Association of β-defensin 1 gene Polymorphism and dental caries susceptibility in Tamil Ethnicity

2021 ◽  
pp. 4731-4735
Author(s):  
Harini Venkata Subbiah ◽  
Usha Subbiah ◽  
Athira Ajith
Keyword(s):  
Dental Caries ◽  
Odds Ratio ◽  
Regulatory Elements ◽  
Microbial Colonization ◽  
Nucleotide Polymorphisms ◽  
First Line ◽  
Single Nucleotide ◽  
Variant Genotype ◽  
Dental Caries Susceptibility ◽  
Genetic And Environmental Factors

Dental caries is a multifactorial disease that affects a large proportion of the population with both genetic and environmental factors contributing to the disease. Even in healthy oral environmental conditions, some individuals are susceptible to dental caries due to potential genetic contribution. Antimicrobial peptides are expressed in oral cavity and play an important role against microbial colonization and form an important first line defense against cariogenic bacteria. In the present study, we attempt to identify genetic variants that would cause significant functional impact towards susceptibility to dental caries. We investigated single nucleotide polymorphisms (SNPs) of beta-defensin 1 (DEFB1) as predictors of dental caries in tamil ethnic population. A total of 120 subjects were recruited for this study, which included 60 dental caries patients (DMFT>5) and 60 healthy controls (DMFT=0). Three SNPs of 5’UTR regulatory elements of DEFB1 were genotyped by PCR followed by Sanger sequencing. The genotypes associated with susceptibility to caries were found to be significant between rs11362 (p=.025, odds ratio = 3.72, 95% confidence interval (CI) = 1.289-10.742), rs1799946 (p=.023, odds ratio=4.32, 95% CI = 1.33-14.028) gene polymorphisms and risk of dental caries (DMFT>5) in tamil ethnicity. The variant genotype GG of rs1800972 polymorphism was found to be high in cases than controls but was not significant (p=0.136). Our data suggested that β-defensin 1 polymorphisms play a role in the susceptibility to dental caries.

scholarly journals Critical Care Management of Decompensated Right Heart Failure in Pulmonary Arterial Hypertension Patients – An Ongoing Approach

2021 ◽  
Vol 7 (3) ◽  
pp. 170-183
Author(s):  
Ioan Tilea ◽  
Andreea Varga ◽  
Anca-Meda Georgescu ◽  
Bianca-Liana Grigorescu
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Intensive Care ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Care Management ◽  
Right Heart Failure ◽  
Right Heart ◽  
Continuous Increase ◽  
Pulmonary Arterial

Abstract Despite substantial advancements in diagnosis and specific medical therapy in pulmonary arterial hypertension patients’ management, this condition continues to represent a major cause of mortality worldwide. In pulmonary arterial hypertension, the continuous increase of pulmonary vascular resistance and rapid development of right heart failure determine a poor prognosis. Against targeted therapy, patients inexorable deteriorate over time. Pulmonary arterial hypertension patients with acute right heart failure who need intensive care unit admission present a complexity of the disease pathophysiology. Intensive care management challenges are multifaceted. Awareness of algorithms of right-sided heart failure monitoring in intensive care units, targeted pulmonary hypertension therapies, and recognition of precipitating factors, hemodynamic instability and progressive multisystem organ failure requires a multidisciplinary pulmonary hypertension team. This paper summarizes the management strategies of acute right-sided heart failure in pulmonary arterial hypertension adult cases based on recently available data.

scholarly journals Effects of Certain cis-Regulatory Elements on Stage-Specific vitellogenin Expression in the Bombyx mori (Lepidoptera: Bombycidae)

2020 ◽  
Vol 20 (3) ◽  
Author(s):  
Guanwang Shen ◽  
Hongling Liu ◽  
Ying Lin ◽  
Dongxu Xing ◽  
Yujing Zhang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Transcription Factors ◽  
Bombyx Mori ◽  
Regulatory Network ◽  
Theoretical Basis ◽  
Regulatory Elements ◽  
Pcr Analysis ◽  
Qrt Pcr ◽  
Stage Specificity ◽  
E Box

Abstract Bombyx mori vitellogenin (BmVg) is highly upregulated during pupation, and the 20-hydroxyecdysone and amino acids may regulate stage-specific BmVg expression. However, previous studies showed that other factors may also affect stage-specific BmVg expression. Here, we characterized effective BmVg transcription factors by identifying the corresponding cis-regulatory elements (CREs). We prepared transgenic B. mori, in which DsRed was driven by various lengths of BmVg promoter. qRT-PCR analysis showed that DsRed expression driven by a 1.0-kb BmVg promoter (VgP1.0K) was consistent with endogenous BmVg. VgP1.0K specificity was closer to the endogenous BmVg promoter than that of VgP0.8K. These results suggest that CREs affecting stage-specific BmVg expression were localized to the 1.0-kb BmVg promoter. We investigated the effects of certain CREs that could influence the stage specificity of BmVg promoter on BmVg expression in transgenic B. mori. The relative DsRed expression was significantly reduced in transgenic female B. mori and the peak in DsRed expression was delayed after E-box CRE mutation. These results demonstrate that the E-box element enhanced BmVg expression and also affected stage-specific BmVg expression. Moreover, the relative DsRed expression was significantly increased in transgenic female of B. mori after 3×BD CRE mutation in BmVg promoter. However, the stage specificity of the mutated promoter was consistent with that of the endogenous BmVg promoter. The 3×BD element downregulated BmVg but had no effect on stage-specific BmVg expression. The present study promoted the process of elucidating the regulatory network for stage-specific BmVg expression and furnished a theoretical basis for the application of BmVg promoter.

scholarly journals Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms

2020 ◽  
Vol 47 (5) ◽  
pp. 385-395
Author(s):  
Brigitte K. Flesch ◽  
Angelika Reil ◽  
Núria Nogués ◽  
Carme Canals ◽  
Peter Bugert ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Human Neutrophil ◽  
Molecular Mechanisms ◽  
Normal Population ◽  
Regulatory Elements ◽  
Population Exposure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Immune Neutropenia ◽  
The Impact

Background: The human neutrophil antigen 2 (HNA-2), which is expressed on CD177, is undetectable in 3–5% of the normal population. Exposure of these HNA-2null individuals to HNA-2-positive cells can cause immunization and pro­duction of HNA-2 antibodies, which can induce immune neutropenia and transfusion-related acute lung injury. In HNA-2-positive individuals, neutrophils are divided into a CD177pos. and a CD177neg. subpopulation. The molecular background of HNA-2 deficiency and the bimodal expression pattern, however, are not completely decoded. Study Design: An international collaboration was conducted on the genetic analysis of HNA-2-phenotyped blood samples, including HNA-2-deficient individuals, mothers, and the respective children with neonatal immune neutropenia and regular blood donors. Results: From a total of 54 HNA-2null individuals, 43 were homozygous for the CD177*787A>T substitution. Six carried the CD177*c.1291G>A single nucleotide polymorphism. All HNA-2-positive samples with >40% CD177pos. neutrophils carried the *787A wild-type allele, whereas a lower rate of CD177pos. neutrophils was preferentially associated with *c.787AT heterozygosity. Interestingly, only the *c.787A allele sequence was detected in complementary DNA (cDNA) sequence analysis carried out on all *c.787AT heterozygous individuals. However, cDNA analysis after sorting of CD177pos. and CD177neg. neutrophil subsets from HNA-2-positive individuals showed identical sequences, which makes regulatory elements within the promoter unlikely to affect CD177 gene transcription in different CD177 neutrophil subsets. Conclusion: This comprehensive study clearly demonstrates the impact of single nucleotide polymorphisms on the expression of HNA-2 on the neutrophil surface but challenges the hypothesis of regulatory epigenetic effects being implicated in the bimodal CD177 expression pattern.

scholarly journals Identification of quantitative trait loci for increased α-tocopherol biosynthesis in wild soybean using a high-density genetic map

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Cheolwoo Park ◽  
Maria Stefanie Dwiyanti ◽  
Atsushi J. Nagano ◽  
Baohui Liu ◽  
Tetsuya Yamada ◽  
...  
Keyword(s):  
Qtl Analysis ◽  
Quantitative Trait ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Wild Soybean ◽  
Regulatory Elements ◽  
High Density ◽  
Wild Accession ◽  
Soybean Seeds ◽  
Nucleotide Polymorphisms

Abstract Background Soybean is one of the most important crop sources of tocopherols (Toc). However, the content of α-Toc, an isoform with the highest vitamin E activity in humans, is low in most cultivars. With the aim of broadening genetic variability, we performed quantitative trait locus (QTL) analysis for a high seed α-Toc trait detected in a wild soybean and characterized the sequence polymorphisms and expression profiles of γ-tocopherol methyltransferase (γ-TMT) genes as potential candidates. Results A recombinant inbred line population was developed from a cross between the low α-Toc breeding line TK780 and the high α-Toc wild accession B04009. The α-Toc content in seeds correlated strongly with the ratio of α-Toc to γ-Toc contents. QTL analysis using a high-density map constructed with 7710 single nucleotide polymorphisms (SNPs) generated by restriction site-associated DNA sequencing detected six QTLs involved in α-Toc biosynthesis. Of these, three in chromosomes (Chr) 9, 11, and 12 produced consistent effects during a 2-year trial. B04009 allele at QTLs in Chr9 and Chr12 and TK780 allele at the QTL in Chr11 each promoted the conversion of γ-Toc to α-Toc, which elevated the seed α-Toc content. SNPs and indels were detected between the parents in three γ-TMT genes (γ-TMT1, γ-TMT2, and γ-TMT3) co-located in the QTLs in Chr9 and Chr12, of which some existed in the cis-regulatory elements associated with seed development and functions. In immature cotyledons, γ-TMT3 was expressed at higher levels in B04009 than TK780, irrespective of two thermal conditions tested, whereas the expression of γ-TMT2 was markedly upregulated under higher temperatures, particularly in B04009. Conclusions We identified QTLs consistently controlling α-Toc biosynthesis in wild soybean seeds in 2-year trials. The QTL on Chr9 had been previously identified in soybean, whereas the QTLs on Chr11 and Chr12 were novel. Further molecular dissections and characterization of the QTLs may facilitate the use of high α-Toc alleles from wild soybean in soybean breeding and an understanding of the molecular mechanisms underlying α-Toc biosynthesis in soybean seeds.

scholarly journals Addressing the Missing Heritability Problem With the Help of Regulatory Features

2019 ◽  
Vol 15 ◽  
pp. 117693431986086
Author(s):  
Shan-Shan Dong ◽  
Yan Guo ◽  
Tie-Lin Yang
Keyword(s):  
Target Genes ◽  
Association Studies ◽  
Complex Diseases ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Missing Heritability ◽  
Genome Wide ◽  
Missing Heritability Problem

Genome-wide association studies (GWASs) have successfully identified thousands of susceptibility loci for human complex diseases. However, missing heritability is still a challenging problem. Considering most GWAS loci are located in regulatory elements, we recently developed a pipeline named functional disease-associated single-nucleotide polymorphisms (SNPs) prediction (FDSP), to predict novel susceptibility loci for complex diseases based on the interpretation of regulatory features and published GWAS results with machine learning. When applied to type 2 diabetes and hypertension, the predicted susceptibility loci by FDSP were proved to be capable of explaining additional heritability. In addition, potential target genes of the predicted positive SNPs were significantly enriched in disease-related pathways. Our results suggested that taking regulatory features into consideration might be a useful way to address the missing heritability problem. We hope FDSP could offer help for the identification of novel susceptibility loci for complex diseases.

scholarly journals Altered Enhancer and Promoter Usage Leads to Differential Gene Expression in the Normal and Failed Human Heart

2020 ◽  
Vol 13 (10) ◽  
Author(s):  
Anthony M. Gacita ◽  
Lisa Dellefave-Castillo ◽  
Patrick G.T. Page ◽  
David Y. Barefield ◽  
J. Andrew Wasserstrom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Regulatory Function ◽  
Specific Gene ◽  
Data Set ◽  
Promoter Usage ◽  
Additional Support ◽  
Cap Analysis ◽  
Genetic Contributions

Background: The failing heart is characterized by changes in gene expression. However, the regulatory regions of the genome that drive these gene expression changes have not been well defined in human hearts. Methods: To define genome-wide enhancer and promoter use in heart failure, cap analysis of gene expression sequencing was applied to 3 healthy and 4 failed human hearts to identify promoter and enhancer regions used in left ventricles. Healthy hearts were derived from donors unused for transplantation and failed hearts were obtained as discarded tissue after transplantation. Results: Cap analysis of gene expression sequencing identified a combined potential for ≈23 000 promoters and ≈5000 enhancers active in human left ventricles. Of these, 17 000 promoters and 1800 enhancers had additional support for their regulatory function. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered aminoterminal protein sequences. Enhancer usage between healthy and failed hearts identified a majority of differentially used heart failure enhancers were intronic and primarily localized within the first intron, revealing this position as a common feature associated with tissue-specific gene expression changes in the heart. Conclusions: This data set defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction. Additionally, regulatory changes contributing to heart failure are attractive therapeutic targets for controlling ventricular remodeling and clinical progression.

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