Abstract 17134: Variation Within a Left Ventricle-Specific Hand1 Enhancer Impairs Gata Transcription Factor Binding and Disrupts Ventricular Conduction System Development

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Joshua W Vincentz ◽  
Beth A Firulli ◽  
Kevin P Toolan ◽  
Dan E Arking ◽  
Nona Sotoodehnia ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Left Ventricle ◽  
Regulatory Element ◽  
Conduction System ◽  
Genome Wide Association ◽  
Regulatory Activity ◽  
Genome Wide ◽  
Gata Transcription Factor ◽  
Qrs Prolongation ◽  
Ventricular Conduction

The ventricular conduction system (VCS), composed of the His bundle, the left and right bundle branches, and the Purkinje fiber network, rapidly propagates electrical impulses through the ventricles to coordinate chamber contraction. An ECG depicts VCS-mediated ventricular depolarization as the QRS interval. Disorders of the VCS may manifest as arrhythmias, and are associated with increased risk of sudden cardiac death and overall mortality. The genetic and developmental mechanisms underlying VCS dysfunction are poorly understood. Genome-wide association studies have identified multiple single nucleotide polymorphisms (SNPs) associated with VCS arrhythmias. A majority of these SNPs occur outside of coding domains, within intergenic or intronic regions. We hypothesize that such pathogenic SNPs may impact VCS development and function by altering the expression of critical genes. Two intergenic SNPs associated with QRS prolongation occur near the bHLH cardiac transcription factor HAND1 . We have identified a left ventricle (LV) enhancer, located between these two SNPs, that is necessary and sufficient for LV cis -regulatory activity. Two evolutionarily conserved GATA transcription factor consensus-binding sites within this enhancer are bound by GATA4 and necessary for cis -regulatory activity. CRISPR-mediated deletion of this enhancer dramatically reduced Hand1 expression solely within the LV. Mice homozygous for this deleted enhancer displayed dysregulated LV gene expression, morphologically abnormal His bundles and left bundle branches, and a VCS phenotype consistent with right bundle branch block. Genome-wide association analyses of human patients with QRS prolongation revealed additional, linked SNPs, one of which overlaps with a critical GATA cis -regulatory element within the LV-specific Hand1 enhancer. This SNP disrupts GATA4 binding. Ongoing studies of mice that genetically mimic these minor SNP variants will assess reduced Hand1 expression and impaired VCS function. We conclude that a LV-specific Hand1 enhancer is necessary for VCS development and a SNP associated with QRS prolongation directly influences GATA4 binding to a critical cis -regulatory element within this enhancer.

scholarly journals TFutils: Data structures for transcription factor bioinformatics

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 152
Author(s):  
Benjamin J. Stubbs ◽  
Shweta Gopaulakrishnan ◽  
Kimberly Glass ◽  
Nathalie Pochet ◽  
Celine Everaert ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Data Structures ◽  
Binding Sites ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Bioconductor Package ◽  
Genome Wide ◽  
Study Results ◽  
Integrative Analyses

DNA transcription is intrinsically complex. Bioinformatic work with transcription factors (TFs) is complicated by a multiplicity of data resources and annotations. The Bioconductor package TFutils includes data structures and functions to enhance the precision and utility of integrative analyses that have components involving TFs. TFutils provides catalogs of human TFs from three reference sources (CISBP, HOCOMOCO, and GO), a catalog of TF targets derived from MSigDb, and multiple approaches to enumerating TF binding sites. Aspects of integration of TF binding patterns and genome-wide association study results are explored in examples.

scholarly journals Genome-wide association study of susceptibility to hospitalised respiratory infections

2021 ◽  
Vol 6 ◽  
pp. 290
Author(s):  
Alexander T. Williams ◽  
Nick Shrine ◽  
Hardeep Naghra-van Gijzel ◽  
Joanna C. Betts ◽  
Edith M. Hessel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Association Study ◽  
Respiratory Infection ◽  
Genome Wide Association Study ◽  
Respiratory Infections ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Biological Mechanisms ◽  
Genome Wide ◽  
Infection Susceptibility

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: In the discovery analysis, we report 56 signals at P<5×10-6, one of which was genome-wide significant (P<5×10-8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate when aggregating effect estimates across 11 independent cohorts. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

scholarly journals Genome-Wide Association Study (GWAS) to Identify Salt-Tolerance QTLs Carrying Novel Candidate Genes in Rice During Early Vegetative Stage

2020 ◽  
Author(s):  
Leila Nayyeripasand ◽  
Ghasem Ali Garoosi ◽  
Asadollah Ahmadikhah
Keyword(s):  
Transcription Factor ◽  
Association Study ◽  
Candidate Gene ◽  
Candidate Genes ◽  
Salinity Tolerance ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Vegetative Stage ◽  
Genome Wide ◽  
Genomic Regions

Abstract Background Rice is considered as a salt-sensitive plant, particularly at early vegetative stage, and its production is suffered from salinity due to expansion of salt affected land in areas under cultivation. Hence, significant increase of rice productivity on salinized lands is really necessary. Today genome-wide association study (GWAS) is a method of choice for fine mapping of QTLs involved in plant responses to abiotic stresses including salinity stress at early vegetative stage. In this study using > 33,000 SNP markers we identified rice genomic regions associated to early stage salinity tolerance. Eight salinity-related traits including SL, RL, RDW, RFW, SFW, SDW, RWC and TW in a diverse panel of rice consisted of 202 varieties were evaluated under salinity (100 mM NaCl) and normal conditions in growth chamber. Genome-wide association study (GWAS) was applied based on MLM(+ Q + K) model.Results Under stress conditions 151 trait-marker associations were identified that were scattered on 10 chromosomes of rice that arranged in 29 genomic regions. A genomic region on chromosome 1 (11.26 Mbp) was identified which co-located with a known QTL region SalTol1 for salinity tolerance at vegetative stage. A candidate gene (Os01g0304100) was identified in this region which encodes a cation chloride cotransporter. Furthermore, on this chromosome two other candidate genes, Os01g0624700 (24.95 Mbp) and Os01g0812000 (34.51 Mbp), were identified that encode a WRKY transcription factor (WRKY 12) and a transcriptional activator of gibberellin-dependent alpha-amylase expression (GAMyb), respectively. Also, a narrow interval on the same chromosome (40.79–42.98 Mbp) carries 12 candidate genes, some of them were not so far reported for salinity tolerance at seedling stage. Two of more interesting genes are Os01g0966000 and Os01g0963000, encoding a plasma membrane (PM) H+-ATPase and a peroxidase BP1 protein. On chromosome 6 a DnaJ-encoding gene and pseudouridine synthase gene were identified. Two novel genes on chromosome 8 including the ABI/VP1 transcription factor and retinoblastoma-related protein (RBR), and 3 novel genes on chromosome 11 including a Lox, F-box and Na+/H+ antiporter, were also identified.Conclusion The results for RDW and RFW were found more important than other traits, and known or novel candidate genes in this research can be used for improvement of salinity tolerance in molecular breeding programmes. Further study and identification of effective genes on salinity tolerance by the use of candidate gene-association analysis can help to precisely uncover the mechanisms of salinity tolerance at molecular level.

scholarly journals Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Caroline Choquet ◽  
Robert G. Kelly ◽  
Lucile Miquerol
Keyword(s):  
Transcription Factor ◽  
Electrical Activity ◽  
Cell Fate ◽  
Clonal Analysis ◽  
Conduction System ◽  
Purkinje Fiber ◽  
Fate Mapping ◽  
Fiber Network ◽  
Apply Genetic ◽  
Ventricular Conduction

Abstract The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.

NAC transcription factor genes: genome-wide identification, phylogenetic, motif and cis-regulatory element analysis in pigeonpea (Cajanus cajan (L.) Millsp.)

2014 ◽  
Vol 41 (12) ◽  
pp. 7763-7773 ◽  
Author(s):  
Viswanathan Satheesh ◽  
P. Tej Kumar Jagannadham ◽  
Parameswaran Chidambaranathan ◽  
P. K. Jain ◽  
R. Srinivasan
Keyword(s):  
Transcription Factor ◽  
Cajanus Cajan ◽  
Regulatory Element ◽  
Nac Transcription Factor ◽  
Element Analysis ◽  
Genome Wide ◽  
Transcription Factor Genes

scholarly journals Genome-Wide Association Study in Rice Revealed a Novel Gene in Determining Plant Height and Stem Development, by Encoding a WRKY Transcription Factor

2021 ◽  
Vol 22 (15) ◽  
pp. 8192
Author(s):  
Xiaoshuang Wei ◽  
Hailian Zhou ◽  
Deying Xie ◽  
Jianguo Li ◽  
Mingchong Yang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Association Study ◽  
Plant Height ◽  
Stress Responses ◽  
Genome Wide Association Study ◽  
Heading Date ◽  
Wrky Transcription Factor ◽  
Genome Wide Association ◽  
Dwarf Phenotype ◽  
Genome Wide

Semi-dwarfism is a main agronomic trait in crop breeding. In this study, we performed genome-wide association study (GWAS) and identified a new quantitative trait nucleotide (QTN) for rice shoot length. The peak QTN (C/T) was located in the first coding region of a group III WRKY transcription factor OsWRKY21 (LOC_Os01g60640). Interestingly, further haplotype analysis showed that C/T difference only existed in the indica group but not in the japonica group, resulting in significant differences in plant height among the different indica rice varieties. OsWRKY21 was expressed in embryo, radicle, shoots, leaves, and stems. Most notably, overexpressing OsWRKY21 resulted in the semi-dwarf phenotype, early heading date and short internodes compared to the wild type, while the knockout mutant plants by CRISPR/Cas9 technology yielded the opposite. The overexpressing lines exhibited the decreased length of the cells near sclerenchyma epidermis, accompanied with the lower levels of indole-3-acetic acid (IAA) and gibberellin 3 (GA3), but increased levels of the abscisic acid (ABA) and salicylic acid (SA) in the internodes at heading stage. Moreover, the semi-dwarf phenotype could be fully rescued by exogenous GA3 application at seedling stage. The RNA-seq and qRT-PCR analysis confirmed the differential expression levels of genes in development and the stress responses in rice, including GA metabolism (GA20ox2, GA2ox6, and YABY1) and cell wall biosynthesis (CesA4, 7, and 9) and regulation (MYB103L). These data suggest the essential role of OsWRKY21 in regulation of internode elongation and plant height in rice.

scholarly journals Integrative analysis identifies bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Victoria Berge-Seidl ◽  
Lasse Pihlstrøm ◽  
Mathias Toft
Keyword(s):  
Transcription Factor ◽  
Genetic Risk ◽  
Temporal Cortex ◽  
Genome Wide Association ◽  
Transcriptional Networks ◽  
Open Chromatin ◽  
Risk Variants ◽  
Genome Wide ◽  
Superior Temporal Cortex ◽  
Bhlh Transcription Factors

AbstractGenome-wide association studies (GWAS) have identified multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses of GWAS findings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome-wide association signals in PD and open chromatin in neurons across multiple brain regions, finding a significant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identified by two de novo motif discovery methods. Analyses were performed in parallel, both finding that PD risk variants significantly overlap with open chromatin regions harboring motifs of basic Helix-Loop-Helix (bHLH) transcription factors. Our findings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms.

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