Functionally Related Genes Cluster into Genomic Regions That Coordinate Transcription at a Distance in Saccharomyces cerevisiae

ABSTRACT Balancing gene expression is a fundamental challenge of all cell types. To properly regulate transcription on a genome-wide level, there are myriad mechanisms employed by the cell. One layer to this regulation is through spatial positioning, with particular chromosomal loci exerting an influence on transcription throughout a region. Many coregulated gene families utilize spatial positioning to coordinate transcription, with functionally related genes clustering together which can allow coordinated expression via adjacent gene coregulation. The mechanisms underlying this process have not been elucidated, though there are many coregulated gene families that exhibit this genomic distribution. In the present study, we tested for a role for the enhancer-promoter (EP) hypothesis, which demonstrates that regulatory elements can exert transcriptional effects over a broad distance, in coordinating transcriptional coregulation using budding yeast, Saccharomyces cerevisiae. We empirically validated the EP model, finding that the genomic distance a promoter can affect varies by locus, which can profoundly affect levels of transcription, phenotype, and the extent of transcriptional disruption throughout a genomic region. Using the nitrogen metabolism, ribosomal protein, toxin response, and heat shock gene families as our test case, we report functionally clustered genes localize to genomic loci that are more conducive to transcriptional regulation at a distance compared to the unpaired members of the same families. Furthermore, we report that the coregulation of functional clusters is dependent, in part, on chromatin maintenance and remodeling, providing one mechanism underlying adjacent gene coregulation. IMPORTANCE The two-dimensional, physical positioning of genes along a chromosome can impact proper transcriptional regulation throughout a genomic region. The transcription of neighboring genes is correlated in a genome-wide manner, which is a characteristic of eukaryotes. Many coregulated gene families can be found clustered with another member of the same set—which can result in adjacent gene coregulation of the pair. Due to the myriad gene families that exhibit a nonrandom genomic distribution, there are likely multiple mechanisms working in concert to properly regulate transcriptional coordination of functionally clustered genes. In this study, we utilized budding yeast in an attempt to elucidate mechanisms that underlie this coregulation: testing and empirically validating the enhancer-promoter hypothesis in this species and reporting that functionally related genes cluster to genomic regions that are more conducive to transcriptional regulation at a distance. These clusters rely, in part, on chromatin maintenance and remodelers to maintain proper transcriptional coordination. Our work provides insight into the mechanisms underlying adjacent gene coregulation.

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Systematic Identification, Characterization, and Conservation of Adjacent-Gene Coregulation in the Budding Yeast Saccharomyces cerevisiae

mSphere ◽

10.1128/msphere.00220-18 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 2

Author(s):

Reem S. Eldabagh ◽

Nelson G. Mejia ◽

Rachel L. Barrett ◽

Christopher R. Monzo ◽

Matthew K. So ◽

...

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Transcriptional Regulation ◽

Ribosome Biogenesis ◽

Budding Yeast ◽

Specific Effect ◽

Gene Families ◽

Adjacent Gene ◽

Genomic Distribution ◽

Content Type

ABSTRACT It is essential that cells orchestrate gene expression for the specific niche that they occupy, and this often requires coordination of the expression of large sets of genes. There are multiple regulatory systems that exist for modulation of gene expression, including the adjacent-gene coregulation of the rRNA and ribosome biogenesis and ribosomal protein families. Both gene families exhibit a nonrandom genomic distribution, often clustered directly adjacent to another member of the same family, which results in a tighter transcriptional coordination among adjacent paired genes than that of the unpaired genes within each regulon and can result in a shared promoter that coordinates expression of the pairs. This nonrandom genomic distribution has been seen in a few functionally related gene families, and many of these functional pairings are conserved across divergent fungal lineages. To date, the significance of these observations has not been extended in a systematic way to characterize how prevalent the role of adjacent-gene coregulation is in transcriptional regulation. In the present study, we systematically analyzed the transcriptional coherence of the functional pairs compared to the singletons within all gene families defined by the Gene Ontology Slim designation, using Saccharomyces cerevisiae as a model system, finding that clusters exhibit a tighter transcriptional correlation under specific contexts. We found that the longer a functional pairing is conserved the tighter its response to broad stress and nutritional responses, that roughly 25% of gene families exhibit a nonrandom genomic distribution, and that many of these clusters are conserved. This suggests that adjacent-gene coregulation is a widespread, yet underappreciated, transcriptional mechanism. IMPORTANCE The spatial positioning of genes throughout the genome arrangement can alter their expression in many eukaryotic organisms. Often this results in a genomic context-specific effect on transcription. One example of this is through the clustering of functionally related genes, which results in adjacent-gene coregulation in the budding yeast Saccharomyces cerevisiae . In the present study, we set out to systematically characterize the prevalence of this phenomenon, finding the genomic organization of functionally related genes into clusters is a characteristic of myriad gene families. These arrangements are found in many evolutionarily divergent fungi and thus represent a widespread, yet underappreciated, layer of transcriptional regulation.

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Genomic and Transcriptomic Analysis Identified Novel Putative Cassava lncRNAs Involved in Cold and Drought Stress

Genes ◽

10.3390/genes11040366 ◽

2020 ◽

Vol 11 (4) ◽

pp. 366

Author(s):

Rungaroon Suksamran ◽

Treenut Saithong ◽

Chinae Thammarongtham ◽

Saowalak Kalapanulak

Keyword(s):

Transcriptional Regulation ◽

Regulation Of Gene Expression ◽

Gene Families ◽

Cellular Processes ◽

Nuclear Factor Y ◽

Genome Wide ◽

A Genome ◽

Non Coding Rnas ◽

Post Transcriptional Regulation ◽

Genome Wide Study

Long non-coding RNAs (lncRNAs) play important roles in the regulation of complex cellular processes, including transcriptional and post-transcriptional regulation of gene expression relevant for development and stress response, among others. Compared to other important crops, there is limited knowledge of cassava lncRNAs and their roles in abiotic stress adaptation. In this study, we performed a genome-wide study of ncRNAs in cassava, integrating genomics- and transcriptomics-based approaches. In total, 56,840 putative ncRNAs were identified, and approximately half the number were verified using expression data or previously known ncRNAs. Among these were 2229 potential novel lncRNA transcripts with unmatched sequences, 250 of which were differentially expressed in cold or drought conditions, relative to controls. We showed that lncRNAs might be involved in post-transcriptional regulation of stress-induced transcription factors (TFs) such as zinc-finger, WRKY, and nuclear factor Y gene families. These findings deepened our knowledge of cassava lncRNAs and shed light on their stress-responsive roles.

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Genome-Wide Association Study (GWAS) for Examining the Genomics Controlling Prickle Production in Red Raspberry (Rubus idaeus L.)

Agronomy ◽

10.3390/agronomy11010027 ◽

2020 ◽

Vol 11 (1) ◽

pp. 27

Author(s):

Archana Khadgi ◽

Courtney A. Weber

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genomic Region ◽

Rubus Idaeus ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Red Raspberry ◽

Genome Wide ◽

A Genome ◽

Genotype By Sequencing

Red raspberry (Rubus idaeus L.) is an expanding high-value berry crop worldwide. The presence of prickles, outgrowths of epidermal tissues lacking vasculature, on the canes, petioles, and undersides of leaves complicates both field management and harvest. The utilization of cultivars with fewer prickles or prickle-free canes simplifies production. A previously generated population segregating for prickles utilizing the s locus between the prickle-free cultivar Joan J (ss) and the prickled cultivar Caroline (Ss) was analyzed to identify the genomic region associated with prickle development in red raspberry. Genotype by sequencing (GBS) was combined with a genome-wide association study (GWAS) using fixed and random model circulating probability unification (FarmCPU) to analyze 8474 single nucleotide polymorphisms (SNPs) and identify significant markers associated with the prickle-free trait. A total of four SNPs were identified on chromosome 4 that were associated with the phenotype and were located near or in annotated genes. This study demonstrates how association genetics can be used to decipher the genetic control of important horticultural traits in Rubus, and provides valuable information about the genomic region and potential genes underlying the prickle-free trait.

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Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity

Nutrients ◽

10.3390/nu13061984 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1984

Author(s):

Majid Nikpay ◽

Sepehr Ravati ◽

Robert Dent ◽

Ruth McPherson

Keyword(s):

Quantitative Trait Locus ◽

Quantitative Trait ◽

Rare Variants ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search ◽

Risk Snps ◽

Trait Locus ◽

Genomic Regions ◽

Eqtl Data

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

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An FGA Frameshift Variant Associated with Afibrinogenemia in Dachshunds

Genes ◽

10.3390/genes12071065 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1065

Author(s):

Reinhard Mischke ◽

Julia Metzger ◽

Ottmar Distl

Keyword(s):

Protein Sequence ◽

Sanger Sequencing ◽

Selective Breeding ◽

Genome Wide Association Study ◽

Frameshift Mutation ◽

Homozygosity Mapping ◽

Genomic Region ◽

Severe Bleeding ◽

Genome Wide ◽

A Genome

Congenital fibrinogen disorders are very rare in dogs. Cases of afibrinogenemia have been reported in Bernese Mountain, Bichon Frise, Cocker Spaniel, Collie, Lhasa Apso, Viszla, and St. Bernard dogs. In the present study, we examined four miniature wire-haired Dachshunds with afibrinogenemia and ascertained their pedigree. Homozygosity mapping and a genome-wide association study identified a candidate genomic region at 50,188,932–64,187,680 bp on CFA15 harboring FGB (fibrinogen beta chain), FGA (fibrinogen alpha chain), and FGG (fibrinogen gamma-B chain). Sanger sequencing of all three fibrinogen genes in two cases and validation of the FGA-associated mutation (FGA:g.6296delT, NC_006597.3:g.52240694delA, rs1152388481) in pedigree members showed a perfect co-segregation with afibrinogenemia-affected phenotypes, obligate carriers, and healthy animals. In addition, the rs1152388481 variant was validated in 393 Dachshunds and samples from 33 other dog breeds. The rs1152388481 variant is predicted to modify the protein sequence of both FGA transcripts (FGA201:p.Ile486Met and FGA-202:p.Ile555Met) leading to proteins truncated by 306 amino acids. The present data provide evidence for a novel FGA truncating frameshift mutation that is very likely to explain the cases of severe bleeding due to afibrinogenemia in a Dachshund family. This mutation has already been spread in Dachshunds through carriers before cases were ascertained. Genetic testing allows selective breeding to prevent afibrinogenemia-affected puppies in the future.

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Drosophila Gain-of-Function Mutant RTK Torso Triggers Ectopic Dpp and STAT Signaling

Genetics ◽

10.1093/genetics/164.1.247 ◽

2003 ◽

Vol 164 (1) ◽

pp. 247-258 ◽

Cited By ~ 1

Author(s):

Jinghong Li ◽

Willis X Li

Keyword(s):

Tyrosine Kinases ◽

Target Genes ◽

Tor Signaling ◽

Gain Of Function ◽

Essential Requirement ◽

Downstream Target ◽

Rtk Signaling ◽

Genome Wide ◽

A Genome ◽

Genomic Regions

Abstract Overactivation of receptor tyrosine kinases (RTKs) has been linked to tumorigenesis. To understand how a hyperactivated RTK functions differently from wild-type RTK, we conducted a genome-wide systematic survey for genes that are required for signaling by a gain-of-function mutant Drosophila RTK Torso (Tor). We screened chromosomal deficiencies for suppression of a gain-of-function mutation tor (torGOF), which led to the identification of 26 genomic regions that, when in half dosage, suppressed the defects caused by torGOF. Testing of candidate genes in these regions revealed many genes known to be involved in Tor signaling (such as those encoding the Ras-MAPK cassette, adaptor and structural molecules of RTK signaling, and downstream target genes of Tor), confirming the specificity of this genetic screen. Importantly, this screen also identified components of the TGFβ (Dpp) and JAK/STAT pathways as being required for TorGOF signaling. Specifically, we found that reducing the dosage of thickveins (tkv), Mothers against dpp (Mad), or STAT92E (aka marelle), respectively, suppressed torGOF phenotypes. Furthermore, we demonstrate that in torGOF embryos, dpp is ectopically expressed and thus may contribute to the patterning defects. These results demonstrate an essential requirement of noncanonical signaling pathways for a persistently activated RTK to cause pathological defects in an organism.

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Learning a genome-wide score of human–mouse conservation at the functional genomics level

Nature Communications ◽

10.1038/s41467-021-22653-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Soo Bin Kwon ◽

Jason Ernst

Keyword(s):

Mouse Model ◽

Functional Genomics ◽

Functional Genomic ◽

Transcriptomic Data ◽

Model Studies ◽

Genome Wide ◽

A Genome ◽

Important Challenge ◽

Genomic Regions ◽

Human And Mouse

AbstractIdentifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we develop a method to learn a score of evidence of conservation at the functional genomics level by integrating information from a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The method, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains neural networks to generate this score for the human and mouse genomes. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations. Analysis with independent datasets shows the score also highlights loci associated with similar phenotypes in both species. LECIF will be a resource for mouse model studies by identifying loci whose functional genomic properties are likely conserved.

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Genome-Wide Analyses Identifies Known and New Markers Responsible of Chicken Plumage Color

Animals ◽

10.3390/ani10030493 ◽

2020 ◽

Vol 10 (3) ◽

pp. 493

Author(s):

Salvatore Mastrangelo ◽

Filippo Cendron ◽

Gianluca Sottile ◽

Giovanni Niero ◽

Baldassare Portolano ◽

...

Keyword(s):

Genome Wide Association Study ◽

Snp Array ◽

Fixation Index ◽

Phenotypic Traits ◽

Plumage Color ◽

Phenotypic Marker ◽

Genome Wide ◽

A Genome ◽

The Difference ◽

Genomic Regions

Through the development of the high-throughput genotyping arrays, molecular markers and genes related to phenotypic traits have been identified in livestock species. In poultry, plumage color is an important qualitative trait that can be used as phenotypic marker for breed identification. In order to assess sources of genetic variation related to the Polverara chicken breed plumage colour (black vs. white), we carried out a genome-wide association study (GWAS) and a genome-wide fixation index (FST) scan to uncover the genomic regions involved. A total of 37 animals (17 white and 20 black) were genotyped with the Affymetrix 600 K Chicken single nucleotide polymorphism (SNP) Array. The combination of results from GWAS and FST revealed a total of 40 significant markers distributed on GGA 01, 03, 08, 12 and 21, and located within or near known genes. In addition to the well-known TYR, other candidate genes have been identified in this study, such as GRM5, RAB38 and NOTCH2. All these genes could explain the difference between the two Polverara breeds. Therefore, this study provides the basis for further investigation of the genetic mechanisms involved in plumage color in chicken.

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Emerging Technologies for Genome-Wide Profiling of DNA Breakage

Frontiers in Genetics ◽

10.3389/fgene.2020.610386 ◽

2021 ◽

Vol 11 ◽

Author(s):

Matthew J. Rybin ◽

Melina Ramic ◽

Natalie R. Ricciardi ◽

Philipp Kapranov ◽

Claes Wahlestedt ◽

...

Keyword(s):

Genome Instability ◽

Dna Double Strand Breaks ◽

Single Nucleotide ◽

Strand Breaks ◽

Single Strand Breaks ◽

Genome Wide ◽

A Genome ◽

Wide Scale ◽

Nucleotide Resolution ◽

Genomic Regions

Genome instability is associated with myriad human diseases and is a well-known feature of both cancer and neurodegenerative disease. Until recently, the ability to assess DNA damage—the principal driver of genome instability—was limited to relatively imprecise methods or restricted to studying predefined genomic regions. Recently, new techniques for detecting DNA double strand breaks (DSBs) and single strand breaks (SSBs) with next-generation sequencing on a genome-wide scale with single nucleotide resolution have emerged. With these new tools, efforts are underway to define the “breakome” in normal aging and disease. Here, we compare the relative strengths and weaknesses of these technologies and their potential application to studying neurodegenerative diseases.

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SNP and Haplotype Regional Heritability Mapping (SNHap-RHM): joint mapping of common and rare variation affecting complex traits

10.1101/2021.08.02.454788 ◽

2021 ◽

Author(s):

Richard F Oppong ◽

Pau Navarro ◽

Chris S Haley ◽

Sara Knott

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Complex Traits ◽

Health Study ◽

P Value ◽

Major Depressive ◽

Genome Wide ◽

A Genome ◽

Joint Mapping ◽

Genomic Regions

We describe a genome-wide analytical approach, SNP and Haplotype Regional Heritability Mapping (SNHap-RHM), that provides regional estimates of the heritability across locally defined regions in the genome. This approach utilises relationship matrices that are based on sharing of SNP and haplotype alleles at local haplotype blocks delimited by recombination boundaries in the genome. We implemented the approach on simulated data and show that the haplotype-based regional GRMs capture variation that is complementary to that captured by SNP-based regional GRMs, and thus justifying the fitting of the two GRMs jointly in a single analysis (SNHap-RHM). SNHap-RHM captures regions in the genome contributing to the phenotypic variation that existing genome-wide analysis methods may fail to capture. We further demonstrate that there are real benefits to be gained from this approach by applying it to real data from about 20,000 individuals from the Generation Scotland: Scottish Family Health Study. We analysed height and major depressive disorder (MDD). We identified seven genomic regions that are genome-wide significant for height, and three regions significant at a suggestive threshold (p-value <1x10^(-5) ) for MDD. These significant regions have genes mapped to within 400kb of them. The genes mapped for height have been reported to be associated with height in humans, whiles those mapped for MDD have been reported to be associated with major depressive disorder and other psychiatry phenotypes. The results show that SNHap-RHM presents an exciting new opportunity to analyse complex traits by allowing the joint mapping of novel genomic regions tagged by either SNPs or haplotypes, potentially leading to the recovery of some of the "missing" heritability.

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