H3K4me3 is neither instructive for, nor informed by, transcription

AbstractH3K4me3 is a near-universal histone modification found predominantly at the 5’ region of genes, with a well-documented association with gene activity. H3K4me3 has been ascribed roles as both an instructor of gene expression and also a downstream consequence of expression, yet neither has been convincingly proven on a genome-wide scale. Here we test these relationships using a combination of bioinformatics, modelling and experimental data from budding yeast in which the levels of H3K4me3 have been massively ablated. We find that loss of H3K4me3 has no effect on the levels of nascent transcription or transcript in the population. Moreover, we observe no change in the rates of transcription initiation, elongation, mRNA export or turnover, or in protein levels, or cell-to-cell variation of mRNA. Loss of H3K4me3 also has no effect on the large changes in gene expression patterns that follow galactose induction. Conversely, loss of RNA polymerase from the nucleus has no effect on the pattern of H3K4me3 deposition and little effect on its levels, despite much larger changes to other chromatin features. Furthermore, large genome-wide changes in transcription, both in response to environmental stress and during metabolic cycling, are not accompanied by corresponding changes in H3K4me3. Thus, despite the correlation between H3K4me3 and gene activity, neither appear to be necessary to maintain levels of the other, nor to influence their changes in response to environmental stimuli. When we compare gene classes with very different levels of H3K4me3 but highly similar transcription levels we find that H3K4me3-marked genes are those whose expression is unresponsive to environmental changes, and that their histones are less acetylated and dynamically turned-over. Constitutive genes are generally well-expressed, which may alone explain the correlation between H3K4me3 and gene expression, while the biological role of H3K4me3 may have more to do with this distinction in gene class.

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ReFeaFi: Genome-wide prediction of regulatory elements driving transcription initiation

10.1101/2021.03.31.437992 ◽

2021 ◽

Author(s):

Ramzan Umarov ◽

Yu Li ◽

Takahiro Arakawa ◽

Satoshi Takizawa ◽

Xin Gao ◽

...

Keyword(s):

Gene Expression ◽

Transcription Initiation ◽

Expression Patterns ◽

Regulatory Elements ◽

Accurate Identification ◽

Regulatory Regions ◽

Genome Wide ◽

Wide Scale ◽

Genome Level ◽

Level Performance

Regulatory elements control gene expression through transcription initiation (promoters) and by enhancing transcription at distant regions (enhancers). Accurate identification of regulatory elements is fundamental for annotating genomes and understanding gene expression patterns. While there are many attempts to develop computational promoter and enhancer identification methods, reliable tools to analyze long genomic sequences are still lacking. Prediction methods often perform poorly on the genome-wide scale because the number of negatives is much higher than that in the training sets. To address this issue, we propose a dynamic negative set updating scheme with a two-model approach, using one model for scanning the genome and the other one for testing candidate positions. The developed method achieves good genome-level performance and maintains robust performance when applied to other species, without re-training. Moreover, the unannotated predicted regulatory regions made on the human genome are enriched for disease-associated variants, suggesting them to be potentially true regulatory elements rather than false positives. We validated high scoring "false positive" predictions using reporter assay and all tested candidates were successfully validated, demonstrating the ability of our method to discover novel human regulatory regions.

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ReFeaFi: Genome-wide prediction of regulatory elements driving transcription initiation

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009376 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009376

Author(s):

Ramzan Umarov ◽

Yu Li ◽

Takahiro Arakawa ◽

Satoshi Takizawa ◽

Xin Gao ◽

...

Keyword(s):

Gene Expression ◽

Transcription Initiation ◽

Expression Patterns ◽

Regulatory Elements ◽

Accurate Identification ◽

Regulatory Regions ◽

Genome Wide ◽

Wide Scale ◽

Genome Level ◽

Level Performance

Regulatory elements control gene expression through transcription initiation (promoters) and by enhancing transcription at distant regions (enhancers). Accurate identification of regulatory elements is fundamental for annotating genomes and understanding gene expression patterns. While there are many attempts to develop computational promoter and enhancer identification methods, reliable tools to analyze long genomic sequences are still lacking. Prediction methods often perform poorly on the genome-wide scale because the number of negatives is much higher than that in the training sets. To address this issue, we propose a dynamic negative set updating scheme with a two-model approach, using one model for scanning the genome and the other one for testing candidate positions. The developed method achieves good genome-level performance and maintains robust performance when applied to other vertebrate species, without re-training. Moreover, the unannotated predicted regulatory regions made on the human genome are enriched for disease-associated variants, suggesting them to be potentially true regulatory elements rather than false positives. We validated high scoring “false positive” predictions using reporter assay and all tested candidates were successfully validated, demonstrating the ability of our method to discover novel human regulatory regions.

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Study strategies for long non-coding RNAs and their roles in regulating gene expression

Cellular & Molecular Biology Letters ◽

10.1515/cmble-2015-0021 ◽

2015 ◽

Vol 20 (2) ◽

Cited By ~ 3

Author(s):

Dan Qin ◽

Cunshuan Xu

Keyword(s):

Gene Expression ◽

Regulatory Network ◽

Experimental Methods ◽

Study Strategies ◽

Mechanisms Of Action ◽

Cellular Processes ◽

Genome Wide ◽

A Genome ◽

Wide Scale ◽

Non Coding Rnas

AbstractLong non-coding RNAs (lncRNAs) have attracted considerable attention recently due to their involvement in numerous key cellular processes and in the development of various disorders. New high-throughput methods enable their study on a genome-wide scale. Numerous lncRNAs have been identified and characterized as important members of the biological regulatory network, with significant roles in regulating gene expression at the epigenetic, transcriptional and post-transcriptional levels. This paper summarizes the diverse mechanisms of action of these lncRNAs and looks at the study strategies in this field. A major challenge in future study is to establish more effective bioinformatics and experimental methods to explore the functions, detailed mechanisms of action and structures deciding the functional diversity of lncRNAs, since the vast majority remain unresolved.

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The Potential Role of Genetic Assimilation during Maize Domestication

10.1101/105940 ◽

2017 ◽

Cited By ~ 2

Author(s):

Anne Lorant ◽

Sarah Pedersen ◽

Irene Holst ◽

Matthew B. Hufford ◽

Klaus Winter ◽

...

Keyword(s):

Gene Expression ◽

Zea Mays ◽

Potential Role ◽

Expression Patterns ◽

Genetic Assimilation ◽

Genome Wide ◽

A Genome ◽

Genetic Mechanisms ◽

Maize Domestication

ABSTRACTDomestication research has largely focused on identification of morphological and genetic differences between extant populations of crops and their wild relatives. Little attention has been paid to the potential effects of environment despite substantial known changes in climate from the time of domestication to modern day. Recent research, in which maize and teosinte (i.e., wild maize) were exposed to environments similar to the time of domestication, resulted in a plastic induction of domesticated phenotypes in teosinte and little response to environment in maize. These results suggest that early agriculturalists may have selected for genetic mechanisms that cemented domestication phenotypes initially induced by a plastic response of teosinte to environment, a process known as genetic assimilation. To better understand this phenomenon and the potential role of environment in maize domestication, we examined differential gene expression in maize (Zea mays ssp. mays) and teosinte (Zea mays ssp. parviglumis) between past and present conditions. We identified a gene set of over 2000 loci showing a change in expression across environmental conditions in teosinte and invariance in maize. In fact, overall we observed both greater plasticity in gene expression and more substantial re-wiring of expression networks in teosinte across environments when compared to maize. While these results suggest genetic assimilation played at least some role in domestication, genes showing expression patterns consistent with assimilation are not significantly enriched for previously identified domestication candidates, indicating assimilation did not have a genome-wide effect.

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Genome-Wide Phylogenetic Analysis, Expression Pattern, and Transcriptional Regulatory Network of the Pig C/EBP Gene Family

Evolutionary Bioinformatics ◽

10.1177/11769343211041382 ◽

2021 ◽

Vol 17 ◽

pp. 117693432110413

Author(s):

Chaoxin Zhang ◽

Tao Wang ◽

Tongyan Cui ◽

Shengwei Liu ◽

Bing Zhang ◽

...

Keyword(s):

Gene Expression ◽

Phylogenetic Analysis ◽

Regulatory Network ◽

Target Genes ◽

Transcriptional Regulatory Network ◽

Expression Patterns ◽

Enrichment Analysis ◽

Functional Enrichment ◽

Genome Wide ◽

A Genome

The CCAAT/enhancer binding protein (C/EBP) transcription factors (TFs) regulate many important biological processes, such as energy metabolism, inflammation, cell proliferation etc. A genome-wide gene identification revealed the presence of a total of 99 C/EBP genes in pig and 19 eukaryote genomes. Phylogenetic analysis showed that all C/EBP TFs were classified into 6 subgroups named C/EBPα, C/EBPβ, C/EBPδ, C/EBPε, C/EBPγ, and C/EBPζ. Gene expression analysis showed that the C/EBPα, C/EBPβ, C/EBPδ, C/EBPγ, and C/EBPζ genes were expressed ubiquitously with inconsistent expression patterns in various pig tissues. Moreover, a pig C/EBP regulatory network was constructed, including C/EBP genes, TFs and miRNAs. A total of 27 feed-forward loop (FFL) motifs were detected in the pig C/EBP regulatory network. Based on the RNA-seq data, gene expression patterns related to FFL sub-network were analyzed in 27 adult pig tissues. Certain FFL motifs may be tissue specific. Functional enrichment analysis indicated that C/EBP and its target genes are involved in many important biological pathways. These results provide valuable information that clarifies the evolutionary relationships of the C/EBP family and contributes to the understanding of the biological function of C/EBP genes.

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A Functional Analysis of Variants Associated with Therapy-Induced Second Malignancies After Hodgkin Lymphoma Identified by a Genome-Wide Scan

Blood ◽

10.1182/blood.v116.21.3892.3892 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3892-3892

Author(s):

Timothy Best ◽

Andrew D Skol ◽

Eric Gamazon ◽

Kenan Onel

Keyword(s):

Gene Expression ◽

Hodgkin Lymphoma ◽

Cell Lines ◽

Risk Haplotype ◽

Regulate Gene Expression ◽

Protein Levels ◽

Genome Wide ◽

A Genome ◽

Protective Haplotype ◽

Regulate Gene

Abstract Abstract 3892 Survivors of Hodgkin lymphoma (HL) are susceptible to radiation-induced second malignant neoplasms (SMNs). In a genome-wide association study (GWAS) of patients treated for HL who did or did not develop SMNs, we identified and validated two SMN-associated single nucleotide polymorphisms (SNPs) at 6q21, intergenic between PRDM1 and ATG5 [rs4946728: P = 1.04×10-9, OR = 3.21 (95% CI = 2.37–6.42), and rs1040411: P = 4.24×10-8, OR = 2.43 (95% CI = 1.76–3.34)]. Recently, it was demonstrated that disease-associated SNPs are more likely to be expression quantitative trait loci (eQTLs), SNPs that regulate gene expression, than are randomly chosen SNPs matched for their population allele frequencies. Indeed, we found that the 1000 SNPs most associated with SMNs are significantly enriched for eQTLs (P = 0.01). Exploring the processes regulated by SMN-associated SNPs can inform the mechanism by which SMNs result in patients treated with radiation therapy. As an initial investigation of the effect of these SNPs on gene expression, we studied the effect of the validated 6q21 haplotype (comprised of rs4946728 and rs1040411) on global gene expression in HapMap lymphoblastoid cell lines (LCLs). Gene set enrichment analysis of genes differentially expressed (log2>0.05) between cell lines carrying either the risk or protective haplotype revealed that carriage of the risk-associated haplotype was associated with increased expression of transmembrane proteins (enrichment P = 2.1×10-13) and immune response proteins (enrichment P = 1.2×10-6). Because the 6q21 haplotype is in close physical proximity to ATG5 and PRDM1, we investigated its functional consequence on expression of these genes. We discovered the risk-associated haplotype was significantly associated with lower levels of PRDM1 mRNA (P = 0.04) but not ATG5 mRNA. As exposure to radiation is the primary etiologic factor for SMNs, we assessed the effect of the risk haplotype on protein levels of PRDM1 and ATG5 in six LCLs (three with the risk haplotype and three with the protective haplotype) following 10Gy of gamma irradiation (IR). PRDM1 protein levels were significantly lower in LCLs carrying the risk-associated haplotype in the absence of IR. In all lines, PRDM1 levels increased following radiation exposure, but this effect was significantly attenuated in presence of the risk haplotype. In sum, these data suggest that SNPs associated with SMNs following HL are enriched for SNPs that regulate gene expression. We demonstrate that the validated risk alleles at 6q21 are associated with differences in PRDM1 mRNA and protein levels and response to radiation. These observations suggest a model in which PRDM1 may be a key regulator of the radiation-response that protects against the emergence of SMNs. Disclosures: No relevant conflicts of interest to declare.

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A genome-wide transcriptional analysis of morphology determination inCandida albicans

Molecular Biology of the Cell ◽

10.1091/mbc.e12-01-0065 ◽

2013 ◽

Vol 24 (3) ◽

pp. 246-260 ◽

Cited By ~ 31

Author(s):

Patricia L. Carlisle ◽

David Kadosh

Keyword(s):

Gene Expression ◽

Fungal Infections ◽

Transcriptional Profiling ◽

Expression Patterns ◽

Global Gene Expression ◽

Transcriptional Analysis ◽

Specific Gene ◽

Genome Wide ◽

A Genome ◽

Genetically Manipulated

Candida albicans, the most common cause of human fungal infections, undergoes a reversible morphological transition from yeast to pseudohyphal and hyphal filaments, which is required for virulence. For many years, the relationship among global gene expression patterns associated with determination of specific C. albicans morphologies has remained obscure. Using a strain that can be genetically manipulated to sequentially transition from yeast to pseudohyphae to hyphae in the absence of complex environmental cues and upstream signaling pathways, we demonstrate by whole-genome transcriptional profiling that genes associated with pseudohyphae represent a subset of those associated with hyphae and are generally expressed at lower levels. Our results also strongly suggest that in addition to dosage, extended duration of filament-specific gene expression is sufficient to drive the C. albicans yeast-pseudohyphal-hyphal transition. Finally, we describe the first transcriptional profile of the C. albicans reverse hyphal-pseudohyphal-yeast transition and demonstrate that this transition involves not only down-regulation of known hyphal-specific, genes but also differential expression of additional genes that have not previously been associated with the forward transition, including many involved in protein synthesis. These findings provide new insight into genome-wide expression patterns important for determining fungal morphology and suggest that in addition to similarities, there are also fundamental differences in global gene expression as pathogenic filamentous fungi undergo forward and reverse morphological transitions.

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Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903549116 ◽

2019 ◽

Vol 116 (30) ◽

pp. 14995-15000 ◽

Cited By ~ 13

Author(s):

Justyna Cholewa-Waclaw ◽

Ruth Shah ◽

Shaun Webb ◽

Kashyap Chhatbar ◽

Bernard Ramsahoye ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Rett Syndrome ◽

Transcription Initiation ◽

Expression Patterns ◽

Global Gene Expression ◽

A Genome ◽

The Impact

Patterns of gene expression are primarily determined by proteins that locally enhance or repress transcription. While many transcription factors target a restricted number of genes, others appear to modulate transcription levels globally. An example is MeCP2, an abundant methylated-DNA binding protein that is mutated in the neurological disorder Rett syndrome. Despite much research, the molecular mechanism by which MeCP2 regulates gene expression is not fully resolved. Here, we integrate quantitative, multidimensional experimental analysis and mathematical modeling to indicate that MeCP2 is a global transcriptional regulator whose binding to DNA creates “slow sites” in gene bodies. We hypothesize that waves of slowed-down RNA polymerase II formed behind these sites travel backward and indirectly affect initiation, reminiscent of defect-induced shockwaves in nonequilibrium physics transport models. This mechanism differs from conventional gene-regulation mechanisms, which often involve direct modulation of transcription initiation. Our findings point to a genome-wide function of DNA methylation that may account for the reversibility of Rett syndrome in mice. Moreover, our combined theoretical and experimental approach provides a general method for understanding how global gene-expression patterns are choreographed.

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Genome organization is a major component of gene expression control in response to stress and during the cell division cycle in trypanosomes

Open Biology ◽

10.1098/rsob.120033 ◽

2012 ◽

Vol 2 (4) ◽

pp. 120033 ◽

Cited By ~ 35

Author(s):

S. Kelly ◽

S. Kramer ◽

A. Schwede ◽

P. K. Maini ◽

K. Gull ◽

...

Keyword(s):

Gene Expression ◽

Cell Division ◽

Rna Polymerase Ii ◽

Transcription Initiation ◽

Expression Patterns ◽

Cell Division Cycle ◽

Control Of Gene Expression ◽

Polycistronic Transcription ◽

A Genome ◽

Gene Expression Control

The trypanosome genome is characterized by RNA polymerase II-driven polycistronic transcription of protein-coding genes. Ten to hundreds of genes are co-transcribed from a single promoter; thus, selective regulation of individual genes via initiation is impossible. However, selective responses to external stimuli occur and post-transcriptional mechanisms are thought to account for all temporal gene expression patterns. We show that genes encoding mRNAs that are differentially regulated during the heat-shock response are selectively positioned in polycistronic transcription units; downregulated genes are close to transcription initiation sites and upregulated genes are distant. We demonstrate that the position of a reporter gene within a transcription unit is sufficient to reproduce this effect. Analysis of gene ontology annotations reveals that positional bias is not restricted to stress–response genes and that there is a genome-wide organization based on proximity to transcription initiation sites. Furthermore, we show that the relative abundance of mRNAs at different time points in the cell division cycle is dependent on the location of the corresponding genes to transcription initiation sites. This work provides evidence that the genome in trypanosomes is organized to facilitate co-coordinated temporal control of gene expression in the absence of selective promoters.

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Genome-wide transcriptional profiling uncovers a similar oligodendrocyte-related transcriptional response to acute and chronic alcohol drinking in the amygdala

10.1101/2021.09.07.459347 ◽

2021 ◽

Author(s):

Sharvari Narendra ◽

Claudia Klengel ◽

Bilal Hamzeh ◽

Drasti Patel ◽

Joy Otten ◽

...

Keyword(s):

Gene Expression ◽

Alcohol Drinking ◽

Brain Area ◽

Transcriptional Profiling ◽

Expression Patterns ◽

Transcriptional Response ◽

Histone Deacetylation ◽

Regulatory Pathways ◽

Genome Wide ◽

A Genome

AbstractAlcohol intake progressively increases after prolonged consumption of alcohol, but relatively few new therapeutics targeting development of alcohol use disorder (AUD) have been validated. Here, we conducted a genome-wide RNA-sequencing (RNA-seq) analysis in mice exposed to different modes (acute vs chronic) of ethanol drinking. We focused on transcriptional profiles in the amygdala including the central and basolateral subnuclei, a brain area previously implicated in alcohol drinking and seeking, demonstrating distinct gene expression patterns and canonical pathways induced by both acute and chronic intake. Surprisingly, both drinking modes triggered similar transcriptional changes, including up-regulation of ribosome-related/translational pathways and myelination pathways, and down-regulation of chromatin binding and histone modification. Notably, multiple genes that were significantly regulated in mouse amygdala with alcohol drinking, including Atp2b1, Slc4a7, Nfkb1, Nts, and Hdac2, among others had previously been associated with human AUD via GWAS or other genomic studies. In addition, analyses of hub genes and upstream regulatory pathways predicted that voluntary ethanol consumption affects epigenetic changes via histone deacetylation pathways, oligodendrocyte and myelin function, and oligodendrocyte-related transcriptional factor, Sox17.Overall, our results suggest that the transcriptional landscape in the central and basolateral subnuclei of the amygdala is sensitive to voluntary alcohol drinking. They provide a unique resource of gene expression data for future translational studies examining transcriptional mechanisms underlying the development of AUD due to alcohol consumption.

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