Dataset Information

Introns control stochastic allele expression bias.

ABSTRACT: Monoallelic expression (MAE) or extreme allele bias can account for incomplete penetrance, missing heritability and non-Mendelian diseases. In cancer, MAE is associated with shorter patient survival times and higher tumor grade. Prior studies showed that stochastic MAE is caused by stochastic epigenetic silencing, in a gene and tissue-specific manner. Here, we used C. elegans to study stochastic MAE in vivo. We found allele bias/MAE to be widespread within C. elegans tissues, presenting as a continuum from fully biallelic to MAE. We discovered that the presence of introns within alleles robustly decreases MAE. We determined that introns control MAE at distinct loci, in distinct cell types, with distinct promoters, and within distinct coding sequences, using a 5'-intron position-dependent mechanism. Bioinformatic analysis showed human intronless genes are significantly enriched for MAE. Our experimental evidence demonstrates a role for introns in regulating MAE, possibly explaining why some mutations within introns result in disease.

SUBMITTER: Sands B

PROVIDER: S-EPMC8585970 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Introns control stochastic allele expression bias.

Sands Bryan B Yun Soo S Mendenhall Alexander R AR

Nature communications 20211111 1

Monoallelic expression (MAE) or extreme allele bias can account for incomplete penetrance, missing heritability and non-Mendelian diseases. In cancer, MAE is associated with shorter patient survival times and higher tumor grade. Prior studies showed that stochastic MAE is caused by stochastic epigenetic silencing, in a gene and tissue-specific manner. Here, we used C. elegans to study stochastic MAE in vivo. We found allele bias/MAE to be widespread within C. elegans tissues, presenting as a con ...[more]

PMID: 34764277

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Project description:Pervasive allelic variation at both gene and single nucleotide level (SNV) between individuals is commonly associated with complex traits in humans and animals. Allele-specific expression (ASE) analysis, using RNA-Seq, can provide a detailed annotation of allelic imbalance and infer the existence of cis-acting transcriptional regulation. However, variant detection in RNA-Seq data is compromised by biased mapping of reads to the reference DNA sequence. In this manuscript, we describe an unbiased standardized computational pipeline for allele-specific expression analysis using RNA-Seq data, which we have adapted and developed using tools available under open license. The analysis pipeline we present is designed to minimize reference bias while providing accurate profiling of allele-specific expression across tissues and cell types. Using this methodology, we were able to profile pervasive allelic imbalance across tissues and cell types, at both the gene and SNV level, in Texel×Scottish Blackface sheep, using the sheep gene expression atlas data set. ASE profiles were pervasive in each sheep and across all tissue types investigated. However, ASE profiles shared across tissues were limited, and instead, they tended to be highly tissue-specific. These tissue-specific ASE profiles may underlie the expression of economically important traits and could be utilized as weighted SNVs, for example, to improve the accuracy of genomic selection in breeding programs for sheep. An additional benefit of the pipeline is that it does not require parental genotypes and can therefore be applied to other RNA-Seq data sets for livestock, including those available on the Functional Annotation of Animal Genomes (FAANG) data portal. This study is the first global characterization of moderate to extreme ASE in tissues and cell types from sheep. We have applied a robust methodology for ASE profiling to provide both a novel analysis of the multi-dimensional sheep gene expression atlas data set and a foundation for identifying the regulatory and expressed elements of the genome that are driving complex traits in livestock.

Project description:The HIV promoter within the viral long terminal repeat (LTR) orchestrates many aspects of the viral life cycle, from the dynamics of viral gene expression and replication to the establishment of a latent state. In particular, after viral integration into the host genome, stochastic fluctuations in viral gene expression amplified by the Tat positive feedback loop can contribute to the formation of either a productive, transactivated state or an inactive state. In a significant fraction of cells harboring an integrated copy of the HIV-1 model provirus (LTR-GFP-IRES-Tat), this bimodal gene expression profile is dynamic, as cells spontaneously and continuously flip between active (Bright) and inactive (Off) expression modes. Furthermore, these switching dynamics may contribute to the establishment and maintenance of proviral latency, because after viral integration long delays in gene expression can occur before viral transactivation. The HIV-1 promoter contains cis-acting Sp1 and NF-kappaB elements that regulate gene expression via the recruitment of both activating and repressing complexes. We hypothesized that interplay in the recruitment of such positive and negative factors could modulate the stability of the Bright and Off modes and thereby alter the sensitivity of viral gene expression to stochastic fluctuations in the Tat feedback loop. Using model lentivirus variants with mutations introduced in the Sp1 and NF-kappaB elements, we employed flow cytometry, mRNA quantification, pharmacological perturbations, and chromatin immunoprecipitation to reveal significant functional differences in contributions of each site to viral gene regulation. Specifically, the Sp1 sites apparently stabilize both the Bright and the Off states, such that their mutation promotes noisy gene expression and reduction in the regulation of histone acetylation and deacetylation. Furthermore, the NF-kappaB sites exhibit distinct properties, with kappaB site I serving a stronger activating role than kappaB site II. Moreover, Sp1 site III plays a particularly important role in the recruitment of both p300 and RelA to the promoter. Finally, analysis of 362 clonal cell populations infected with the viral variants revealed that mutations in any of the Sp1 sites yield a 6-fold higher frequency of clonal bifurcation compared to that of the wild-type promoter. Thus, each Sp1 and NF-kappaB site differentially contributes to the regulation of viral gene expression, and Sp1 sites functionally "dampen" transcriptional noise and thereby modulate the frequency and maintenance of this model of viral latency. These results may have biomedical implications for the treatment of HIV latency.

Project description:BackgroundArbuscular mycorrhizal (AM) fungi are arguably the most important symbionts of plants, offering a range of benefits to their hosts. However, the provisioning of these benefits does not appear to be uniform among AM fungal individuals, with genetic variation between fungal symbionts having a substantial impact on plant performance. Interestingly, genetic variation has also been reported within fungal individuals, which contain millions of haploid nuclei sharing a common cytoplasm. In the model AM fungus, Rhizophagus irregularis, several isolates have been reported to be dikaryotes, containing two genetically distinct types of nuclei recognized based on their mating-type (MAT) locus identity. However, their extremely coenocytic nature and lack of a known single nucleus stage has raised questions on the origin, distribution and dynamics of this genetic variation.ResultsHere we performed DNA and RNA sequencing at the mycelial individual, single spore and single nucleus levels to gain insight into the dynamic genetic make-up of the dikaryote-like R. irregularis C3 isolate and the effect of different host plants on its genetic variation. Our analyses reveal that parallel spore and root culture batches can have widely variable ratios of two main genotypes in C3. Additionally, numerous polymorphisms were found with frequencies that deviated significantly from the general genotype ratio, indicating a diverse population of slightly different nucleotypes. Changing host plants did not show consistent host effects on nucleotype ratio's after multiple rounds of subculturing. Instead, we found a major effect of host plant-identity on allele-specific expression in C3.ConclusionOur analyses indicate a highly dynamic/variable genetic organization in different isolates of R. irregularis. Seemingly random fluctuations in nucleotype ratio's upon spore formation, recombination events, high variability of non-tandemly repeated rDNA sequences and host-dependent allele expression all add levels of variation that may contribute to the evolutionary success of these widespread symbionts.

Dataset Information

Introns control stochastic allele expression bias.

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Introns control stochastic allele expression bias.

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