scholarly journals Transcriptional bursting shape autosomal dynamic random monoallelic expression in pre-gastrulation embryos

2020 ◽  
Author(s):  
C H Naik ◽  
D Chandel ◽  
S Mandal ◽  
S Gayen
Keyword(s):  
Monoallelic Expression ◽  
Wide Spread ◽  
Mammalian Development ◽  
Burst Frequency ◽  
Genome Wide ◽  
Allele Specific ◽  
Transcriptional Bursting ◽  
Burst Kinetics ◽  
Cell Expression ◽  
Early Mammalian Development

AbstractRecent years, allele-specific single cell RNA-seq (scRNA-seq) analysis have demonstrated wide-spread dynamic random monoallelic expression of autosomal genes (aRME). However, the origin of dynamic aRME remains poorly understood. It is believed that dynamic aRME is originated from discrete transcriptional burst of two alleles. Here, for the first time, we have profiled genome-wide pattern of dynamic aRME and allele-specific burst kinetics in mouse pre-gastrulation embryos. We found wide-spread dynamic aRME across the different lineages of pre-gastrulation embryos and which is linked to the allelic burst kinetics. Specially, we found that expression level and burst frequency are the key determinants of dynamic aRME. Altogether, our study provides significant insight about the origin of prevalent dynamic aRME and cell to cell expression heterogeneity during the early mammalian development.

scholarly journals Transcriptional bursts explain autosomal random monoallelic expression and affect allelic imbalance

2019 ◽  
Author(s):  
Anton J.M. Larsson ◽  
Björn Reinius ◽  
Tina Jacob ◽  
Tim Dalessandri ◽  
Gert-Jan Hendriks ◽  
...  
Keyword(s):  
Allelic Imbalance ◽  
Expression Patterns ◽  
Monoallelic Expression ◽  
Biological Noise ◽  
Burst Frequency ◽  
Large Numbers ◽  
Single Cell Rna Sequencing ◽  
Transcriptional Bursting ◽  
Burst Kinetics ◽  
Shed Light

AbstractTranscriptional bursts render substantial biological noise in cellular transcriptomes. Here, we investigated the theoretical extent of monoallelic expression resulting from transcriptional bursting and how it compared to the amounts of monoallelic expression of autosomal genes observed in single-cell RNA-sequencing (scRNA-seq) data. We found that transcriptional bursting can explain frequent observations of autosomal monoallelic gene expression in cells. Importantly, the burst frequency largely determined the fraction of cells with monoallelic expression, whereas both burst frequency and size contributed to allelic imbalance. Allelic observations deviate from the expected when analysed across heterogeneous groups of cells, suggesting that allelic modelling can provide an unbiased assessment of heterogeneity within cells. Finally, large numbers of cells are required for analyses of allelic imbalance to avoid confounding observations from transcriptional bursting. Altogether, our results shed light on the implications of transcriptional burst kinetics on allelic expression patterns and phenotypic variation between cells.

scholarly journals Transcriptional bursting explains the noise-versus-mean relationship in mRNA and protein levels

2016 ◽  
Author(s):  
Roy D. Dar ◽  
Sydney M. Schaffer ◽  
Siddarth S. Dey ◽  
Jonathan E. Foley ◽  
Abhyudai Singh ◽  
...  
Keyword(s):  
Conflict Of Interest ◽  
Burst Size ◽  
Inverse Correlation ◽  
Recent Analysis ◽  
Mrna Levels ◽  
Burst Frequency ◽  
Expression Variability ◽  
Protein Levels ◽  
Transcriptional Bursting ◽  
Cell Expression

Recent analysis (Dey et al, 2015), demonstrates that the HIV-1 Long Terminal Repeat (HIV LTR) promoter exhibits a range of possible transcriptional burst sizes and frequencies for any mean-expression level. However, these results have also been interpreted as demonstrating that cell-to-cell expression variability (noise) and mean are uncorrelated, a significant deviation from previous results. Here, we re-examine the available mRNA and protein abundance data for the HIV LTR and find that noise in mRNA and protein expression scales inversely with the mean along analytically predicted transcriptional burst-size manifolds. We then experimentally perturb transcriptional activity to test a prediction of the multiple burst-size model: that increasing burst frequency will cause mRNA noise to decrease along given burst-size lines as mRNA levels increase. The data show that mRNA and protein noise decrease as mean expression increases, supporting the canonical inverse correlation between noise and mean.Conflict of InterestThe authors declare that they have no conflict of interest.

scholarly journals Genome-Wide Analysis of Allele-Specific Expression Patterns in Seventeen Tissues of Korean Cattle (Hanwoo)

Animals ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 727
Author(s):  
Kyu-Sang Lim ◽  
Sun-Sik Chang ◽  
Bong-Hwan Choi ◽  
Seung-Hwan Lee ◽  
Kyung-Tai Lee ◽  
...  
Keyword(s):  
Phenotypic Variation ◽  
Expression Patterns ◽  
Monoallelic Expression ◽  
Specific Expression ◽  
Adult Cattle ◽  
Korean Cattle ◽  
Family Trio ◽  
Epigenetic Effects ◽  
Genome Wide ◽  
Allele Specific

The functional hemizygosity could be caused by the MAE of a given gene and it can be one of the sources to affect the phenotypic variation in cattle. We aimed to identify MAE genes across the transcriptome in Korean cattle (Hanwoo). For three Hanwoo family trios, the transcriptome data of 17 tissues were generated in three offspring. Sixty-two MAE genes had a monoallelic expression in at least one tissue. Comparing genotypes among each family trio, the preferred alleles of 18 genes were identified (maternal expression, n = 9; paternal expression, n = 9). The MAE genes are involved in gene regulation, metabolic processes, and immune responses, and in particular, six genes encode transcription factors (FOXD2, FOXM1, HTATSF1, SCRT1, NKX6-2, and UBN1) with tissue-specific expression. In this study, we report genome-wide MAE genes in seventeen tissues of adult cattle. These results could help to elucidate epigenetic effects on phenotypic variation in Hanwoo.

scholarly journals Dppa2/4 Counteract De Novo Methylation to Establish a Permissive Epigenome for Development

2020 ◽  
Author(s):  
Kristjan H. Gretarsson ◽  
Jamie A. Hackett
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Developmental Competence ◽  
Epigenetic Memory ◽  
Mammalian Development ◽  
Dna Hypomethylation ◽  
Lineage Specification ◽  
Regulatory Pathways ◽  
Genome Wide ◽  
Early Mammalian Development

ABSTRACTEarly mammalian development entails genome-wide epigenome remodeling, including DNA methylation erasure and reacquisition, which facilitates developmental competence. To uncover the mechanisms that orchestrate DNA methylation (DNAme) dynamics, we coupled a single-cell ratiometric DNAme reporter with unbiased CRISPR screening in ESC. We identify key genes and regulatory pathways that drive global DNA hypomethylation, and characterise roles for Cop1 and Dusp6. We also identify Dppa2 and Dppa4 as essential safeguards of focal epigenetic states. In their absence, developmental genes and evolutionary-young LINE1 elements, which DPPA2 specifically binds, lose H3K4me3 and gain ectopic de novo DNA methylation in pluripotent cells. Consequently, lineage-associated genes (and LINE1) acquire a repressive epigenetic memory, which renders them incompetent for activation during future lineage-specification. Dppa2/4 thereby sculpt the pluripotent epigenome by facilitating H3K4me3 and bivalency to counteract de novo methylation; a function co-opted by evolutionary young LINE1 to evade epigenetic decommissioning.

scholarly journals Genome-wide decoupling of H2Aub and H3K27me3 in early mouse development

2021 ◽  
Author(s):  
Yezhang Zhu ◽  
Jiali Yu ◽  
Yan Rong ◽  
Yun-Wen Wu ◽  
Heng-Yu Fan ◽  
...  
Keyword(s):  
Polycomb Group ◽  
Mammalian Development ◽  
Mouse Development ◽  
Chromatin Regulators ◽  
Genome Wide ◽  
A Genome ◽  
Independent Functions ◽  
Preimplantation Mouse ◽  
Early Mouse ◽  
Early Mammalian Development

Polycomb group (PcG) proteins are crucial chromatin regulators during development. H2Aub and H3K27me3 are catalyzed by Polycomb-repressive Complex 1 and 2 (PRC1/2) respectively, and largely overlap in the genome due to mutual recruitment of the two complexes. However, whether PRC1/H2Aub and PRC2/H3K27me3 can function independently remains obscure. Here we uncovered a genome-wide decoupling of H2Aub and H3K27me3 in preimplantation mouse embryos, at both canonical PcG targets and broad distal domains. H2Aub represses future bivalent genes without H3K27me3 but does not contribute to maintenance of H3K27me3-dependent non-canonical imprinting. Our study thus revealed their distinct and independent functions in early mammalian development.

scholarly journals Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive demethylation in mammals

2018 ◽  
Author(s):  
Christopher B. Mulholland ◽  
Atsuya Nishiyama ◽  
Joel Ryan ◽  
Ryohei Nakamura ◽  
Merve Yiğit ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Ectopic Expression ◽  
Dna Demethylation ◽  
Mammalian Development ◽  
Dna Hypomethylation ◽  
Tet Proteins ◽  
Genome Wide ◽  
Recent Emergence ◽  
High Conservation ◽  
Early Mammalian Development

AbstractGenome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline marker Dppa3 (Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression of Dppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have a Dppa3 gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.

scholarly journals Transcriptional bursts explain autosomal random monoallelic expression and affect allelic imbalance

2021 ◽  
Vol 17 (3) ◽  
pp. e1008772
Author(s):  
Anton J. M. Larsson ◽  
Christoph Ziegenhain ◽  
Michael Hagemann-Jensen ◽  
Björn Reinius ◽  
Tina Jacob ◽  
...  
Keyword(s):  
Allelic Imbalance ◽  
Burst Size ◽  
Single Cells ◽  
Expression Patterns ◽  
Allelic Expression ◽  
Monoallelic Expression ◽  
Burst Frequency ◽  
Biallelic Expression ◽  
High Consistency ◽  
Transcriptional Bursting

Transcriptional bursts render substantial biological noise in cellular transcriptomes. Here, we investigated the theoretical extent of allelic expression resulting from transcriptional bursting and how it compared to the amount biallelic, monoallelic and allele-biased expression observed in single-cell RNA-sequencing (scRNA-seq) data. We found that transcriptional bursting can explain the allelic expression patterns observed in single cells, including the frequent observations of autosomal monoallelic gene expression. Importantly, we identified that the burst frequency largely determined the fraction of cells with monoallelic expression, whereas the burst size had little effect on monoallelic observations. The high consistency between the bursting model predictions and scRNA-seq observations made it possible to assess the heterogeneity of a group of cells as their deviation in allelic observations from the expected. Finally, both burst frequency and size contributed to allelic imbalance observations and reinforced that studies of allelic imbalance can be confounded from the inherent noise in transcriptional bursting. Altogether, we demonstrate that allele-level transcriptional bursting renders widespread, although predictable, amounts of monoallelic and biallelic expression in single cells and cell populations.

scholarly journals Modeling allele-specific gene expression by single-cell RNA sequencing

2017 ◽  
Author(s):  
Yuchao Jiang ◽  
Nancy R Zhang ◽  
Mingyao Li
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Rna Sequencing ◽  
Specific Gene ◽  
Burst Frequency ◽  
Specific Expression ◽  
Genome Wide ◽  
Single Cell Rna Sequencing ◽  
Allelic Differences ◽  
Allele Specific

AbstractAllele-specific expression is traditionally studied by bulk RNA sequencing, which measures average expression across cells. Single-cell RNA sequencing (scRNA-seq) allows the comparison of expression distribution between the two alleles of a diploid organism and thus the characterization of allele-specific bursting. We propose SCALE to analyze genome-wide allele-specific bursting, with adjustment of technical variability. SCALE detects genes exhibiting allelic differences in bursting parameters, and genes whose alleles burst non-independently. We apply SCALE to mouse blastocyst and human fibroblast cells and find that, globally, cis control in gene expression overwhelmingly manifests as differences in burst frequency.

scholarly journals 3 ′-5 ′ crosstalk contributes to transcriptional bursting

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Massimo Cavallaro ◽  
Mark D. Walsh ◽  
Matt Jones ◽  
James Teahan ◽  
Simone Tiberi ◽  
...  
Keyword(s):  
Stochastic Process ◽  
Mammalian Cells ◽  
Burst Size ◽  
Noise Analysis ◽  
Cell Populations ◽  
Burst Frequency ◽  
Transcriptional Noise ◽  
Mrna Species ◽  
Genome Wide ◽  
Transcriptional Bursting

Abstract Background Transcription in mammalian cells is a complex stochastic process involving shuttling of polymerase between genes and phase-separated liquid condensates. It occurs in bursts, which results in vastly different numbers of an mRNA species in isogenic cell populations. Several factors contributing to transcriptional bursting have been identified, usually classified as intrinsic, in other words local to single genes, or extrinsic, relating to the macroscopic state of the cell. However, some possible contributors have not been explored yet. Here, we focus on processes at the 3 ′ and 5 ′ ends of a gene that enable reinitiation of transcription upon termination. Results Using Bayesian methodology, we measure the transcriptional bursting in inducible transgenes, showing that perturbation of polymerase shuttling typically reduces burst size, increases burst frequency, and thus limits transcriptional noise. Analysis based on paired-end tag sequencing (PolII ChIA-PET) suggests that this effect is genome wide. The observed noise patterns are also reproduced by a generative model that captures major characteristics of the polymerase flux between the ends of a gene and a phase-separated compartment. Conclusions Interactions between the 3 ′ and 5 ′ ends of a gene, which facilitate polymerase recycling, are major contributors to transcriptional noise.

scholarly journals 3’-5’ crosstalk contributes to transcriptional bursting

2019 ◽  
Author(s):  
Massimo Cavallaro ◽  
Mark D. Walsh ◽  
Matt Jones ◽  
James Teahan ◽  
Simone Tiberi ◽  
...  
Keyword(s):  
Stochastic Process ◽  
Mammalian Cells ◽  
Burst Size ◽  
Noise Analysis ◽  
Cell Populations ◽  
Burst Frequency ◽  
Transcriptional Noise ◽  
Mrna Species ◽  
Genome Wide ◽  
Transcriptional Bursting

AbstractBackgroundTranscription in mammalian cells is a complex stochastic process involving shuttling of polymerase between genes and phase-separated liquid condensates. It occurs in bursts, which results in vastly different numbers of an mRNA species in isogenic cell populations. Several factors contributing to transcriptional bursting have been identified, usually classified as intrinsic, in other words local to single genes, or extrinsic, relating to the macroscopic state of the cell. However, some possible contributors have not been explored yet. Here, we focus on processes at the 3’ and 5’ ends of a gene that enable reinitiation of transcription upon termination.ResultsUsing Bayesian methodology, we measure the transcriptional bursting in inducible transgenes, showing that perturbation of polymerase shuttling typically reduces burst size, increases burst frequency, and thus limits transcriptional noise. Analysis based on paired-end tag sequencing (PolII ChIA-PET) suggests that this effect is genome wide. The observed noise patterns are also reproduced by a generative model that captures major characteristics of the polymerase flux between the ends of a gene and a phase-separated compartment.ConclusionsInteractions between the 3’ and 5’ ends of a gene, which facilitate polymerase recycling, are major contributors to transcriptional noise.

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