Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming

Jeffries, Aaron R.; Uwanogho, Dafe; Cocks, Graham; Perfect, Leo; Dempster, Emma; Mill, Jonathan; Price, John

doi:10.1261/rna.058347.116

Cited by 10 publications

(7 citation statements)

References 52 publications

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“…That is, sample pairs generated from separate iPSC clones from the same subject were considered independent given our prior work showing allelic expression discordance in neural cultures derived from independent iPSC clones from the same donor 26 . This is consistent with the observation that many of the allelic effects on gene expression that occur in somatic cells are randomly reassigned in iPSCs after reprogramming and subsequent neural differentiation 35 .…”

Section: Methodssupporting

confidence: 90%

Alcohol-responsive genes identified in human iPSC-derived neural cultures

et al. 2019

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Alcohol use contributes to numerous diseases and injuries. The nervous system is affected by alcohol in diverse ways, though the molecular mechanisms of these effects are not clearly understood. Using human-induced pluripotent stem cells (iPSCs), we developed a neural cell culture model to identify the mechanisms of alcohol's effects. iPSCs were generated from fibroblasts and differentiated into forebrain neural cells cultures that were treated with 50 mM alcohol or sham conditions (same media lacking alcohol) for 7 days. We analyzed gene expression using total RNA sequencing (RNA-seq) for 34 samples derived from 10 subjects and for 10 samples from 5 subjects in an independent experiment that had intermittent exposure to the same dose of alcohol. We also analyzed genetic effects on gene expression and conducted a weighted correlation network analysis. We found that differentiated neural cell cultures have the capacity to recapitulate gene regulatory effects previously observed in specific primary neural tissues and identified 226 genes that were differentially expressed (FDR < 0.1) after alcohol treatment. The effects on expression included decreases in INSIG1 and LDLR, two genes involved in cholesterol homeostasis. We also identified a module of 58 co-expressed genes that were uniformly decreased following alcohol exposure. The majority of these effects were supported in independent alcohol exposure experiments. Enrichment analysis linked the alcohol responsive genes to cell cycle, notch signaling, and cholesterol biosynthesis pathways, which are disrupted in several neurological disorders. Our findings suggest that there is convergence between these disorders and the effects of alcohol exposure.

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Section: Methodssupporting

confidence: 90%

Alcohol-responsive genes identified in human iPSC-derived neural cultures

et al. 2019

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“…Given that polyploidy and aneuploidy are linked to cancer progression and evolution, and appear to predict worse outcomes (Coward and Harding, 2014;Krajcovic and Overholtzer, 2012), it is possible that cancer cells benefit from increases in ploidy by increasing cellular diversity through stochastic allelespecific epigenetic and gene expression effects. Previous studies found that progenitor versus differentiated cellular states are associated with dramatic differences in RME, suggesting these mechanisms have roles in defining different cellular proliferative versus differentiated states (Miyanari and Torres-Padilla, 2013;Eckersley-Maslin et al, 2014;Gendrel et al, 2014;Jeffries et al, 2016;Branciamore et al, 2018;Ng et al, 2018). Recent studies have also begun to show how stochastic allele-specific epigenetic effects can interact with allele-specific genetic variants to create allelic diversity (Onuchic et al, 2018;Zhang S. et al, 2020).…”

Section: Stochastic Gene Regulatory Effects At the Allele Level As A Potential Driver Of Tumor Cell Diversity And Adaptabilitymentioning

confidence: 99%

Starvation and Climate Change—How to Constrain Cancer Cell Epigenetic Diversity and Adaptability to Enhance Treatment Efficacy

Gregg

2021

Front. Ecol. Evol.

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Advanced metastatic cancer is currently not curable and the major barrier to eliminating the disease in patients is the resistance of subpopulations of tumor cells to drug treatments. These resistant subpopulations can arise stochastically among the billions of tumor cells in a patient or emerge over time during therapy due to adaptive mechanisms and the selective pressures of drug therapies. Epigenetic mechanisms play important roles in tumor cell diversity and adaptability, and are regulated by metabolic pathways. Here, I discuss knowledge from ecology, evolution, infectious disease, species extinction, metabolism and epigenetics to synthesize a roadmap to a clinically feasible approach to help homogenize tumor cells and, in combination with drug treatments, drive their extinction. Specifically, cycles of starvation and hyperthermia could help synchronize tumor cells and constrain epigenetic diversity and adaptability by limiting substrates and impairing the activity of chromatin modifying enzymes. Hyperthermia could also help prevent cancer cells from entering dangerous hibernation-like states. I propose steps to a treatment paradigm to help drive cancer extinction that builds on the successes of fasting, hyperthermia and immunotherapy and is achievable in patients. Finally, I highlight the many unknowns, opportunities for discovery and that stochastic gene and allele level epigenetic mechanisms pose a major barrier to cancer extinction that warrants deeper investigation.

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“…Stochastic allelic switching has been found to be required for antigenic variation in Trypanosoma brucei parasites 18 , 19 . The study of clonal cell lineages has furthermore demonstrated that aASE can be acquired through development and differentiation and can be propagated to the clonal progeny of the cells 7 , 8 , 20 . However, recent advances in single cell genomics suggest that aASE effects are more dynamic even within near isogenic clonal cell lines 4 , 21 – 23 .…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of allele-specific expression of genes in the model diatom Phaeodactylum tricornutum

Hoguin

Rastogi

Bowler

et al. 2021

Sci Rep

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Recent advances in next generation sequencing technologies have allowed the discovery of widespread autosomal allele-specific expression (aASE) in mammals and plants with potential phenotypic effects. Extensive numbers of genes with allele-specific expression have been described in the diatom Fragilariopsis cylindrus in association with adaptation to external cues, as well as in Fistulifera solaris in the context of natural hybridization. However, the role of aASE and its extent in diatoms remain elusive. In this study, we investigate allele-specific expression in the model diatom Phaeodactylum tricornutum by the re-analysis of previously published whole genome RNA sequencing data and polymorphism calling. We found that 22% of P. tricornutum genes show moderate bias in allelic expression while 1% show nearly complete monoallelic expression. Biallelic expression associates with genes encoding components of protein metabolism while moderately biased genes associate with functions in catabolism and protein transport. We validated candidate genes by pyrosequencing and found that moderate biases in allelic expression were less stable than monoallelically expressed genes that showed consistent bias upon experimental validations at the population level and in subcloning experiments. Our approach provides the basis for the analysis of aASE in P. tricornutum and could be routinely implemented to test for variations in allele expression under different environmental conditions.

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Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming

Cited by 10 publications

References 52 publications

Alcohol-responsive genes identified in human iPSC-derived neural cultures

Alcohol-responsive genes identified in human iPSC-derived neural cultures

Starvation and Climate Change—How to Constrain Cancer Cell Epigenetic Diversity and Adaptability to Enhance Treatment Efficacy

Genome-wide analysis of allele-specific expression of genes in the model diatom Phaeodactylum tricornutum

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