Genetic and Epigenetic Regulation of Pvt1 Monoallelic Expression [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE287456 | GEO | 2025/09/26
REPOSITORIES: GEO
Similar Datasets
Project description:Each gene exists as two copies in the same nucleus of mammalian cells. Although most genes are equivalently controlled on both alleles, Random Monoallelic Expressing (RME) genes stably maintain the expression from only one of two alleles, but the mechanisms and functional consequences of RME remains unclear. Here we performed allele-specific RNA-seq on over 100 neural progenitor cell (NPC) clonal lines to reveal the extent of RME for genes across clonal lines. Interestingly out of 297 autosomal RME genes, Pvt1, a well-studied oncogenic long non-coding RNA, is monoallelically expressed with a skewed genetic bias towards the Castaneous allele in F1-hybrid NPCs. In the absence of genetic differences, allelic tracking by gene editing reveals Pvt1 undergoes balanced RME that is maintained across somatic cell generations. Monoallelic expression is maintained by a poised Pvt1 promoter with bivalent active histone marks, H3K4me3 and H3K27ac, and silencing histone marks, H3K4me3 and H3K27me3, demonstrating its ability to switch transcriptional states depending on the cellular context. Leveraging our large RNA-seq data set and the genetic skew, we use differential gene expression analysis on clonal lines based on their Pvt1 allelic status to reveal a transcription factor, Tfap2a, with differential binding at the Pvt1 promoter, providing a mechanism for the initiation and allelic choice for RME genes. Additionally, we demonstrate monoallelic Pvt1 expression results in an increase in Pvt1 expression leading to a growth advantage relative to Pvt1 biallelic expressing clonal lines These findings provide an example of how genetic differences can skew a stochastic process which results in an epigenetic phenomenon with a phenotypic consequence in early development.
2025-09-26 | GSE287457 | GEO
Project description:Each gene exists as two copies in the same nucleus of mammalian cells. Although most genes are equivalently controlled on both alleles, Random Monoallelic Expressing (RME) genes stably maintain the expression from only one of two alleles, but the mechanisms and functional consequences of RME remains unclear. Here we performed allele-specific RNA-seq on over 100 neural progenitor cell (NPC) clonal lines to reveal the extent of RME for genes across clonal lines. Interestingly out of 297 autosomal RME genes, Pvt1, a well-studied oncogenic long non-coding RNA, is monoallelically expressed with a skewed genetic bias towards the Castaneous allele in F1-hybrid NPCs. In the absence of genetic differences, allelic tracking by gene editing reveals Pvt1 undergoes balanced RME that is maintained across somatic cell generations. Monoallelic expression is maintained by a poised Pvt1 promoter with bivalent active histone marks, H3K4me3 and H3K27ac, and silencing histone marks, H3K4me3 and H3K27me3, demonstrating its ability to switch transcriptional states depending on the cellular context. Leveraging our large RNA-seq data set and the genetic skew, we use differential gene expression analysis on clonal lines based on their Pvt1 allelic status to reveal a transcription factor, Tfap2a, with differential binding at the Pvt1 promoter, providing a mechanism for the initiation and allelic choice for RME genes. Additionally, we demonstrate monoallelic Pvt1 expression results in an increase in Pvt1 expression leading to a growth advantage relative to Pvt1 biallelic expressing clonal lines These findings provide an example of how genetic differences can skew a stochastic process which results in an epigenetic phenomenon with a phenotypic consequence in early development.
2025-09-26 | GSE287455 | GEO
Project description:Each gene exists as two copies in the same nucleus of mammalian cells. Although most genes are equivalently controlled on both alleles, Random Monoallelic Expressing (RME) genes stably maintain the expression from only one of two alleles, but the mechanisms and functional consequences of RME remains unclear. Here we performed allele-specific RNA-seq on over 100 neural progenitor cell (NPC) clonal lines to reveal the extent of RME for genes across clonal lines. Interestingly out of 297 autosomal RME genes, Pvt1, a well-studied oncogenic long non-coding RNA, is monoallelically expressed with a skewed genetic bias towards the Castaneous allele in F1-hybrid NPCs. In the absence of genetic differences, allelic tracking by gene editing reveals Pvt1 undergoes balanced RME that is maintained across somatic cell generations. Monoallelic expression is maintained by a poised Pvt1 promoter with bivalent active histone marks, H3K4me3 and H3K27ac, and silencing histone marks, H3K4me3 and H3K27me3, demonstrating its ability to switch transcriptional states depending on the cellular context. Leveraging our large RNA-seq data set and the genetic skew, we use differential gene expression analysis on clonal lines based on their Pvt1 allelic status to reveal a transcription factor, Tfap2a, with differential binding at the Pvt1 promoter, providing a mechanism for the initiation and allelic choice for RME genes. Additionally, we demonstrate monoallelic Pvt1 expression results in an increase in Pvt1 expression leading to a growth advantage relative to Pvt1 biallelic expressing clonal lines These findings provide an example of how genetic differences can skew a stochastic process which results in an epigenetic phenomenon with a phenotypic consequence in early development.
2025-09-26 | GSE287458 | GEO
Project description:The two copies of a gene are canonically believed to be indistinguishable to the cell and are expressed in the same spatiotemporal manner in the absence of a loss-of-function mutation. The mechanisms by which cells break this symmetry and express a gene from only one of the two alleles of the diploid genome are of great interest. Monoallelic gene expression on the X-chromosome, at imprinted genes, and at olfactory receptor genes has been studied in detail and involves combinations of non-coding RNAs, DNA methylation, and histone modifications. Recently, random monoallelic gene expression (RME), in which a gene can be expressed from either or both alleles in a clonal manner, has been described across many cell types and disease-relevant genes. However little is known about how RME is established and regulated. Here we develop allele-specific ATAC-seq, a rapid and sensitive method for profiling active regulatory DNA allelically and genome-wide, and find that monoallelic chromatin accessibility is extensive, developmentally regulated, and epigenetically inherited. In clonal hybrid F1 murine neural progenitor cells, we find over 1800 monoallelically-accessible DNA elements across autosomes. Randomly monoallelic regulatory elements tend to be promoter-proximal and located at RME genes identified by RNA-seq. Following differentiation, they are highly stable across passages and bookmarked during mitosis. Most RME genes have monoallelic promoters, but surprisingly, the nearby enhancer landscape around RME genes is biallelic. This suggests that RME genes are regulated at the chromatin, not post-transcriptional level, and that highly localized promoter accessibility is the gatekeeper within a permissive regulatory landscape dictating monoallelic vs. biallelic expression. These randomly monoallelic promoters are biallelically accessible in a previous developmental state, indicating that one allele is randomly shut down during NPC specification. Furthermore, the distribution of active alleles for a subset of these randomly monoallelic regulatory elements across clones deviates from a binomial distribution, indicating a highly regulated, non-stochastic mechanism of establishment.
2016-11-29 | GSE84646 | GEO
Project description:Genes are generally thought to be expressed from both alleles. There are some exceptions, including Random monoallelic expression (RME), even though its extent is still somewhat debated. We assessed whether and how some autosomal genes that we previously identified as being RME are prone to persistent and stable monoallelic expression. Not only do we confirm the occurrence of RME at large frequencies, our results also reveal unforeseen modes of allelic expression,that appear to be gene specific and epigenetically regulated. This non-canonical allelic regulation has large physiological and pathological implications and represents novel therapeutic perspectives.
2021-06-02 | GSE148348 | GEO
Project description:X-chromosome inactivation (XCI) in females and allelic exclusion of olfactory receptor or immunoglobulin loci, represent classic examples of random monoallelic expression (RME). RME of some single copy genes has also been reported, but the in vivo relevance of this remains unclear. Here we identify several hundred RME genes in clonal neural progenitor cell lines derived from embryonic stem cells. RME occurs during differentiation and once established, the monoallelic state can be highly stable. We show that monoallelic expression also occurs in vivo, in the absence of DNA sequence polymorphism, similarly to XCI. Several of the genes identified play important roles in development and have also been implicated in human autosomal dominant disorders. We propose that monoallelic expression of such genes contributes to the fine-tuning of the developmental regulatory pathways they control and in the context of a mutation, RME can predispose to loss of function in a proportion of cells and thus contribute to disease.
2014-02-27 | GSE54016 | GEO
Project description:X-chromosome inactivation (XCI) in females and allelic exclusion of olfactory receptor or immunoglobulin loci, represent classic examples of random monoallelic expression (RME). RME of some single copy genes has also been reported, but the in vivo relevance of this remains unclear. Here we identify several hundred RME genes in clonal neural progenitor cell lines derived from embryonic stem cells. RME occurs during differentiation and once established, the monoallelic state can be highly stable. We show that monoallelic expression also occurs in vivo, in the absence of DNA sequence polymorphism, similarly to XCI. Several of the genes identified play important roles in development and have also been implicated in human autosomal dominant disorders. We propose that monoallelic expression of such genes contributes to the fine-tuning of the developmental regulatory pathways they control and in the context of a mutation, RME can predispose to loss of function in a proportion of cells and thus contribute to disease. The hybrid mouse ES cell lines F1-21.6 and F1-23 (129Sv-Cast/EiJ), previously described in (Luikenhuis et al., 2001) and (Jonkers et al., 2009), were grown on mitomycin C-inactivated MEFs in ES cell media containing 15% FBS (Gibco), 10-4 M b-mercaptoethanol (Sigma), 1000U/ml of leukaemia inhibitory factor (LIF, Chemicon). Mouse ES cells were differentiated into neural progenitor cells (NPC) as previously described (Conti et al., 2005; Splinter et al., 2011). Total RNAs were prepared from the mouse ES cell lines, 4 NPC clones derived from ES cell line F1-21.6 plus one replicate, and 4 NPC clones derived from ES cell line F1-23 plus one replicate. Library preparation after polyadenylated RNA purification was performed according to the standard Illumina instructions. Paired-end 100bp reads were generated using the HiSeq 2000 sequencing platform.
2014-02-27 | E-GEOD-54016 | biostudies-arrayexpress
Project description:In diploid eukaryotic organisms, both alleles of each autosomal gene are usually assumed to be simultaneously expressed at similar levels. However, some genes can be expressed preferentially or strictly from a single allele, a process known as monoallelic expression. Classic monoallelic expression of X-chromosome-linked genes, olfactory receptor genes and developmentally imprinted genes is the result of epigenetic modifications. Genetic-origin-dependent monoallelic expression, however, is caused by cis-regulatory differences between the alleles. There is a paucity of systematic study to investigate these phenomena across multiple tissues, and the mechanisms underlying such monoallelic expression are not yet fully understood. Here we provide a detailed portrait of monoallelic gene expression across multiple tissues/cell lines in a hybrid mouse cross between the Mus musculus strain C57BL/6J and the Mus spretus strain SPRET/EiJ. We observed pervasive tissue-dependent allele-specific gene expression: in total, 1,839 genes exhibited monoallelic expression in at least one tissue, and 410 genes in at least two tissues. Among these 88 are monoallelic genes with different active alleles between tissues, probably representing genetic-origin-dependent monoallelic expression. We also identified six autosomal monoallelic genes with the active allele being identical in all eight tissues, which are likely novel candidates of imprinted genes. To depict the underlying regulatory mechanisms at the chromatin layer, we performed ATAC-seq in two different cell lines derived from the F1 mouse. Consistent with the global expression pattern, cell-type dependent monoallelic peaks were found, and a higher proportion of C57BL/6J-active peaks were observed in both cell types, implying possible species-specific regulation. Finally, only a small part of monoallelic gene expression could be explained by allelic differences in chromatin organization in promoter regions, suggesting that other distal elements may play important roles in shaping the patterns of allelic gene expression across tissues.
2021-06-08 | GSE176259 | GEO
Project description:Random monoallelic expression is defined by the allele-specific expression of genes, and by the fact that for an individual cell this monoallelic expression is neither obligate nor necessarily coordinated with the allelic expression in other cells. In order to find novel examples of random monoallelic expression in mouse, we did a transcriptome-wide survey of allele-specific gene expression in two different immortalized cell types. Lymphoblast cell lines and fibroblast cell lines were established (both clonal and nonclonal) and were used as a source of both nuclear RNA and genomic DNA. These samples were assessed for allele-specific gene expression using a custom-designed Mouse SNP Chip. A large number of genes (over 10% of those that were assessed in lymphoblast clones) displayed random monoallelic expression. For each cell line, two replicate samples of ds-cDNA were assessed for monoallelic expression, while genomic DNA was assessed as a control for possible LOH events. Nonclonal samples were used as controls for cis-acting allelic bias.
2012-02-10 | E-GEOD-35678 | biostudies-arrayexpress
Project description:In mammalian cells, large groups of genes show epigenetically controlled unequal transcription of maternal and paternal alleles. Thousands of autosomal genes subject to monoallelic expression (MAE) comprise the largest such group. The initial random allelic choice in these loci is followed by mitotically stable transmission of the allele-specific state, leading to stable epigenetic and functional differences between clonal cell lineages. Molecular mechanisms underpinning MAE maintenance are not known. We devised and performed a drug screen for reactivation of epigenetically silenced alleles in mouse cells, using a new strategy based on deep targeted allele-specific RNA sequencing, which can read out multiple loci simultaneously. We found that, contrary to previous observations, DNA methylation plays a key role in mitotic memory of MAE in multiple autosomal loci. Having established that a specific perturbation can affect multiple loci, we assessed genome-wide impact of the drug exposure in several clonal cell lines, identifying over 600 genes with allele-specific expression changing with DNA methylation. We found that multiple distinct states of allele-specific expression correspond to the extent of DNA methylation and can be stably maintained, indicating allelic rheostat role of DNA methylation. Our findings reveal a previously unappreciated interplay of genetic and epigenetic control of allele-specific expression and reinforce the role of such regulation in maintaining differences between developmentally equivalent clonal cell lineages.
2023-09-20 | GSE144006 | GEO