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Exploring the Stability of Genomic Imprinting and X-Chromosome Inactivation in the Aged Brain (RNA-Seq)

ABSTRACT: DNA methylation is a common mechanism regulating monoallelic expression of different genes, including imprinted genes. How age-induced alterations of methylation levels vary across alleles and impact on monoallelic expression is unknown. In the brain, this phenomenon may contribute mechanistically to neuronal dysfunction and disease. In order to investigate the allele specific transcriptional and epigenetic signatures of aging, we used key brain areas, hippocampus and cerebellum, of juvenile and old hybrid mice obtained from BL6×CAST/EiJ (CAST) reciprocal crosses. We set out to explore whether epigenetic drift affects global DNA methylation machinery by investigating 5- methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels. Mass spectrometry analysis showed a significant increase of 5hmC levels in hippocampus of old mice, but this was not accompanied by measurable differences in methylating and demethylating enzymes. The expression of several repetitive elements (LINEs, SINEs, IAP) was also analysed, strictly dependent on 5mC and 5hmC levels, and reporting a reduction of the intracisternal A-particle (IAP) retrotransposons in HCP of old mice. We uncovered the allelic-specific DNA methylation profile of aging using genomic imprinting as a read-out by IMPLICON and allelic expression by RNA sequencing. Here, imprinting is not substantially changed during aging, not affecting their normal monoallelic expression. This work provides the first epigenetic and transcriptional landscape of aging with allelic resolution and confirms that genomic imprinting is a stable epigenetic phenomenon across the whole lifespan.

ORGANISM(S): Mus musculus

PROVIDER: GSE232546 | GEO | 2024/07/15

REPOSITORIES: GEO

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Exploring the Stability of Genomic Imprinting and X-Chromosome Inactivation in the Aged Brain (IMPLICON-Seq)

Project description:DNA methylation is a common mechanism regulating monoallelic expression of different genes, including imprinted genes. How age-induced alterations of methylation levels vary across alleles and impact on monoallelic expression is unknown. In the brain, this phenomenon may contribute mechanistically to neuronal dysfunction and disease. In order to investigate the allele-specific transcriptional and epigenetic signatures of aging, we used key brain areas, hippocampus and cerebellum, of juvenile and old hybrid mice obtained from BL6×CAST reciprocal crosses. We set out to explore whether epigenetic drift affects global DNA methylation machinery by investigating 5- methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels. Mass spectrometry analysis showed a significant increase of 5hmC levels in hippocampus of old mice, but this was not accompanied by measurable differences in methylating or demethylating enzymes. The expression of several repetitive elements (LINEs, SINEs, IAP) was also analysed with a reduction of the intracisternal A-particle (IAP) retrotransposons seen in HCP of old mice. We uncovered the allelic-specific DNA methylation profile of aging using genomic imprinting as a read-out by IMPLICON and allelic-expression by RNA sequencing. Here, imprinting is not substantially changed during aging, not affecting their normal monoallelic expression. This work provides the first epigenetic and transcriptional landscape of aging with allelic resolution and confirms that genomic imprinting is a stable epigenetic phenomenon across the whole lifespan.

2024-07-15 | GSE232547 | GEO

Parent-of-Origin Allelic Expression in the Mouse Cerebellum

Project description:The maternal and paternal genomes play different roles in mammalian brains as a result of genomic imprinting, an epigenetic regulation leading to differential expression of the parental alleles of some genes. Here we investigate genomic imprinting in the cerebellum using a newly developed Bayesian statistical model that provides unprecedented transcript-level resolution. We uncover 160 imprinted transcripts, including 41 novel and independently validated imprinted genes. Strikingly, many genes exhibit parentally biased -rather than monoallelic- expression, with different magnitudes according to age, organ, and brain region. Developmental changes in parental bias and overall gene expression are strongly correlated, suggesting combined roles in regulating gene dosage. These findings reveal the remarkable complexity of genomic imprinting, with important implications for understanding the normal and diseased brain. 48 samples of F1 mouse hybrids produced by crossing C57Bl/6J males with Cast/EiJ females (denoted as F1i) and reciprocally crossing Cast/EiJ males and C57Bl/6J famales (denoted as F1r).

2015-07-07 | E-GEOD-67556 | biostudies-arrayexpress

Detecting parent of origin allelic expression bias in mouse olfaction system

Project description:An allele of a gene can be epigenetically regulated to show a parent-of-origin biasedexpression pattern, a phenomenon referring to as genomic imprinting. Genomic imprinting ishighly tissue-specific, and mammalian brains are hotspots for this effect. Social behaviourdefects in human and various behavioural changes in mouse, had been linked toinappropriate imprinting, but little is known about how and why such effects occur.The olfactory system in the brain is the essential sensory circuitry that mediates rodent innatebehaviour. Meanwhile, monoallelic expression, a related process, is used extensively inchemosensory neurons to regulate olfactory and vomeronasal receptor choice. We have datashowing receptor gene choice is not a random process, which implies allele choice may bebiased also. The olfactory system is therefore a promising target for detecting allelicimbalance, or even novel imprinting genes, by high-resolution RNA-sequencing followed byallelic-specific transcriptomic mapping.This project is designed to detect parent-of-origin and strain-of-origin allelic expression bias inneurons from two olfactory tissues: main olfactory epithelium (MOE) and olfaction bulb (OB). RNA from reciprocally crossed F1 hybrid mice (S-cross and M-cross) from two distinct inbred strains (C57BL/6J and CAST) have been extracted respectively (two crosses, two tissue types). After sequencing,expression levels from each allele will be distinguished by incorporating SNP and indeldifferences to the strain-specific reference genomes. Analysis will be carried out incollaboration with Gary Churchill's team at the Jackson Laboratory (who have developed amethod of analysing RNAseq data from CAST x C57BL/6J F1s).Genes with strong, reproducible allelic imbalances will be followed up to assess the functional consequences.

2014-05-27 | E-ERAD-239 | biostudies-arrayexpress

Parent of origin allelic expression bias in mouse vomernasal organ

Project description:An allele of a gene can be epigenetically regulated to show a parent-of-origin biasedexpression pattern, a phenomenon referring to as genomic imprinting. Genomic imprinting ishighly tissue-specific, and mammalian brains are hotspots for this effect. Social behaviourdefects in human and various behavioural changes in mouse, had been linked toinappropriate imprinting, but little is known about how and why such effects occur.The olfactory system in the brain is the essential sensory circuitry that mediates rodent innatebehaviour. Meanwhile, monoallelic expression, a related process, is used extensively inchemosensory neurons to regulate olfactory and vomeronasal receptor choice. We have datashowing receptor gene choice is not a random process, which implies allele choice may bebiased also. The olfactory system is therefore a promising target for detecting allelicimbalance, or even novel imprinting genes, by high-resolution RNA-sequencing followed byallelic-specific transcriptomic mapping.This project is designed to detect parent-of-origin and strain-of-origin allelic expression bias inneurons from a key olfactory tissues in rodents: vomernasal organ (VNO) . RNA from reciprocally crossed F1 hybrid mice (S-cross and M-cross) from two distinct inbred strains (C57BL/6J and CAST) have been extracted respectively. After sequencing,expression levels from each allele will be distinguished by incorporating SNP and indeldifferences to the strain-specific reference genomes. Analysis will be carried out incollaboration with Gary Churchill's team at the Jackson Laboratory (who have developed amethod of analysing RNAseq data from CAST x C57BL/6J F1s).Genes with strong, reproducible allelic imbalances will be followed up to assess the functional consequences.

2014-12-09 | E-ERAD-318 | biostudies-arrayexpress

Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues [RNA-Seq]

Project description:Background: Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on parent-of-origin, and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages and, uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally-inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored. Results: We identify imprinted regions in post-implantation epiblast and extra-embryonic ectoderm (ExE) by assaying allelic histone modifications (H3K4me3, H3K36me3, H3K27me3), gene expression and DNA methylation in reciprocal C57BL/6 and CAST hybrid embryos. We distinguish loci with DNA methylation- dependent (canonical) and independent (non-canonical) imprinting by assaying hybrid embryos with ablated maternally-inherited DNA methylation. We find that non-canonical imprints are localized to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs), which act as imprinted promoters specifically in extra-embryonic lineages. Transcribed ERVK LTRs are CpG-rich and located in close proximity to gene promoters, and imprinting status is determined by their epigenetic patterning in the oocyte. Finally, we show that oocyte-derived H3K27me3 associates with non-canonical imprints is not maintained beyond pre-implantation development, and is replaced by secondary imprinted DNA methylation on the maternal allele in post-implantation ExE, while being completely silenced by bi-allelic DNA methylation in epiblast. Conclusions: This study reveals distinct epigenetic mechanisms regulating non-canonical imprinted gene expression between embryonic and extra-embryonic development, and identifies an integral role for ERVK LTR repetitive elements.

2019-09-19 | GSE124215 | GEO

Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues [Bisulfite-Seq]

2019-09-19 | GSE124213 | GEO

Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues [ChIP-Seq]

2019-09-19 | GSE124212 | GEO

DNA sequence and chromatin modifiers cooperate to confer epigenetic bistability at imprinting control regions

Project description:DNA methylation is essential for embryonic development and implicated in the regulation of genomic imprinting. Genomic imprinting is established in the germline through parent-specific methylation of distinct cis-regulatory DNA sequences, called imprinting control regions (ICRs). Which factors bind to the opposing chromatin states at ICRs within the same nuclear environment was not systematically addressed. By using a proximity labelling approach with the methylation sensitive transcription factor ZFP57, we identified ATF7IP and other major components of the epigenetic maintenance machinery at ICRs.

2023-03-10 | PXD034918 | Pride

Allele-specific binding of ZFP57 in the regulation of imprinted and mono-allelic expression

Project description:Selective maintenance of genomic methylation imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions (ICRs) in early mouse embryos and ES cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. In addition, several cases of human transient neonatal diabetes (TND) are associated with somatic mutations in ZFP57 coding sequence. Here we comprehensively map sequence-specific ZFP57 binding sites in an allele-specific manner using hybrid ES cell lines from reciprocal crosses between C57BL/6J and Cast/EiJ mice assigning allele specificity to approximately two thirds of all binding sites. While half of these are biallelic and include ERV targets, the rest show mono-allelic binding based either on parental-origin or on genetic background of the allele. Parental-origin allele-specific binding was methylation-dependent and mapped only to imprinted DMRs established in the germline (gDMRs). No binding was evident at secondary somatically-derived DMRs. ZFP57-bound gDMRs can predict imprinted gene expression and we identify new imprinted genes, including the Fkbp6 gene with a critical function in mouse male germ cell development. Genetic-background specific sequence differences also influence ZFP57 binding. We show that genetic variation that disrupts the consensus binding motif and its methylation is associated with mono-allelic expression of neighbouring genes. The work described here uncovers further roles for ZFP57 mediated regulation of genomic imprinting and identifies a novel mechanism for genetically determined mono-allelic gene expression. Input and Zfp57 CHiP-Seq profiles of hybrid Black6/Cast ES cells were generated by sequencing using the Illumina GAIIx platform.

2015-05-08 | E-GEOD-55382 | biostudies-arrayexpress

Base-resolution analyses of parent-of-origin and sequence dependent allele specific DNA methylation in the mouse genome (MRE-seq)

Project description:Allele specific DNA methylation (ASM) is crucial for genomic imprinting and mammalian development. Here we present a base-resolution, genome-wide allelic DNA methylation map for both CG and non-CG sites in the mouse brain. We found parent-of-origin dependent (imprinted) ASM at 1,952 CGs which form 55 discrete clusters. This uncovers 31 reported differentially methylated regions (DMRs), including virtually all known germline DMRs, and 24 novel candidate DMRs with some occurring at microRNA genes. In the same adult tissue we also report a surprising presence of non-CG methylation with some showing evidence of imprinting. Finally, we identified sequence dependent ASM at 131,765 CGs. Interestingly, methylation at these sites exhibits a strong dependence on the immediate adjacent bases, allowing us to define a conserved sequence preference for the mammalian DNA methylation machinery. Our genome-wide ASM map should help with understanding the epigenetic differences between two parental genomes in mammals. The crosses of the two mouse strains 129x1/SvJ (129) and Cast/EiJ (Cast) were performed at Jackson Laboratories (http://jaxmice.jax.org/) and the male mice F1 offspring and males of each of the two parental strains were shipped to investigator laboratories at 8 to 9 weeks of age. A total of 500ng genomic DNA isolated from IMR90, MEF, and the frontal cortex of F1i and F1r was digested in parallel by the DNA methylation dependent restriction enzyme FspEI. FspEI recognizes the CmC site (the second cytosine is methylated and can be in the context of CG, CHG or CHH) and creates a 5 protruding end 17 bases downstream of the methylcytosine. A similar experiment was performed by incubating the F1i genomic DNA with a DNA methylation independent restriction enzyme BstNI. The digested DNA was gel purified, size selected for fragments within 100-600bp. The resulting DNA was then prepared as genomic DNA libraries for high-throughput sequencing (Illumina).

2012-02-15 | E-GEOD-33579 | biostudies-arrayexpress

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