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

ORGANISM(S): Mus musculus

PROVIDER: GSE232547 | GEO | 2024/07/15

REPOSITORIES: GEO

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Project description:In plants, imprinted gene expression occurs in endosperm seed tissue and can be associated with differential DNA methylation between maternal and paternal alleles. Imprinting is theorized to have been selected for because of conflict between parental genomes in offspring, but most studies of imprinting have been conducted in Arabidopsis thaliana, an inbred primarily self-fertilizing species that should have limited parental conflict. We examined embryo and endosperm allele-specific expression and DNA methylation genome-wide in the wild outcrossing species Arabidopsis lyrata. Here we show that the majority of A. lyrata imprinted genes exhibit parentally-biased expression in A. thaliana, suggesting that there is evolutionary conservation in gene imprinting. Surprisingly, we discovered substantial interspecies differences in methylation features associated with paternally expressed imprinted genes (PEGs). Unlike A. thaliana, the maternal allele of many A. lyrata PEGs was hypermethylated in the CHG context. Increased maternal allele CHG methylation was associated with increased expression bias in favor of the paternal allele. We propose that CHG methylation maintains or reinforces repression of maternal alleles of PEGs. These data suggest that while the genes subject to imprinting are largely conserved, there is flexibility in the epigenetic mechanisms employed between closely related species to maintain monoallelic expression. This supports the idea that imprinting of specific genes is a functional phenomenon, and not simply a byproduct of seed epigenomic reprogramming. Examination of total gene expression, parent-of-origin specific allelic bias, or DNA methylation in embryo, endosperm, flower bud or seedcoat tissue from Arabidopsis lyrata accessions MN47 (MN), Karhumaki (Kar or KA), and crosses between them. High-throughput Illumina poly-A-selected mRNA-seq was used to identify imprinted genes in A. lyrata, and high-throughput Illumina whole genome bisulfite-sequencing was used to examine DNA methylation. mRNA-seq samples are designated MMxFF_T# where MM is the mother of the cross (either MN for MN47 or KA for Kar), FF is the father, T is the tissue (E for embryo, N for endosperm, S for seedcoat, b for buds), and # is the replicate numbers. Samples obtained from bisulfite sequencing follow the same naming but have suffix _BS and indicate cytosine methylation context (CpG, CHG, or CHH). For KAxMN bisulfite sequencing, additional files MMxFF_T#_BS_P_C.txt follow the same naming scheme but contain context-specific methylation data (C) from reads that mapped preferentially to one parent strain (P).

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

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