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Sequence and parent-of-origin dependent m6A contribute to allele-specific gene expression [GLORI]

ABSTRACT: Multiple regulatory layers influence allele-specific expression (ASE), particularly through sequence-dependent and parent-of-origin-dependent mechanisms at the transcriptional level. However, little is known about allele-specific gene regulation at the post-transcriptional level. Here, we conduct transcriptome-wide analysis of allele-specific m6A in mice. Using early postnatal cerebellum and cerebrum samples from reciprocal crosses of two divergent mouse strains, we employed quantitative m6A assays to measure allelic differences in m6A at single-base resolution. Our study reveals widespread sequence-dependent allelic imbalance in m6A methylation, identifying thousands of allele-specific m6A (ASm6A) sites with statistically significant and reproducible allelic methylation differences across diverse samples. We find evidence of potential cis-regulatory variants within 50-nt flanking regions of these ASm6A sites, with the highest enrichment at the motif positions. Intriguingly, we detect parental effects on allelic methylation across m6A sites exhibiting parent-of-origin-dependent ASE. For both sequence- and parent-of-origin-dependent allelic m6A methylation, we observe opposing allelic preferences between methylation and expression, suggesting a potential role of ASm6A in regulating ASE through negative effects on gene expression. Overall, our findings reveal that both cis-acting and parent-of-origin effects influence ASm6A, offering new insights into post-transcriptional mechanisms of ASE regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE265978 | GEO | 2024/04/26

REPOSITORIES: GEO

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Sequence and parent-of-origin dependent m6A contribute to allele-specific gene expression [m6A-seq]

Project description:Multiple regulatory layers influence allele-specific expression (ASE), particularly through sequence-dependent and parent-of-origin-dependent mechanisms at the transcriptional level. However, little is known about allele-specific gene regulation at the post-transcriptional level. Here, we conduct transcriptome-wide analysis of allele-specific m6A in mice. Using early postnatal cerebellum and cerebrum samples from reciprocal crosses of two divergent mouse strains, we employed quantitative m6A assays to measure allelic differences in m6A at single-base resolution. Our study reveals widespread sequence-dependent allelic imbalance in m6A methylation, identifying thousands of allele-specific m6A (ASm6A) sites with statistically significant and reproducible allelic methylation differences across diverse samples. We find evidence of potential cis-regulatory variants within 50-nt flanking regions of these ASm6A sites, with the highest enrichment at the motif positions. Intriguingly, we detect parental effects on allelic methylation across m6A sites exhibiting parent-of-origin-dependent ASE. For both sequence- and parent-of-origin-dependent allelic m6A methylation, we observe opposing allelic preferences between methylation and expression, suggesting a potential role of ASm6A in regulating ASE through negative effects on gene expression. Overall, our findings reveal that both cis-acting and parent-of-origin effects influence ASm6A, offering new insights into post-transcriptional mechanisms of ASE regulation.

2024-04-26 | GSE265977 | GEO

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

2012-02-15 | GSE33579 | GEO

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

2012-02-15 | GSE33468 | GEO

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

2012-02-15 | GSE30199 | GEO

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

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

2015-05-08 | GSE55382 | GEO

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

Extensive and coordinated control of allele-specific expression by both transcription and translation in Candida albicans

Project description:Though sequence differences between alleles are often limited to a few polymorphisms, these differences can cause large and widespread allelic variation at the expression level. Such allele-specific expression (ASE) has been extensively explored at the level of transcription but not translation. Here we measured ASE in the diploid yeast Candida albicans at both the transcriptional and translational levels using RNA-seq and ribosome profiling, respectively. Since C. albicans is an obligate diploid, our analysis isolates ASE arising from cis elements in a natural, non-hybrid organism, where allelic effects reflect evolutionary forces. Importantly, we find that ASE arising from translation is of a similar magnitude as transcriptional ASE, both in terms of the number of genes affected and the magnitude of the bias. We further observe coordination between ASE at the levels of transcription and translation for single genes. Specifically, reinforcing relationships—where transcription and translation favor the same allele—are more frequent than expected by chance, consistent with selective pressure tuning ASE at multiple regulatory steps. Finally, we parameterize alleles based on a range of properties and find that SNP location and predicted mRNA-structure stability are associated with translational ASE in cis. Since this analysis probes more than 4,000 allelic pairs spanning a broad range of variations, our data provide a genome-wide view into the relative impacts of cis elements that regulate translation.

2014-03-14 | GSE52236 | GEO

Extensive and coordinated control of allele-specific expression by both transcription and translation in Candida albicans

Project description:Though sequence differences between alleles are often limited to a few polymorphisms, these differences can cause large and widespread allelic variation at the expression level. Such allele-specific expression (ASE) has been extensively explored at the level of transcription but not translation. Here we measured ASE in the diploid yeast Candida albicans at both the transcriptional and translational levels using RNA-seq and ribosome profiling, respectively. Since C. albicans is an obligate diploid, our analysis isolates ASE arising from cis elements in a natural, non-hybrid organism, where allelic effects reflect evolutionary forces. Importantly, we find that ASE arising from translation is of a similar magnitude as transcriptional ASE, both in terms of the number of genes affected and the magnitude of the bias. We further observe coordination between ASE at the levels of transcription and translation for single genes. Specifically, reinforcing relationshipsM-bM-^@M-^Twhere transcription and translation favor the same alleleM-bM-^@M-^Tare more frequent than expected by chance, consistent with selective pressure tuning ASE at multiple regulatory steps. Finally, we parameterize alleles based on a range of properties and find that SNP location and predicted mRNA-structure stability are associated with translational ASE in cis. Since this analysis probes more than 4,000 allelic pairs spanning a broad range of variations, our data provide a genome-wide view into the relative impacts of cis elements that regulate translation. Two biological replicates of WT Candida albicans ribosome profiling and RNA-seq

2014-03-14 | E-GEOD-52236 | biostudies-arrayexpress

A Novel Approach Identifies New Differentially Methylated Regions (DMRs) Associated with Imprinted Genes

Project description:Imprinted genes are critical for normal human growth and neurodevelopment. We developed a strategy to identify new DNA differentially methylated regions (DMRs), a hallmark of imprinted genes. Using genome-wide methylation profiling, candidate DMRs were selected by identifying CpGs with putative allelic differential methylation in normal biparental tissues. In parallel, we looked for parent of origin-specific DNA methylation patterns in paternally derived human androgenetic complete hydatidiform mole (AnCHM), and maternally derived mature cystic ovarian teratoma (MCT). Using this approach, we found known DMRs associated with imprinted genomic regions as well as new DMRs for known imprinted genes, NAP1L5 and ZNF597. Most importantly, novel candidate imprinted genes were identified. The paternally methylated DMR for one candidate, AXL, a receptor tyrosine kinase, was validated by methylation analyses in humans. Further validation in mouse embryos showed that Axl was expressed preferentially from the maternal allele in a DNA methylation–dependent manner. We have analyzed 3 androgenetic complete hydatidiform mole (AnCHM), 16 white blood cell (WBC), 1 mature cystic ovarian teratoma (MCT), 5 placenta, and 1 lymphoblastoid cell line paternal UPD4 sample

2011-01-26 | E-GEOD-22091 | biostudies-arrayexpress

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