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Biallelic non-productive enhancer-promoter interaction precedes imprinted expression of KcnK9 during mouse neural commitment [ChIP-seq]

ABSTRACT: How constitutive allelic methylation at imprinting control regions (ICRs) interacts with other levels of regulation to drive timely parental allele-specific expression along large imprinted domains remains partially understood at most imprinted loci. To gain insight into the regulation of the Peg13-KcnK9 domain, an imprinted domain with important brain functions, during neural commitment, we performed a detailed integrative analysis of the epigenetic, transcriptomic and cis-spatial organisation in an allele-specific manner in a mouse stem cell-based model of corticogenesis that recapitulates the control of imprinted gene expression in the embryonic brain. We have evidence that despite an allelic higher order chromatin structure associated with the paternally CTCF-bound Peg13 ICR, enhancer-Kcnk9 promoter contacts can occur on both alleles, although they are only productive on the maternal allele. This observation challenges the canonical model in which CTCF binding isolates the enhancer and its target gene on either side, and suggests a more nuanced role for allelic CTCF binding at the ICR of this locus.

ORGANISM(S): Mus musculus

PROVIDER: GSE244144 | GEO | 2024/02/05

REPOSITORIES: GEO

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Biallelic non-productive enhancer-promoter interaction precedes imprinted expression of KcnK9 during mouse neural commitment [RNA-seq]

Project description:How constitutive allelic methylation at imprinting control regions (ICRs) interacts with other levels of regulation to drive timely parental allele-specific expression along large imprinted domains remains partially understood at most imprinted loci. To gain insight into the regulation of the Peg13-KcnK9 domain, an imprinted domain with important brain functions, during neural commitment, we performed a detailed integrative analysis of the epigenetic, transcriptomic and cis-spatial organisation in an allele-specific manner in a mouse stem cell-based model of corticogenesis that recapitulates the control of imprinted gene expression in the embryonic brain. We have evidence that despite an allelic higher order chromatin structure associated with the paternally CTCF-bound Peg13 ICR, enhancer-Kcnk9 promoter contacts can occur on both alleles, although they are only productive on the maternal allele. This observation challenges the canonical model in which CTCF binding isolates the enhancer and its target gene on either side, and suggests a more nuanced role for allelic CTCF binding at the ICR of this locus.

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Biallelic non-productive enhancer-promoter interaction precedes imprinted expression of KcnK9 during mouse neural commitment [Cut&Run]

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Allelic chromatin structure primes imprinted expression of Kcnk9 during neurogenesis

Project description:Differences in chromatin state inherited from the parental gametes influence the regulation of maternal and paternal alleles in offspring. This phenomenon, known as genomic imprinting, results in genes preferentially transcribed from one parental allele. While local epigenetic factors such as DNA methylation are known to be important for the establishment of imprinted gene expression, less is known about the mechanisms by which differentially methylated regions (DMRs) lead to differences in allelic expression across broad stretches of chromatin. Allele-specific higher-order chromatin structure has been observed at multiple imprinted loci, consistent with the observation of allelic binding of the chromatin-organizing factor CTCF at multiple DMRs. However, whether allelic chromatin structure impacts allelic gene expression is not known for most imprinted loci. Here we characterize the mechanisms underlying brain-specific imprinted expression of the Peg13-Kcnk9 locus, an imprinted region associated with intellectual disability. We performed region capture Hi-C on mouse brain from reciprocal hybrid crosses and found imprinted higher-order chromatin structure caused by the allelic binding of CTCF to the Peg13 DMR. Using an in vitro neuron differentiation system, we show that on the maternal allele, an enhancer-promoter contact formed early in development primes the brain-specific potassium leak channel Kcnk9 for maternal expression prior to neurogenesis. In contrast, this enhancer-promoter contact is blocked by CTCF on the paternal allele, preventing paternal Kcnk9 activation. This work provides a high-resolution map of imprinted chromatin structure and demonstrates that chromatin state established in early development can promote imprinted expression upon differentiation.

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ERCC1-XPF Cooperates with CTCF and the Cohesin to Facilitate the Developmental Silencing of Imprinted Genes

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Transcription profiling of mouse G9a-/- knockouts vs controls reveals G9a histone methyltransferase maintains genomic imprinting IN THE mouse placenta.

Project description:Whereas DNA methylation is essential for genomic imprinting, the importance of histone methylation in the allelic repression of imprinted genes is unclear. âImprinting control regionsâ (ICRs), however, are consistently marked by histone H3 K9 methylation on their DNA-methylated allele. In the placenta, the paternal silencing along the Kcnq1 domain on distal chromosome 7 also correlates with the presence of H3-K9 methylation, but imprinted repression at these genes is maintained independently of DNA methylation. To explore which histone methyltransferase (HMT) could mediate the allelic H3-K9 methylation on distal chromosome 7, and at ICRs, we generated mouse conceptuses deficient for the SET-domain protein G9a. We find that in the embryo and placenta, the differential DNA methylation at ICRs and imprinted genes is maintained in the absence of G9a. Accordingly, in embryos, imprinted gene expression is unchanged at the domains analysed, in spite of a global loss of H3-K9 di-methylation (H3K9me2). In contrast, the placenta-specific imprinting of genes on distal chromosome 7 is lost in the absence of G9, and this correlates with a loss of H3K9me2 and H3K9me3. These findings provide the first in vivo evidence for the involvement of a SET domain protein in imprinting and highlight the importance of histone lysine methylation rather than DNA methylation in the maintenance of imprinting in the trophoblast lineage. Experiment Overall Design: Number of samples: four (two biologically replicate G9a-/- pooled placentae samples, and two biologically replicate wildtype pooled placentae samples). The first G9a-/- and wildtype replicates were used to hybridize Affymetrix MOE430A and MOE430B arrays (four arrays total). The second replicates were used to hybridize Affymetrix Mouse430_2 arrays (two arrays total).

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Allele-specific regulation of gene expression through enhancer function and transcriptional elongation control at imprinted loci

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Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

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G9a histone methyltransferase maintains genomic imprinting in the mouse placenta.

Project description:Whereas DNA methylation is essential for genomic imprinting, the importance of histone methylation in the allelic repression of imprinted genes is unclear. ‘Imprinting control regions’ (ICRs), however, are consistently marked by histone H3 K9 methylation on their DNA-methylated allele. In the placenta, the paternal silencing along the Kcnq1 domain on distal chromosome 7 also correlates with the presence of H3-K9 methylation, but imprinted repression at these genes is maintained independently of DNA methylation. To explore which histone methyltransferase (HMT) could mediate the allelic H3-K9 methylation on distal chromosome 7, and at ICRs, we generated mouse conceptuses deficient for the SET-domain protein G9a. We find that in the embryo and placenta, the differential DNA methylation at ICRs and imprinted genes is maintained in the absence of G9a. Accordingly, in embryos, imprinted gene expression is unchanged at the domains analysed, in spite of a global loss of H3-K9 di-methylation (H3K9me2). In contrast, the placenta-specific imprinting of genes on distal chromosome 7 is lost in the absence of G9, and this correlates with a loss of H3K9me2 and H3K9me3. These findings provide the first in vivo evidence for the involvement of a SET domain protein in imprinting and highlight the importance of histone lysine methylation rather than DNA methylation in the maintenance of imprinting in the trophoblast lineage. Keywords: genetic modification

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