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The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus

BACKGROUND: Genomic imprinting is the epigenetic marking of genes that results in parent-of-origin monoallelic expression. Most imprinted domains are associated with differentially DNA methylated regions (DMRs) that originate in the gametes, and are maintained in somatic tissues after fertilization....

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Autores principales: Court, Franck, Camprubi, Cristina, Garcia, Cristina Vicente, Guillaumet-Adkins, Amy, Sparago, Angela, Seruggia, Davide, Sandoval, Juan, Esteller, Manel, Martin-Trujillo, Alex, Riccio, Andrea, Montoliu, Lluis, Monk, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986935/
https://www.ncbi.nlm.nih.gov/pubmed/24667089
http://dx.doi.org/10.1186/1756-8935-7-5
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author Court, Franck
Camprubi, Cristina
Garcia, Cristina Vicente
Guillaumet-Adkins, Amy
Sparago, Angela
Seruggia, Davide
Sandoval, Juan
Esteller, Manel
Martin-Trujillo, Alex
Riccio, Andrea
Montoliu, Lluis
Monk, David
author_facet Court, Franck
Camprubi, Cristina
Garcia, Cristina Vicente
Guillaumet-Adkins, Amy
Sparago, Angela
Seruggia, Davide
Sandoval, Juan
Esteller, Manel
Martin-Trujillo, Alex
Riccio, Andrea
Montoliu, Lluis
Monk, David
author_sort Court, Franck
collection PubMed
description BACKGROUND: Genomic imprinting is the epigenetic marking of genes that results in parent-of-origin monoallelic expression. Most imprinted domains are associated with differentially DNA methylated regions (DMRs) that originate in the gametes, and are maintained in somatic tissues after fertilization. This allelic methylation profile is associated with a plethora of histone tail modifications that orchestrates higher order chromatin interactions. The mouse chromosome 15 imprinted cluster contains multiple brain-specific maternally expressed transcripts including Ago2, Chrac1, Trappc9 and Kcnk9 and a paternally expressed gene, Peg13. The promoter of Peg13 is methylated on the maternal allele and is the sole DMR within the locus. To determine the extent of imprinting within the human orthologous region on chromosome 8q24, a region associated with autosomal recessive intellectual disability, Birk-Barel mental retardation and dysmorphism syndrome, we have undertaken a systematic analysis of allelic expression and DNA methylation of genes mapping within an approximately 2 Mb region around TRAPPC9. RESULTS: Utilizing allele-specific RT-PCR, bisulphite sequencing, chromatin immunoprecipitation and chromosome conformation capture (3C) we show the reciprocal expression of the novel, paternally expressed, PEG13 non-coding RNA and maternally expressed KCNK9 genes in brain, and the biallelic expression of flanking transcripts in a range of tissues. We identify a tandem-repeat region overlapping the PEG13 transcript that is methylated on the maternal allele, which binds CTCF-cohesin in chromatin immunoprecipitation experiments and possesses enhancer-blocker activity. Using 3C, we identify mutually exclusive approximately 58 and 500 kb chromatin loops in adult frontal cortex between a novel brain-specific enhancer, marked by H3K4me1 and H3K27ac, with the KCNK9 and PEG13 promoters which we propose regulates brain-specific expression. CONCLUSIONS: We have characterised the molecular mechanism responsible for reciprocal allelic expression of the PEG13 and KCNK9 transcripts. Therefore, our observations may have important implications for identifying the cause of intellectual disabilities associated with the 8q24 locus.
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spelling pubmed-39869352014-04-16 The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus Court, Franck Camprubi, Cristina Garcia, Cristina Vicente Guillaumet-Adkins, Amy Sparago, Angela Seruggia, Davide Sandoval, Juan Esteller, Manel Martin-Trujillo, Alex Riccio, Andrea Montoliu, Lluis Monk, David Epigenetics Chromatin Research BACKGROUND: Genomic imprinting is the epigenetic marking of genes that results in parent-of-origin monoallelic expression. Most imprinted domains are associated with differentially DNA methylated regions (DMRs) that originate in the gametes, and are maintained in somatic tissues after fertilization. This allelic methylation profile is associated with a plethora of histone tail modifications that orchestrates higher order chromatin interactions. The mouse chromosome 15 imprinted cluster contains multiple brain-specific maternally expressed transcripts including Ago2, Chrac1, Trappc9 and Kcnk9 and a paternally expressed gene, Peg13. The promoter of Peg13 is methylated on the maternal allele and is the sole DMR within the locus. To determine the extent of imprinting within the human orthologous region on chromosome 8q24, a region associated with autosomal recessive intellectual disability, Birk-Barel mental retardation and dysmorphism syndrome, we have undertaken a systematic analysis of allelic expression and DNA methylation of genes mapping within an approximately 2 Mb region around TRAPPC9. RESULTS: Utilizing allele-specific RT-PCR, bisulphite sequencing, chromatin immunoprecipitation and chromosome conformation capture (3C) we show the reciprocal expression of the novel, paternally expressed, PEG13 non-coding RNA and maternally expressed KCNK9 genes in brain, and the biallelic expression of flanking transcripts in a range of tissues. We identify a tandem-repeat region overlapping the PEG13 transcript that is methylated on the maternal allele, which binds CTCF-cohesin in chromatin immunoprecipitation experiments and possesses enhancer-blocker activity. Using 3C, we identify mutually exclusive approximately 58 and 500 kb chromatin loops in adult frontal cortex between a novel brain-specific enhancer, marked by H3K4me1 and H3K27ac, with the KCNK9 and PEG13 promoters which we propose regulates brain-specific expression. CONCLUSIONS: We have characterised the molecular mechanism responsible for reciprocal allelic expression of the PEG13 and KCNK9 transcripts. Therefore, our observations may have important implications for identifying the cause of intellectual disabilities associated with the 8q24 locus. BioMed Central 2014-03-25 /pmc/articles/PMC3986935/ /pubmed/24667089 http://dx.doi.org/10.1186/1756-8935-7-5 Text en Copyright © 2014 Court et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Court, Franck
Camprubi, Cristina
Garcia, Cristina Vicente
Guillaumet-Adkins, Amy
Sparago, Angela
Seruggia, Davide
Sandoval, Juan
Esteller, Manel
Martin-Trujillo, Alex
Riccio, Andrea
Montoliu, Lluis
Monk, David
The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus
title The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus
title_full The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus
title_fullStr The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus
title_full_unstemmed The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus
title_short The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus
title_sort peg13-dmr and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986935/
https://www.ncbi.nlm.nih.gov/pubmed/24667089
http://dx.doi.org/10.1186/1756-8935-7-5
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