Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions

Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK.
Human Molecular Genetics (Impact Factor: 6.68). 03/2003; 12(3):295-305.
Source: PubMed

ABSTRACT Imprinted genes and their control elements occur in clusters in the mammalian genome and carry epigenetic modifications. Observations from imprinting disorders suggest that epigenetic modifications throughout the clusters could be under regional control. However, neither the elements that are responsible for regional control, nor its developmental timing, particularly whether it occurs in the germline or postzygotically, are known. Here we examine regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline specific methylation was reprogrammed after fertilization in two differentially methylated regions (DMRs) in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, we found that the DMRs themselves are involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination. These observations are likely to be relevant to other gene clusters in which epigenetic regulation plays a role, and in pathological situations in which epigenetic regulation is disrupted.

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Available from: Adele Murrell, Jul 27, 2015
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    • "However, the germline status of most human imprinted DMRs is currently unknown. Several germline DMRs have been shown to govern postzygotic secondary DMRs that are regulated in a hierarchical fashion [Coombes et al., 2003; Kagami et al., 2010; Lopes et al., 2003]. In all cases to date, the imprinted methylation profile is maintained irrespective of gene expression levels, with some imprinted transcripts being highly expressed during embryonic development and showing a temporal decrease after birth [Iglesias-Platas et al., 2012]. "
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    • "In mammals, chromosome conformation capture experiments revealed that chromosome looping is involved in imprinting control (Lopes et al. 2003; Kurukuti et al. 2006; Yoon et al. 2007; Engel et al. 2008). More specifically , interactions of differentially methylated regions (DMRs) at the mouse H19/Igf2 locus were shown to partition maternal and paternal chromatin into distinct loops, generating an epigenetic switch to control allelespecific expression (Murrell et al. 2004). "
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    • "In mammals, imprinted genes are often found in clusters throughout the genome (Ferguson-Smith, 2011; Wood and Oakey , 2006), and this clustering might relate to the mechanism by which they are regulated (Caspary et al., 1998; Mancini- Dinardo et al., 2006; Lewis et al., 2004; Lopes et al., 2003). "
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