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Higher Order Chromosomal Network of Imprinted Loci

ABSTRACT: It is increasingly being recognized that physical interactions between distant chromosomal loci influence the expressivity of the genome. Thus, multiple enhancers may converge on a single gene promoter 1,2 and a single enhancer can stochastically loop to multiple promoters 3. Regulatory elements from neighboring domains or from other chromosomes may interact to generate chromatin structures poised for transcription4-8 or repression 9-11. However, a broader perspective on the formation and function of such networks remains largely unexplored. Using the high-resolution 4C (Circular Chromosome Conformation Capture) analysis, we identify here a genome-wide physical network between genomically imprinted domains impinging H19 imprinting control region (ICR). Sequences interacting with the H19 ICR constitutively map at or within most of known imprinted domains both in mouse embryonic stem cells and in vitro-derived embryoid bodies, despite distinct differences in chromatin environments. Moreover, all-to-all 3D DNA FISH analyses revealed that imprinted domains from 7 different chromosomes co-localize with each other in pair-wise patterns, highlighting the dynamic nature of these interactions. The observed interaction network is dependent on CTCF binding sites within the maternally inherited H19 ICR allele and delays reprogramming of epigenetic features at imprinted domains during male germline development. As other imprinted regions can interact with each other in an H19 ICR-dependent manner, the H19 ICR emerges as an organizer of chromosomal networks by specifically recognizing and reconfiguring imprinted domains. We propose that an ancient key regulatory region, such as the H19 ICR, gradually impacted epigenetic modifications via long-range interactions in the germline to facilitate the recruitment of imprinted genes and their formation in clusters during mammalian radiation. Furthermore, the perspective of epigenetic lesions de-stabilizing such chromosomal networks may advance our understanding of how quantitative traits influence human diseases, such as cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE14074 | GEO | 2009/12/14

SECONDARY ACCESSION(S): PRJNA110375

REPOSITORIES: GEO

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Project description:Experimental design Using Circular chromosome conformation capture (4C) assay to uncovers epigenetically regulated intra- and inter-chromosomal interaction network To examine restrictions imposed by the nuclear structure on such cis/trans-chromosomal networks, we developed a high-throughput screening assay 4C and identified 114 different sequences from all autosomes in mouse liver cells. To check the relative frequencies of interactions, the 114 sequences were PCR amplified and spotted on glass to make dedicated microarray. The microarray and 3C validation showed that most of the sequences interact with primarily the maternally inherited H19 imprinting control region (ICR). The epigenetic feature of these interactions was highlighted by the observation that 19% of 4C library sequences are derived from 11 different imprinted domains. In some of these instances, differentially methylated regions (DMRs) interact both in cis and in trans. Moreover, the patterns of chromosomal interactions undergo reprogramming during in vitro maturation of embryonic stem cells. We propose that the nuclear organization of mammalian cells displays considerable plasticity to potentially throw new light on development, cancer epigenetics and evolution of imprinting. Key words: Chromosome conformation capture, CTCF, ICR(Imprinting Control Region) Experimental factors: Genetic variation Experimental design: The 4C samples from both neonatal liver cell SD7 x 142* and 142* x SD7; differentiated embryonic cells and undifferentiated embryonic cells were amplified, fluorescently labeled, and hybridized to 4C dedicated microarray. Quality control steps taken: using pooled samples and gDNA as input, about half of most frequently interactions were confirmed by replicates and dyes swaps. Processed data and a data transformation protocol can be download from ftp://ftp.ebi.ac.uk/pub/databases/microarray/data/experiment/MEXP/E-MEXP-870/

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Higher Order Chromosomal Network of Imprinted Loci

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