Dataset Information

Nonallelic transcriptional roles of CTCF and cohesins at imprinted loci.

ABSTRACT: The cohesin complex holds sister chromatids together and is essential for chromosome segregation. Recently, cohesins have been implicated in transcriptional regulation and insulation through genome-wide colocalization with the insulator protein CTCF, including involvement at the imprinted H19/Igf2 locus. CTCF binds to multiple imprinted loci and is required for proper imprinted expression at the H19/Igf2 locus. Here we report that cohesins colocalize with CTCF at two additional imprinted loci, the Dlk1-Dio3 and the Kcnq1/Kcnq1ot1 loci. Similar to the H19/Igf2 locus, CTCF and cohesins preferentially bind to the Gtl2 differentially methylated region (DMR) on the unmethylated maternal allele. To determine the functional importance of the binding of CTCF and cohesins at the three imprinted loci, CTCF and cohesins were depleted in mouse embryonic fibroblast cells. The monoallelic expression of imprinted genes at these three loci was maintained. However, mRNA levels for these genes were typically increased; for H19 and Igf2 the increased level of expression was independent of the CTCF-binding sites in the imprinting control region. Results of these experiments demonstrate an unappreciated role for CTCF and cohesins in the repression of imprinted genes in somatic cells.

SUBMITTER: Lin S

PROVIDER: S-EPMC3147605 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Nonallelic transcriptional roles of CTCF and cohesins at imprinted loci.

Lin Shu S Ferguson-Smith Anne C AC Schultz Richard M RM Bartolomei Marisa S MS

Molecular and cellular biology 20110531 15

The cohesin complex holds sister chromatids together and is essential for chromosome segregation. Recently, cohesins have been implicated in transcriptional regulation and insulation through genome-wide colocalization with the insulator protein CTCF, including involvement at the imprinted H19/Igf2 locus. CTCF binds to multiple imprinted loci and is required for proper imprinted expression at the H19/Igf2 locus. Here we report that cohesins colocalize with CTCF at two additional imprinted loci, t ...[more]

PMID: 21628529

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Project description: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.

Dataset Information

Nonallelic transcriptional roles of CTCF and cohesins at imprinted loci.

Publications

Nonallelic transcriptional roles of CTCF and cohesins at imprinted loci.

Similar Datasets

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