Novel cis-regulatory function in ICR-mediated imprinted repression of H19

作者：Ideraabdullah Folami Y; Abramowitz Lara K; Thorvaldsen Joanne L; Krapp Christopher; Wen Sherry C; Engel Nora; Bartolomei Marisa S^*

来源：Developmental Biology, 2011, 355(2): 349-357.

DOI：10.1016/j.ydbio.2011.04.036

• Genomic imprinting
• H19
• DNA methylation
• Transcriptional regulation
• Imprinted repression
• CpG density

Expression of coregulated imprinted genes, H19 and Igf2, is monoallelic and parent-of-origin-dependent. Like most imprinted genes, H19 and Igf2 are regulated by a differentially methylated imprinting control region (ICR). CTCF binding sites and DNA methylation at the ICR have previously been identified as key cis-acting elements required for proper H19/Igf2 imprinting. Here, we use mouse models to elucidate further the mechanism of ICR-mediated gene regulation. We specifically address the question of whether sequences outside of CTCF sites at the ICR are required for paternal H19 repression. To this end, we generated two types of mutant ICRs in the mouse: (i) deletion of intervening sequence between CTCF sites (H19(ICR Delta IVS)), which changes size and CpG content at the ICR; and (ii) CpG depletion outside of CTCF sites (H19(ICR-8nrCG)), which only changes CpG content at the ICR. Individually, both mutant alleles (H19(ICR Delta IVS) and H19(ICR-8nrCG)) show loss of imprinted repression of paternal H19. Interestingly, this loss of repression does not coincide with a detectable change in methylation at the H19 ICR or promoter. Thus, neither intact CTCF sites nor hypermethylation at the ICR is sufficient for maintaining the fully repressed state of the paternal H19 allele. Our findings demonstrate, for the first time in vivo, that sequence outside of CTCF sites at the ICR is required in cis for ICR-mediated imprinted repression at the H19/Igf2 locus. In addition, these results strongly implicate a novel role of ICR size and CpG density in paternal H19 repression.

• 出版日期2011-7-15