Abstract
The mechanisms underlying the phenomenon of genomic imprinting remain poorly understood. In one instance, a differentially methylated imprinting control region (ICR) at the H19 locus has been shown to involve a methylation-sensitive chromatin insulator function that apparently partitions the neighboring Igf2 and H19 genes in different expression domains in a parent of origin-dependent manner. It is not known, however, if this mechanism is unique to the Igf2/H19 locus or if insulator function is a common feature in the regulation of imprinted genes. To address this question, we have studied an ICR in the Kcnq1 locus that regulates long range repression on the paternally derived p57Kip2 and Kcnq1 alleles in an imprinting domain that includes Igf2 and H19. We show that this ICR appears to possess a unidirectional chromatin insulator function in somatic cells of both mesodermal and endodermal origins. Moreover, we document that CpG methylation regulates this insulator function suggesting that a methylation-sensitive chromatin insulator is a common theme in the phenomenon of genomic imprinting.
Highlights
Human chromosome 11p15.5 and the distal part of chromosome 7 in mouse harbor a well characterized cluster of imprinted genes: Ipl, Orctl2, Cdnk1c, Kcnq1, KcnqI A-S/LIT1, Mash2, Ins2, Igf2, and H19 [1, 2]
This region is methylated on the active maternal allele but unmethylated on the inactive paternal allele of Kcnq1 [1] and overlaps with an oppositely oriented and paternally expressed gene known as Kcnq1 A-S or LIT1 [4, 5]
To examine whether chromatin insulator properties is a common feature of imprinting control regions, we analyzed the activity of the Kcnq1 ICR in enhancer-blocking assays
Summary
Vol 277, No 20, Issue of May 17, pp. 18106 –18110, 2002 Printed in U.S.A. A Differentially Methylated Imprinting Control Region within the Kcnq Locus Harbors a Methylation-sensitive Chromatin Insulator*. A differentially methylated imprinting control region (ICR) at the H19 locus has been shown to involve a methylation-sensitive chromatin insulator function that apparently partitions the neighboring Igf and H19 genes in different expression domains in a parent of origin-dependent manner. It is not known, if this mechanism is unique to the Igf2/H19 locus or if insulator function is a common feature in the regulation of imprinted genes. Our results are consistent with the notion that a CpG methylationsensitive chromatin insulator function is not restricted to the H19 ICR but includes the Kcnq ICR as well
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