Pausing for Thought on the Boundaries of Imprinting

imprinted expression of most, though not all, known imprinted genes (reviewed in Tilghman, 1999). Differentially methylated regions have also been consistently Edinburgh EH4 2XU correlated with imprinted loci. On mouse chromosome United Kingdom 7, the region upstream of H19 (the imprinting control region—ICR) is methylated only on the paternally derived allele. It is now clear that the ICR orchestrates the All chromosomes are not created equal. Large chromo-reciprocal and imprinted expression of H19 and Igf2 somal regions, or even whole chromosomes, can carry a by acting as a methylation-sensitive boundary element mark (imprint) that reflects their parental origin. Imprints (Figure 1). On the maternally derived chromosome, the modify genetic information allowing transmission of dif-ubiquitous transcriptional regulator CTCF is able to bind ferent heritable states through multiple cell divisions. In to CpG-rich recognition sites within the ICR (Kanduri et mammals, imprints can manifest as differential expres-al., 2000). CTCF bound at this site acts as an insulator— sion of paternally and maternally derived genes. Imprints preventing the Igf2 promoter from " seeing " an enhancer must be established differentially during gametogenesis located downstream of H19 and leaving H19 free to in sperm and oocyte, then be stably maintained through use the enhancer to stimulate transcription (Bell and multiple rounds of cell division in the zygote. Finally Felsenfeld, 2000; Hark et al., 2000). CTCF binding, and imprints are erased and reset in the germline. The first hence boundary function, is blocked by methylation at solid molecular basis for understanding imprinted gene the paternally derived ICR. On these chromosomes, ex-expression has come from studying the linked and recip-pression from Igf2 appears to be enhanced at the expense of H19, perhaps through higher affinity of the Igf2 rocally imprinted mouse Igf2 and H19 genes. Igf2/H19 promoter for the enhancer. Thus, differential methylation are located within an extensive imprinted region on and CTCF binding of the ICR could be sufficient to ex-mouse chromosome 7. The behavior of other genes in plain how the imprint might be established and trans-this region (or its region of conserved synteny in hu-lated into transcriptional differences between Igf2 and mans—11p15.5) suggests that in general it is the pater-H19. But is it necessary for long-term maintenance/ nally derived regions that are transcriptionally silenced. propagation of these states? Several recent papers provide evidence that parent of So Does the Boundary Then Have a Limited Role? origin–specific DNA methylation modulates the forma-Srivastava et al. …