Abstract
The imprinting control region (ICR) located far upstream of the H19 gene, in conjunction with enhancers, modulates the transcription of Igf2 and H19 genes in an allele-specific manner. On paternal inheritance, the methylated ICR silences the H19 gene and indirectly facilitates transcription from the distant Igf2 promoter, whereas on the maternal chromosome the unmethylated ICR, together with enhancers, activates transcription of the H19 gene and thereby contributes to the repression of Igf2. This repression of maternal Igf2 has recently been postulated to be due to a chromatin boundary or insulator function of the unmethylated ICR. Central to the insulator model is the site-specific binding of a ubiquitous nuclear factor CTCF which exhibits remarkable flexibility in functioning as transcriptional activator or silencer. We suggest that the ICR positioned close to the enhancers in an episomal context might function as a transcriptional silencer by virtue of interaction of CTCF with its modifiers such as SIN3A and histone deacetylases. Furthermore, a localised folded chromatin structure resulting from juxtaposition of two disparate regulatory sequences (enhancer ICR) could be the mechanistic basis of ICR-mediated position-dependent (ICR-promoter) transcriptional repression in transgenic Drosophila.
Highlights
The imprinting control region (ICR) located far upstream of the H19 gene, in conjunction with enhancers, modulates the transcription of Insulin-like growth factor 2 (Igf2) and H19 genes in an allele-specific manner
We proposed [1] that transcriptional regulation of Igf2/H19 genes could be explained by considering that Igf2 and H19 genes are partitioned into two topologically independent chromatin loops
In the last few years, the imprinting control region (ICR) located far upstream of the mouse/human H19 gene has been a major focus of research because of its pivotal role in Igf2/H19 imprinting [2,3,4,5,6,7,8]
Summary
The imprinting control region (ICR) located far upstream of the H19 gene, in conjunction with enhancers, modulates the transcription of Igf2 and H19 genes in an allele-specific manner. This is achieved by DNA methylation-dependent heterochromatization of ICR most probably inherited from the sperm [15] and thereby allowing the enhancers to interact with the regulatory elements of the Igf2 gene. The unmethylated ICR interacting with enhancers activates H19 transcription as well as negatively regulating the distant Igf2 gene.
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