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Known imprinting control regions (ICRs) contain unusual tandem arrays of DNA-binding sites for transcription factors, including YY1 for the Peg3, Gnas and Xist/Tsix domains and CTCF for the H19/Igf2 domain. These multiple DNA-binding sites are known to be the only functionally shared and evolutionarily selected feature among these ICRs. However, it is not well understood why the imprinting control regions tend to maintain a high density of a particular transcription factor-binding site. We hypothesize that the multiplicity associated with the YY1 and CTCF binding sites may be designed for attracting and maintaining the relatively high levels of YY1 and CTCF proteins or for covering the relatively large genomic sizes of the associated ICRs. This idea remains to be tested in the near future, but it is one of the most likely explanations for all those unusual features that are associated with the functionally critical regions (ICRs) of genomic imprinting. © 2008 Landes Bioscience.

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