Human Molecular Genetics, 2000, Vol. 9, No. 18 2575-2587
© 2000 Oxford University Press
Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant
Departments of 1Medicine, 8Zoology and 9Genetics, Box 357360, University of Washington, Seattle, WA 98195, USA, 2Program in Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA, 3Department of Medical Genetics, Wilhelmina Children’s Hospital, Utrecht, The Netherlands, 4International Institute of Genetics and Biophysics, Naples, Italy, 5Programme in Developmental Genetics, The Babraham Institute, Cambridge, UK, 6Laboratorio de Citogenetica, Istituto G. Gaslini, Genova, Italy and 7University Hospital of Nijmegen, Nijmegen, The Netherlands
Chromosomal abnormalities associated with hypomethylation of classical satellite regions are characteristic for the ICF immunodeficiency syndrome. We, as well as others, have found that these effects derive from mutations in the DNMT3B DNA methyltransferase gene. Here we examine further the molecular phenotype of ICF cells and report several examples of extensive hypomethylation that are associated with advanced replication time, nuclease hypersensitivity and a variable escape from silencing for genes on the inactive X and Y chromosomes. Our analysis suggests that all genes on the inactive X chromosome may be extremely hypomethylated at their 5' CpG islands. Our studies of G6PD in one ICF female and SYBL1 in another ICF female provide the first examples of abnormal escape from X chromosome inactivation in untransformed human fibroblasts. XIST RNA localization is normal in these cells, arguing against an independent silencing role for this RNA in somatic cells. SYBL1 silencing is also disrupted on the Y chromosome in ICF male cells. Increased chromatin sensitivity to nuclease was found at all hypomethylated promoters examined, including those of silenced genes. The persistence of inactivation in these latter cases appears to depend critically on delayed replication of DNA because escape from silencing was only seen when replication was advanced to an active X-like pattern.
+ To whom correspondence should be addressed. Tel: +1 206 543 4184; Fax: +1 206 543 0754; Email: supreme@u.washington.edu
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