Abstract

The specific aims of this proposal are: i) characterization of the molecular defects in ICF syndrome, and ii) the role of shifting replication borders in tissue-specific gene regulation. I. The ICF syndrome is characterized at the molecular level by DNA hypomethylation of certain heterochromatic regions including centromeric satellite II and the inactive X. Three questions will be considered: a) the identity of the defective gene in ICF which will furnish an important clue as to the control of genomic methylation; b) the effect on X inactivation of congenital hypomethylation of the inactive X; and c) the identity of genes whose regulation is disturbed by hypomethylation of centromeric satellite II regions. II. We have discovered that the position of the late-early replication border of Xq27-Xq28 differs by nearly a megabase between fibroblasts and lymphoid cells. The region that is late in fibrloblasts and early in lymphoid cells contains genes that are candidates for repression by late replication. We hypothesize that the replication borders in expressing tissues are shifted so as to place these genes in the transcriptionally permissive early domain. Such border shifting may have evolutionary implications for genome organization. We propose an extensive test of this model.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD016659-20
Application #
6520772
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Moody, Sally Ann
Project Start
1982-09-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
20
Fiscal Year
2002
Total Cost
$403,274
Indirect Cost

  Institution

Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Hansen, R Scott; Thomas, Sean; Sandstrom, Richard et al. (2010) Sequencing newly replicated DNA reveals widespread plasticity in human replication timing. Proc Natl Acad Sci U S A 107:139-44
De Bonis, M L; Cerase, A; Matarazzo, M R et al. (2006) Maintenance of X- and Y-inactivation of the pseudoautosomal (PAR2) gene SPRY3 is independent from DNA methylation and associated to multiple layers of epigenetic modifications. Hum Mol Genet 15:1123-32
Gartler, Stanley M; Varadarajan, Kartik R; Luo, Ping et al. (2006) Abnormal X: autosome ratio, but normal X chromosome inactivation in human triploid cultures. BMC Genet 7:41
Burden, Alice F; Manley, Nathan C; Clark, Aaron D et al. (2005) Hemimethylation and non-CpG methylation levels in a promoter region of human LINE-1 (L1) repeated elements. J Biol Chem 280:14413-9
Laird, Charles D; Pleasant, Nicole D; Clark, Aaron D et al. (2004) Hairpin-bisulfite PCR: assessing epigenetic methylation patterns on complementary strands of individual DNA molecules. Proc Natl Acad Sci U S A 101:204-9
Gartler, Stanley M; Varadarajan, Kartik R; Luo, Ping et al. (2004) Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins. BMC Biol 2:21
Miner, Brooks E; Stoger, Reinhard J; Burden, Alice F et al. (2004) Molecular barcodes detect redundancy and contamination in hairpin-bisulfite PCR. Nucleic Acids Res 32:e135
Hansen, R Scott (2003) X inactivation-specific methylation of LINE-1 elements by DNMT3B: implications for the Lyon repeat hypothesis. Hum Mol Genet 12:2559-67
Gartler, S M; Hansen, R S (2002) ICF syndrome cells as a model system for studying X chromosome inactivation. Cytogenet Genome Res 99:25-9
Matarazzo, Maria Rosaria; De Bonis, Maria Luigia; Gregory, Richard I et al. (2002) Allelic inactivation of the pseudoautosomal gene SYBL1 is controlled by epigenetic mechanisms common to the X and Y chromosomes. Hum Mol Genet 11:3191-8

Showing the most recent 10 out of 44 publications