UW Genome Sciences

Research:

Dr. Gartler's laboratory has two main areas of activity: X-chromosome inactivation and autosomal imprinting.

X-chromosome inactivation: In mammals the two X chromosomes in the female become equivalent to the single X chromosome in the male through the mechanism of X-chromosome inactivation, a form of dosage compensation. This system is critical for normal development and results in monallelic expression in females for X-linked loci subject to X-chromosome inactivation. These active and inactive alleles differ in chromatin configuration, DNA methylation, XIST expression, histone acetylation and replication timing. At present, the work is focused on replication timing differences. Dr. Gartler’s lab has shown that the fragile X syndrome, which is characterized by an X-chromosome cytological aberration and mental retardation, exhibits delayed replication and hypermethylation. Further analysis has shown that the replication delay may extend millions of bases beyond the borders of the fragile X gene. How this very late zone of replication develops is one of the projects being pursued at present. In the course of this work Dr. Gartler’s lab has determined the replication timing of genes near the border of late and early replicating bands. These genes appear to constitute a special group, in that their replication timing changes depending on the tissue under study. This finding may have considerable evolutionary significance and constitutes a major laboratory project.

Imprinting: Monoallelic expression is also known in some autosomal genes, which is said to result from imprinting. That is, the expression of such genes is dependent on parent of origin. The alleles at an imprinted locus will differ in replication timing, as for alleles subject to X-inactivation. Using a method based on replication timing differences, a procedure to detect imprinted genes in the human genome has been developed. Development of a methylation screen to find imprinted genes is underway.

Selected Publications:

Hansen RS, Canfield TK, Lamb MM, Gartler SM, Laird CD: Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell 73:1403-1409, 1993

Hansen RS, Canfield TK, Gartler SM: Unusual replication timing for the XIST gene in human fibroblasts. Hum Mol Genet: 4:813-820, 1995

Kawame H, Gartler SM, Hansen RS: Allele-specific replication timing in imprinted domains: Absence of asynchrony at several loci. Hum Mol Genet 4:2287-2293, 1995

Hansen RS, Canfield TK, Fjeld AD, Gartler SM: Role of late replication timing in the silencing of X-linked genes. Hum Mol Genet 5:1345-1353, 1996

Hansen RS, Canfield TK, Fjeld AD, Munn S, Laird CD, Gartler SM: A variable domain of delayed replication of FRAXA fragile X chromosomes: X inactivation-like spread of late replication. Proc Natl Acad Sci USA 94:4587-4592, 1997

Litt MD, Hansen RS, Hornstra IK, Gartler SM, Yang TP: 5-Azadeoxycytidine induced chromatin remodeling of the inactive X-linked HPRT gene promoter occurs prior to transcription factor binding and gene reactivation. J Biol Chem 272:14921-14926, 1997

Cheng E, Chen YJ, Bonnet G, Gartler SM: An analysis of meiotic pairing in trisomy 21 oocytes using fluorescent in situ hybridization. Cytogenet Cell Genet 80:48-53, 1998

Hansen RS, Canfield TK, Stanek AM, Keitges EA, Gartler SM: Reactivation of XIST in normal fibroblasts and a somatic cell hybrids: Abnormal localization of XIST RNA in hybrid cells. Proc Natl Acad Sci USA 95:5133-5138, 1998

Widrow RJ, Hansen RS, Kawame H, Gartler SM, Laird CD: Very late DNA replication in the human cell cycle. Proc Natl Acad Sci USA 95:11246-11250, 1998