During X inactivation in female mammals, one of the two X chromosomes acquires features of heterochromatin (late replication, histone deacetylation, transcriptional silencing etc), a process known as X-inactivation. X-inactivation requires the X-linked Xist gene and appears to also require a high density of long interspersed nuclear elements (LINE transposons). Evidence for ongoing signaling between the two X chromosomes was obtained in the Marahrens lab when the deletion of the transcriptionally silent Xist allele from the active X chromosome (Xa) was found to cause the entire inactive X chromosome (Xi) to shift from late replication timing to earlier replication timing. A low-resolution replication timing analysis of the earlier replicating Xi showed a complex but highly reproducible pattern of replication timing with different chromosomal regions replicating at different times. Since chromatin structure dictates replication timing, the uneven replication timing induced by the Xist deletion appears to be due to different changes in heterochromatin structure in different chromosomal regions. These differences are presumably caused by differences in chromosomal context. We plan to precisely map the replication timing of all X-linked genes in the S phase of mutant cells lacking Xist on Xa or lacking Xist on Xi using microarrays and to identify the chromosomal sequence features that determine the replication timing.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM068976-03
Application #
6984119
Study Section
Special Emphasis Panel (ZRG1-F05 (29))
Program Officer
Gaillard, Shawn R
Project Start
2004-01-02
Project End
2007-01-01
Budget Start
2006-01-02
Budget End
2007-01-01
Support Year
3
Fiscal Year
2006
Total Cost
$28,270
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Goldstine, Jimena V; Nahas, Shareef; Gamo, Kristin et al. (2006) Constitutive phosphorylation of ATM in lymphoblastoid cell lines from patients with ICF syndrome without downstream kinase activity. DNA Repair (Amst) 5:432-43