Elements controlling X chromosome replication

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): 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.