X chromosome inactivation

In female mammals, most genes on one X chromosome are silenced as a result of X-chromosome inactivation.  Previous studies have included determining the profile of X-linked genes that appear to "escape" inactivation, identifying and characterizing the X inactivation center in mouse and humans that appears to be required for inactivation to occur, and examining the cytological, genomic and chromatin patterns of epigenetic modification along the inactive X chromosome.  Mechanisms of inactivation, chromosome choice and factors responsible for the escape ability of some X genes are all issues being addressed in the Willard Lab.  A variety of approaches include in vitro studies, use of mouse models, comparative genomics between humans and lemurs, computational, and epigenetic studies.

Lemur X chromosome inactivation

Lemurs are basal primates and will therefore provide a deeper understanding of primate specific mechanisms and processes, such as X-inactivation. Previous genomic analyses in one lemur species suggested a smaller genome size relative to human, due to a decrease in interspersed repeats such as LINEs and SINEs (Liu et al. 2003). As LINEs have been implicated to play a role in X-inactivation, this repeat difference in lemurs could correlate with the number of, and which genes escape the silencing process.

XIST, a non-coding RNA located at Xq13 in humans, is a key player in X-inactivation. Reverse transciptase PCR using conserved XIST primer pairs indicates that XIST is expressed from female lemur cell lines and therefore undergoes X-inactivation. Comparative genomic sequencing across XIST in two lemurs (Lemur catta and Eulemur macaco macaco) indicates approximately 80% identity to the human sequence across this 30kb locus. Further work using these comparative data will provide an important evolutionary perspective for correlating epigenetic differences with sequence changes and will shed light on critical questions of the X-inactivation process.

Key Recent Publications

• Wang Z, Willard HF, Mukherjee S, Furey TS  (2006) Evidence of Influence of Genomic DNA Sequence on Human X Chromosome Inactivation.  PLoS Comput Biol. 2: 979-988. NCBI Link
   

• Valley CM, Pertz LM, Balakumaran BS, Willard HF  (2006) Chromosome-wide, allele-specific analysis of the histone code on the human X chromosome. Hum Mol Genet.15: 2335-2347. NCBI Link
   

• Chadwick LH, Willard HF  (2005) Genetic and parent-of-origin influences on X chromosome choice in X ce heterozygous mice.  Mammalian Genome. 16: 691-699. NCBI Link
   

• Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 434: 400-404. NCBI Link
   

• Chadwick BP, Willard HF (2004) Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. Proc Natl Acad Sci U S A. 101: 17450-17455. NCBI Link