Global regulation of the C. elegans X chromosome

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DESCRIPTION (provided by applicant): The SMC family of proteins participates in several aspects of chromosome biology, including mitotic chromosome condensation and sister chromatid cohesion. In the nematode, C. elegans. SMC protein containing complexes are also involved in dosage compensation. The process of chromosome-wide modulation of X-linked gene expression that equalizes X transcripts in males (IX) and females (2X) despite their difference in X chromosome dose. The similarity between the worm dosage compensation machinery and mitotic chromosome condensation complexes indicate that the two processes may be mechanistically related. As the development of many genetic diseases and cancers correlate with chromosomal abnormalities, understanding the function of protein complexes involved in different aspects of chromosome biology wilt be crucial in our search for treatments and cures for these diseases. Although many of the protein and RNA molecules involved in dosage compensation have been identified, their biochemical function is not well understood. The first step toward deciphering the biochemical function of the dosage compensation machinery is to determine where the complex binds and thus how the X is recognized. Then the level of regulation imposed on all X-linked genes will need to be determined. Expression levels of genes on dosage compensated and non-dosage compensated chromosomes in the C. elegans genome will be studied using DNA microarrays. Then a search for chromosomal binding sites of the dosage compensation machinery will be performed using two techniques: (i) chromatin immunoprecipitation (ChIP) of the dosage compensation complex and bound DNA and (ii) Dam identification (DamID) involving in viva methylation of DNA using Dam methyltransferase tethered to dosage compensation proteins.