Caenorhabditis elegans Dosage Compensation Directs Chromatin and Transcriptional Regulation on Hermaphrodite X Chromosomes.

Abstract

Dosage compensation is the essential process that balances sex-chromosome gene expression in organisms which use a chromosome-based method of sex determination. Of the three most understood mechanisms of dosage compensation, two (fly and mammalian) are known to involve histone modification and transcriptional regulation. In the worm Caenorhabditis elegans, dosage compensation involves binding of a condensin-like complex, a recruitment complex, and two additional proteins (collectively known as the DCC), to both hermaphrodite X chromosomes for two-fold down-regulation of gene expression hypothesized to be driven by changes in X chromosome structure. Further, it has been shown that the DCC regulates levels of RNA polymerase II on the X chromosomes, but no further details regarding this mechanism of transcriptional regulation are known. In this research, I have identified dosage compensation-driven regulation of two antagonistic histone modifications, H4K16ac and H4K20me1, to create a repressive chromatin environment on the X chromosomes. I also created a compendium of chromatin modification and transcription factor occupancy across the genome, and with respect to dosage compensation, from available datasets. Finally, I demonstrate that different subsets of DCC proteins function at multiple points in the transcription cycle to regulate RNA polymerase II, either just on X or across the genome. This novel work serves as a mechanistic basis for C. elegans dosage compensation and reveals profound insights regarding the true function of a poorly characterized DCC component, DPY-21. Further, this work serves as a characterization of a dramatic example of interphase gene expression regulation by a protein complex best known for its roles in meiosis and mitosis.