Caenorhabditis elegans Dosage Compensation Regulates Histone H4 Chromatin State on X Chromosomes

Abstract

Dosage compensation equalizes X-linked gene expression between the sexes. This process is achieved in Caenorhabditis elegans by hermaphrodite-specific, dosage compensation complex (DCC)-mediated, 2-fold X chromosome downregulation. How the DCC downregulates gene expression is not known. By analyzing the distribution of histone modifications in nuclei using quantitative fluorescence microscopy, we found that H4K16 acetylation (H4K16ac) is underrepresented and H4K20 monomethylation (H4K20me1) is enriched on hermaphrodite X chromosomes in a DCC-dependent manner. Depletion of H4K16ac also requires the conserved histone deacetylase SIR-2.1, while enrichment of H4K20me1 requires the activities of the histone methyltransferases SET-1 and SET-4. Our data suggest that the mechanism of dosage compensation in C. elegans involves redistribution of chromatin-modifying activities, leading to a depletion of H4K16ac and an enrichment of H4K20me1 on the X chromosomes. These results support conserved roles for histone H4 chromatin modification in worm dosage compensation analogous to those seen in flies, using similar elements and opposing strategies to achieve differential 2-fold changes in X-linked gene expression.

ACKNOWLEDGMENTS

We thank Anna Cacciaglia for laboratory assistance and Susan Strome for the set-1 mutant strain, as well as Ken Cadigan, Ray Chan, Yali Dou, Kentaro Nabeshima, Andrzej Wierzbicki, and several members of the worm modENCODE consortium for insightful project discussions. The sir-2.1(ok434) strain was generated by the C. elegans Reverse Genetics Core Facility at UBC, which is part of the International C. elegans Gene Knockout Consortium. The set-1(tm1821) allele was generated by the Mitani laboratory (National Bioresource Project, Japan) and was backcrossed and balanced to generate the SS1075 strain in the laboratory of Susan Strome (UC Santa Cruz).

This work was supported by National Institutes of Health grant RO1 GM079533 (to G.C.), National Science Foundation grant MCB 1021013 (to G.C.), and the Biological Sciences Scholars Program at the University of Michigan. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources.