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.

A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2

“…Triplicate analyses of set-1 and set-4 RNAi were consistent (supplementary material Table S7). sir-2.1, which has been reported to act to deacetylate lysine 16 of H4 (H4K16Ac) downstream of the DCC (Wells et al, 2012), also modestly suppressed developmental delay in rict-1 mutants ( Fig. 6C; supplementary material Table S7).…”

“…SET-4 activity, which di-and trimethylates H4K20, is correspondingly decreased during embryonic dosage compensation (Vielle et al, 2012), but SET-4 has been reported to mediate some of the effects of the DCC (Wells et al, 2012). H4K20me1 likely contributes to the chromosomal condensation Rice et al, 2002), restricting expression of X chromosomal genes during dosage compensation.…”

“…Other associated members of the DCC include the SDC-1, SDC-2, SDC-3, DPY-30 and DPY-21, which, through SDC-2, SDC-3 and DPY-30, allow for the DCC to be recruited specifically to the X chromosome in the hermaphrodite. The mechanism of DCC downregulation of X chromosomal genes remains elusive; however, two recent investigations suggest that the DCC stimulates formation of the repressive epigenetic mark histone 4, lysine 20 monomethyl (H4K20me1) (Vielle et al, 2012;Wells et al, 2012). Further, the DCC is required for the enrichment of H4K20me1 on the X chromosome, as loss of dpy-21 reduces H4K20me1 (Vielle et al, 2012).…”

“…Further, the DCC is required for the enrichment of H4K20me1 on the X chromosome, as loss of dpy-21 reduces H4K20me1 (Vielle et al, 2012). The histone 4 lysine 20 (H4K20) monomethyltransferase SET-1 and di/trimethyltransferase SET-4, as well as the histone deacetylase SIR-2.1, play key roles in regulating the methylation state and acetylation state of histone H4 on the X chromosome downstream of the DCC (Wells et al, 2012).…”

Linking dosage compensation and X chromosome nuclear organization inC. elegans

“…16 At the chromatin level, the dosage compensated X chromosomes are depleted for the histone variant H2A.Z (HTZ-1) and H4K16 acetylation while they carry high H4K20 monomethylation. [17][18][19][20] The first two might be a consequence of lower transcription levels, while the latter is a consequence of DCC binding as the methylation mark spreads with the DCC. 18 The function of this methylation marks remains however elusive.…”