Abstract
The methylation of histone H3 at lysine 79 is a feature of open chromatin. It is deposited by the conserved histone methyltransferase DOT1. Recently, DOT1 localization and H3K79 methylation (H3K79me) have been correlated with enhancers in C. elegans and mammalian cells. Since earlier research implicated H3K79me in preventing heterochromatin formation both in yeast and leukemic cells, we sought to inquire whether a H3K79me deficiency would lead to higher levels of heterochromatic histone modifications, specifically H3K9me2, at developmental enhancers in C. elegans. Therefore, we used H3K9me2 ChIP-seq to compare its abundance in control and dot-1.1 loss-of-function mutant worms, as well as in rde-4; dot-1.1 and rde-1; dot-1.1 double mutants. The rde-1 and rde-4 genes are components of the RNAi pathway in C. elegans, and RNAi is known to initiate H3K9 methylation in many organisms, including C. elegans. We have previously shown that dot-1.1(−) lethality is rescued by rde-1 and rde-4 loss-of-function. Here we found that H3K9me2 was elevated in enhancer, but not promoter, regions bound by the DOT-1.1/ZFP-1 complex in dot-1.1(−) worms. We also found increased H3K9me2 at genes targeted by the ALG-3/4-dependent small RNAs and repeat regions. Our results suggest that ectopic H3K9me2 in dot-1.1(−) could, in some cases, be induced by small RNAs.
Highlights
Histone modifications play important roles in the regulation of gene expression by affecting chromatin compaction and by serving as recognition modules for chromatin remodelers and transcription regulators
To begin the investigation of chromatin changes associated with a depletion of H3K79 methylation (H3K79me) at enhancers in C. elegans, we performed a genome-wide analysis of the heterochromatic H3K9me2 modification in two sets of experiments using larval stage 3 (L3) worms
We have suggested that an elevated antisense transcription upon ZFP-1/DOT-1.1 loss-of-function may lead to ectopic dsRNA formation and the activation of the nuclear RNAi pathway, leading to heterochromatin formation at all gene body and/or enhancer regions bound by ZFP-1/DOT-1.1 [4]
Summary
Histone modifications play important roles in the regulation of gene expression by affecting chromatin compaction (e.g., histone tail acetylation) and by serving as recognition modules for chromatin remodelers and transcription regulators. The majority of studies dedicated to mammalian DOT1-like (DOT1L) are focused on its oncogenic role in acute leukemias (reviewed in [7,8,9]), it is becoming clear that DOT1L has a profound impact on development (reviewed in [10]). It is essential for murine embryogenesis [6], proper cardiac function [11], and hematopoiesis [5,12]
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