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Genome-wide mapping of the heterochromatin mark H3K9me2 in loss-of-function mutant worms

ABSTRACT: Histone modification marks such as H3K4me1 and H3K27ac have been used to map putative enhancers, but these marks represent only a fraction of the full repertoire of histone modifications decorating these regulatory regions. In mammals, methylation of histone H3 on lysine 79 (H3K79me), deposited by the methyltransferase DOT1L, is present at enhancers. In C. elegans, putative enhancers have been predicted based on chromatin modifications and regions of chromatin accessibility. Our own overlap analysis has revealed that both DOT-1.1, the C. elegans DOT1L homologue, and its major interacting partner, the chromatin-binding factor ZFP-1 (AF10 in mammals), are enriched at both distal and intragenic enhancers. Previous work has shown that Dot1 proteins prevent encroachment of heterochromatin to actively transcribed regions in yeast and in MLL-rearranged leukemias. Here we find that, in C. elegans, loss of DOT-1.1 is accompanied by ectopic H3K9me2, a hallmark of heterochromatin, at distal and intragenic enhancers. This observation suggests a new role for DOT1L in the control of heterochromatin formation at enhancers, which may partake on the control of developmentally regulated genes.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE150407 | GEO | 2020/09/08

REPOSITORIES: GEO

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Project description:Transcriptional control is mediated by interactions of transcription factors with their cognate DNA elements, as well as by epigenetic modifications to chromatin catalyzed by a variety of enzymes. Thus, understanding the crosstalk between transcription factors and epigenetic modifiers is of prime importance. The Dot1-like protein (DOT1L) is an evolutionary conserved methyltransferase with catalytic specificity towards histone 3 lysine 79 (H3K79). DOT1L is essential for mammalian development and has been studied mostly in the context of aggressive leukemias. Recent observations suggest that the role of DOT1L in malignant transformation can be generalized to contexts beyond leukemia. For instance, DOT1L has been implicated in breast cancer progression, and this has been attributed to its cooperation with c-Myc. However, the mechanistic details underlying this association are unknown. Previous work in our lab has shown that DOT-1.1, the C. elegans DOT1L homologue, is recruited to chromatin by ZFP-1 (similarly to DOT1L recruitment by AF10 in mammals), and this complex negatively modulates transcription. Interestingly, promoters of ZFP-1/DOT-1.1 target genes are enriched in E-boxes, the consensus binding motif for c-Myc. Prompted by the exciting hypothesis that DOT-1.1 and MML-1, the C. elegans c-Myc homologue, cooperate genome-wide, we profiled gene expression in wild-type worms and dot-1.1(gk105059), zfp-1(ok554), and mml-1(gk402844) loss-of-function mutants by microarray. We found significant overlaps between genes upregulated in the three mutants, and the same was observed for downregulated genes. A significant global increase of non-coding transcripts was observed in either mutant compared with wild-type. Therefore, ZFP-1/DOT-1.1 and MML-1 co-regulate both coding and non-coding genes and globally inhibit non-coding transcription. Further investigation is underway to uncover the mechanism of cooperation of ZFP-1/DOT-1.1 and MML-1. Profiling of gene expression in wild-type third larval stage (L3) larvae and zfp-1(ok554), dot-1.1(gk105059) and mml-1(gk402844) mutant worms.

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Genome-wide mapping of the heterochromatin mark H3K9me2 in loss-of-function mutant worms

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