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Localization and function of histone methylation at active genes in "Drosophila"

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  • Biology

Abstract

In the eukaryotic nucleus, DNA is bound by an octamer of four core histones forming the fundamental repeating unit of chromatin, called the nucleosome. Presenting a barrier to virtually all DNA-templated events, nucleosomal packaging is subject to dynamic alterations. Nucleosomal histone modifications have emerged as a major determinant of chromatin structure and gene expression. Genome-wide and local profiling of chromatin structure in Drosophila cells reveals a complex landscape of histone methylation marks along the body of active genes. Methylation of lysine 4 and lysine 79 of histone H3 coincide at promoters and gradually decrease towards the 3’ end. Conversely, H3 lysine 36 methylation states show very different distribution patterns. Dimethylation of H3K36 peaks downstream of promoter-proximal K4 methylation, whereas trimethylation accumulates towards the 3’ end of genes. These topographic differences do not reflect deposition-coupled targeting by histone variant H3.3 but instead argue for discrete regulation and function of active methylation marks during transcription elongation. Indeed, H3K36 di- and trimethylation states rely on two distinct HMTs and display opposite effects on H4K16 acetylation at autosomal genes. This crosstalk is reminiscent of K36me3-dependent deacetylase recruitment in budding yeast, yet it is more intricate as dimethylation appears to signal for increased H4K16 acetylation. Apart from its autosomal function, H3K36me3 has a separate role to enhance H4K16 acetylation at the dosage-compensated X chromosome in male Drosophila cells. This additional function most likely involves MSL complex recruitment to dosage compensated genes. Together, our results reveal a complex pattern of histone methylation marks at active genes, which may enable dynamic chromatin changes during transcription elongation in higher eukaryotes. Furthermore, the context-dependent readout of H3K36me3 implies that methylation marks act as general signaling platforms, which impart their specificity by recruiting effector proteins to characteristic landmarks along the transcription unit.

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