Abstract
Deposition of histone H3 lysine 4 (H3K4) methylation at promoters is catalyzed by the SET1/COMPASS complex and is associated with context-dependent effects on gene expression and local changes in chromatin organization. The role of SET1/COMPASS in shaping chromosome architecture has not been investigated. Here we used Caenorhabditis elegans to address this question through a live imaging approach and genetic analysis. Using quantitative FRET (Förster resonance energy transfer)-based fluorescence lifetime imaging microscopy (FLIM) on germ cells expressing histones eGFP-H2B and mCherry-H2B, we find that SET1/COMPASS influences meiotic chromosome organization, with marked effects on the close proximity between nucleosomes. We further show that inactivation of set-2, encoding the C. elegans SET1 homologue, or CFP-1, encoding the chromatin targeting subunit of COMPASS, enhances germline chromosome organization defects and sterility of condensin-II depleted animals. set-2 loss also aggravates germline defects resulting from conditional inactivation of topoisomerase II, another structural component of chromosomes. Expression profiling of set-2 mutant germlines revealed only minor transcriptional changes, suggesting that the observed effects are at least partly independent of transcription. Altogether, our results are consistent with a role for SET1/COMPASS in shaping meiotic chromosomes in C. elegans, together with the non-histone proteins condensin-II and topoisomerase. Given the high degree of conservation, our findings expand the range of functions attributed to COMPASS and suggest a broader role in genome organization in different species.
Highlights
The spatial configuration of chromatin is essential to ensure fundamental processes from gene expression to cell divisions [1], but how higher-order structures are formed in various cellular processes remains unclear
In chromosome organization, we found that loss of either set-2 or cfp-1 enhanced chromatin compaction defects in germ cells depleted of condensin-II, a major regulator of chromosome structure [24]
Nanoscale Chromatin Compaction Is Decreased in Set-2 Mutant Germlines
Summary
The spatial configuration of chromatin is essential to ensure fundamental processes from gene expression to cell divisions [1], but how higher-order structures are formed in various cellular processes remains unclear. Mitosis and meiosis are essential cellular functions that require restructuring and reorganization of chromatin architecture, and are both associated with specific changes in histone modifications. Specific histone PTMs, including H3 lysine-4 tri-methylation (H3K4me3), are associated with meiotic double strand breaks (DSBs) during recombination, and are dynamically. During mammalian spermatogenesis a large fraction of the observed dynamic changes in H3K4me do not coincide with either gene promoters, or double strand breaks (DSBs) [5], suggesting additional functions. Levels of COMPASS-dependent H3K4 methylation generally correlate with mRNA levels, but evidence for an instructive role for H3K4me in transcription is lacking, and recent data suggest that its function depends on different chromatin and cellular contexts [8]
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