The SUMO Ligase Su(var)2-10 Controls Hetero- and Euchromatic Gene Expression via Establishing H3K9 Trimethylation and Negative Feedback Regulation

Abstract

Сhromatin is critical for genome compaction and gene expression. On a coarse scale, the genome is divided into euchromatin, which harbors the majority of genes and is enriched in active chromatin marks, and heterochromatin, which is gene-poor but repeat-rich. The conserved molecular hallmark of heterochromatin is the H3K9me3 modification, which is associated with gene silencing. We found that in Drosophila deposition of most of the H3K9me3 mark depends on SUMO and the SUMO-ligase Su(var)2-10, which recruits the histone methyltransferase complex SetDB1/Wde. In addition to repressing repeats, H3K9me3 also influences expression of both hetero-and euchromatic host genes. High H3K9me3 levels in heterochromatin are required to suppress spurious non-canonical transcription and ensure proper gene expression. In euchromatin, a set of conserved genes is repressed by Su(var)2-10/SetDB1-induced H3K9 trimethylation ensuring tissue-specific gene expression. Several components of heterochromatin are themselves repressed by this pathway providing a negative feedback mechanism to ensure chromatin homeostasis.

SUMOylation in the control of cholesterol homeostasis

“…In the case of H4, SUMOylation increases its interaction with histone deacetylase HDAC1 and the heterochromatin protein 1 HP1γ, which is in agreement with a role for SUMO in transcriptional repression [34]. More recently, SUMO has been shown to be necessary for deposition of the H3K9me3 molecular hallmark of heterochromatin associated with gene silencing [35,36]. Furthermore, SUMO is required for piRNA-guided deposition of repressive chromatin marks necessary for transcriptional silencing [37].…”

Double-edged sword: The evolutionary consequences of the epigenetic silencing of transposable elements

“…The most obvious functional consequences of TEs' epigenetic effects that could impact host fitness is the perturbation of neighboring gene expression. Genetic manipulations that disrupted the epigenetic silencing of TEs result in a lowered enrichment of repressive epigenetic marks and increased expression of TE-neighboring genes in Drosophila [44,56], indicating that TE-mediated spreading of repressive marks reduces the expression of neighboring genes. Studies using individuals derived from natural populations suggest a similar picture.…”

A Small-RNA-Mediated Feedback Loop Maintains Proper Levels of 22G-RNAs in C. elegans

“…A recent study in Drosophila melanogaster that focused on the SUMO ligase Su(var)2–10, which links the piRNA-loaded Piwi complex to the silencing effector complex that induces H3K9me3 deposition at target loci, identified an autoregulatory feedback loop in which several factors involved in heterochromatin formation and maintenance were marked by H3K9me3 in a Su(var)2–10-dependent manner to maintain the proper ratio and boundaries of heterochromatin versus euchromatin ( Ninova et al, 2020 ). In addition, the loss of Su(var)2–10-dependent H3K9me3 at target gene loci resulted in spurious differential expression of isoforms or internal genes ( Ninova et al, 2020 ), similar to the spurious expression of sosi-1 and eri-6[e – f] we observed in mut-16 mutants. In yeast, a similar feedback mechanism was identified in which the H3K9 methyltransferase clr4 is suppressed by H3K9me3 to ensure there is not inappropriate spreading of heterochromatin ( Wang et al, 2015 ).…”