Synergistic lethality between BRCA1 and H3K9me2 loss reflects satellite derepression

Abstract

Caenorhabditis elegans has two histone H3 Lys9 methyltransferases, MET-2 (SETDB1 homolog) and SET-25 (G9a/ SUV39H1 related). In worms, we found simple repeat sequences primarily marked by H3K9me2, while transposable elements and silent tissue-specific genes bear H3K9me3. RNA sequencing (RNA-seq) in histone methyltransferase (HMT) mutants shows that MET-2-mediated H3K9me2 is necessary for satellite repeat repression, while SET-25 silences a subset of transposable elements and tissue-specific genes through H3K9me3. A genome-wide synthetic lethality screen showed that RNA processing, nuclear RNA degradation, the BRCA1/BARD1 complex, and factors mediating replication stress survival are necessary for germline viability in worms lacking MET-2 but not SET-25. Unlike set-25 mutants, met-2-null worms accumulated satellite repeat transcripts, which form RNA:DNA hybrids on repetitive sequences, additively with the loss of BRCA1 or BARD1. BRCA1/BARD1-mediated H2A ubiquitination and MET-2 deposited H3K9me2 on satellite repeats are partially interdependent, suggesting both that the loss of silencing generates BRCA-recruiting DNA damage and that BRCA1 recruitment by damage helps silence repeats. The artificial induction of MSAT1 transcripts can itself trigger damage-induced germline lethality in a wild-type background, arguing that the synthetic sterility upon BRCA1/BARD1 and H3K9me2 loss is directly linked to the DNA damage provoked by unscheduled satellite repeat transcription.

Caenorhabditis elegans Deficient in DOT-1.1 Exhibit Increases in H3K9me2 at Enhancer and Certain RNAi-Regulated Regions

“…Next, we used the coordinates of enhancer domains, either predicted based on a specific histone modification signature [46] or based on the open chromatin configuration, annotated using ATAC-seq [47], to evaluate the H3K9me2 levels at these potential regulatory regions. We found a depletion of H3K9me2 (Figure 1b), which is consistent with its preferential localization at repetitive elements [51,[56][57][58]. At the same time, ZFP-1 is enriched at enhancers (Figure 1b), as we reported earlier [4].…”

Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring

“…Hence the worm provides a unique opportunity to explore the functions of H3K9me in a metazoan. Eliminating H3K9me by disrupting the histone H3K9 methyltransferases does derepress repetitive DNA elements in germlines of adults and does cause accumulation of RNA:DNA hybrids at high growth temperatures, ultimately leading to genome instability and sterility (37)(38)(39).…”

“…5B) (P = 5 × −5 ), although the differences were much smaller. Transcription of repetitive sequences was affected by loss of H3K9me (37,38), but the inability to map repetitive reads uniquely prevented attribution of these changes to repeats in Arm versus Center compartments. To understand the mechanisms underlying the relative elevation in Arm gene expression in mutants, we asked whether the elevation resulted from 1) loss of heterochromatic marks having local effects on genes with H3K9me peaks in wild-type embryos (45,46), which are over-represented in Arm compartments (SI Appendix, Fig.…”

Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs

“…HR requires the function of ATM, but the level of ATM is low in GBM cells due to the high expression of miR-100 10,11 . The term synthetic lethality describes a phenomenon in which simultaneous perturbation of two (or more) functionally complementary genes results in loss of cell viability [12][13][14] . The application of PARP inhibitors as components in synthetic lethal treatments pioneered a promising clinical therapeutic strategy for breast cancers with mutations in BRCA1 or BRCA2 15 .…”