Haensel-Hertsch, R. | Search bioRxiv

bioRxiv2023

Activation of automethylated PRC2 by dimerization on chromatin

Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit EZH2 stimulates its activity by an unknown mechanism. Here, we show that PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a novel mechanism mediating context- dependent activation of PRC2. Our work showcases the molecular mechanism of auto- modification coupled dimerization in the regulation of chromatin modifying complexes.

biochemistry↗

bioRxiv2023

G-quadruplex DNA structures mediate non-autonomous instruction of breast tumour microenvironments

Breast cancer is characterised by genetic and epigenetic alterations, such as G-quadruplex (G4) DNA secondary structures. Here, we uncover differentially enriched G4 structure-forming regions ({triangleup}G4Rs) and interlinked transcriptomes in the tumour microenvironment (TME) of breast cancer PDX models in vivo. We show that well-defined breast cancer cell models non-autonomously instruct {triangleup}G4Rs and transcriptomes in the epigenomes of primary macrophages in vitro. Mechanistically, we uncover that TNBC secretes, amongst other factors, glucocorticoids to promote G4-linked activation of octamer-binding transcription factor 1 (OCT-1) and thereby reprogramme macrophages into an immunosuppressed and immunosuppressive state. This epigenetic mechanism is of clinical importance since instructed macrophages selectively associate with the triple-negative breast cancer (TNBC) basal-like 2 (BL2) subtype and with the distinct TNBC molecular signature derived from 2,000 primary breast cancer samples. Altogether, our data suggest that G4 formation is not only prevalent in breast cancer genomes but relevant in their TMEs as well, which is of clinical importance for cancer stratification and the discovery of novel actionable drivers.

cancer biology↗