Biology subjects

Hoehne, M. N.

Publications and source records attributed to Hoehne, M. N..

3 recordsLinked to original sources

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↗

bioRxiv2021

Thioredoxin reductase controls the capacity of peroxiredoxins to limit mitochondrial H2O2 release

H2O2 performs central roles in signaling at physiological levels, while at elevated levels it causes molecular damage. Mitochondria are major producers of H2O2, which has been implied in regulating diverse processes inside and outside the organelle. However, it still remains unclear whether and how mitochondria in intact cells release H2O2. Here we employed the genetically encoded high-affinity H2O2 sensor HyPer7 in mammalian tissue culture cells to investigate different modes of mitochondrial H2O2 release. We found substantial heterogeneity of HyPer7 dynamics between individual cells, and observed H2O2 released from mitochondria directly at the surface of the organelle and in the bulk cytosol, but not in the nucleus nor on the plasma membrane, pointing to steep gradients emanating from mitochondria. These gradients are controlled by cytosolic peroxiredoxins that act redundantly and are present with a substantial reserve capacity. Furthermore, dynamic adaptation of cytosolic thioredoxin reductase levels during metabolic changes results in improved H2O2 handling and explains previously observed cell-to-cell differences. Thus, our data indicate that H2O2-mediated signaling likely occurs close to mitochondria during specific metabolic conditions. HIGHLIGHTSO_LIMitochondrial H2O2 can be detected in the cytosol in intact human cells C_LIO_LIMitochondrial H2O2 gradients are steep and controlled by peroxiredoxins 1 and 2 C_LIO_LIPeroxiredoxins 1 and 2 complement for each other C_LIO_LIPeroxiredoxins 1 and 2 are present with a substantial reserve capacity C_LIO_LIMetabolism-induced changes of reducing processes control peroxiredoxin activity C_LI

biochemistry↗