GSE237287 Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3 [RNA-seq]

Contributors : Marco Seehawer ; Li Zheqi ; Jun Nishida ; Pierre Foidart ; Andrew Reiter ; Ernesto Rojas ; Marie-Anne Goyette ; Paloma Cejas ; Seth Goldman ; Karen Adelman ; Henry Long ; Malvina Papanastasiou ; Kornelia PolyakSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusHistone lysine methyltransferases KMT2C and KMT2D are among the most commonly mutated genes in the highly metastatic TNBC subtype of breast cancer. However, it is not known if mutations of either of these genes similarly effect epigenomic and transcriptomic landscape or if a specific downstream target might influence metastases. Here, we generated heterogenous Kmt2c or Kmt2d KO murine TNBC cell lines side-by-side and performed in vivo metastases assay in syngeneic immunocompetent mice. Deficiency for either Kmt2c or Kmt2d, both, induced brain metastases from formerly non-metastatic cells. scRNAseq showed activation of pro-inflammatory pathways but conversely also increase of immune checkpoint blocking genes. Interestingly, histone mass spectrometry revealed changes of H3K27 but not the main substrate H3K4. However, ChIPseq for both, H3K4 and H3K27 modifications showed significant changes compared to wildtype cells. Strikingly, genome occupancy of H3K27me3 was reduced while H3K27 demethylase KDM6A was enriched on genomes of KO cells. Integration with gene expression data revealed significant correlations with histone and KDM6A ChIPseq, identifying them as a ...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research