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Series GSE237390 Query DataSets for GSE237390
Status Public on Apr 24, 2024
Title Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3 [ChIP-seq]
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Histone 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 main driver of Kmt2c or Kmt2d KO-specific gene regulation. Although our datasets revealed more unique than shared signatures, we found Mmp3 being a common target upon Kmt2c or Kmt2d KO. Indeed, downregulation of Mmp3 reversed induction of Kmt2c and Kmt2d KO-dependent brain metastases. Finally, we found that Kdm6a knockdown reduces Mmp3 levels, again, leading to reduction of brain metastases of Kmt2c or Kmt2d KO cells.
 
Overall design We generated either Kmt2c or Kmt2d KO derivatives of the 168FARN an 67NR cell line using CRISPR/Cas9
Web link https://pubmed.ncbi.nlm.nih.gov/38926506/
 
Contributor(s) Seehawer M, Zheqi L, Nishida J, Foidart P, Reiter A, Rojas E, Goyette M, Cejas P, Goldman S, Adelman K, Long H, Papanastasiou M, Polyak K
Citation(s) 38926506
NIH grant(s)
Grant ID Grant title Affiliation Name
P01 CA250959 New therapeutic vulnerabilities in breast cancer DANA-FARBER CANCER INSTITUTE Kornelia Polyak
R35 CA197623 Targeting intratumor heterogeneity in breast cancer DANA-FARBER CANCER INSTITUTE Kornelia Polyak
Submission date Jul 14, 2023
Last update date Jul 24, 2024
Contact name Kornelia Polyak
E-mail(s) kornelia_polyak@dfci.harvard.edu
Phone 617-632-2106
Organization name Dana-Farber Cancer Institute
Department Medical Oncology
Lab Polyak
Street address 450 Brookline Ave
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (54)
GSM7610706 168_WT_H3K4me1_rep1
GSM7610707 168_WT_H3K4me1_rep2
GSM7610708 168_WT_H3K4me1_rep3
This SubSeries is part of SuperSeries:
GSE237392 Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3
Relations
BioProject PRJNA994871

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Supplementary file Size Download File type/resource
GSE237390_RAW.tar 7.7 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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