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Status |
Public on Jun 09, 2023 |
Title |
MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [epigenomics] |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
The histone variant macroH2A has been implicated as a tumor suppressor in melanoma and other cancers, yet its role in the tumor microenvironment remains unappreciated. Here we show that mice constitutively lacking macroH2A variants exhibit increased melanoma tumor burden compared to their wild-type counterparts, which is associated with an altered intratumoral immune cell compartment. MacroH2A-deficient tumors display an accumulation of immunosuppressive monocytes and decreased functional cytotoxic T cells. Consistent with this compromised anti-tumor response, macroH2A-deficient tumors displayed upregulation of chemokines such as Ccl2, Cxcl1 and Il6. Through single cell transcriptomics of the entire melanoma microenvironment, we identified the source of these pro-tumor myeloid chemoattractants as cancer-associated fibroblasts, whose frequency and activation were increased in the absence of macroH2A. Chemokine gene expression was hyper-inducible in the absence of macroH2A and accompanied by an altered epigenetic landscape. In sum, we uncovered a tumor suppressive role for macroH2A through repression of chemokine induction in the tumor stroma.
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Overall design |
Epigenomic analysis of sorted or cultured CAFs from WT and macroH2A melanomas was carried out to understand how macroH2A regulates inflammatory gene expression in this cell type. iDFs were used as a related cell type, developed individually, to validate these findings.
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Contributor(s) |
Filipescu D, Bernstein E |
Citation(s) |
37605008 |
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Submission date |
Apr 13, 2022 |
Last update date |
Sep 20, 2023 |
Contact name |
Dan Filipescu |
E-mail(s) |
dan.filipescu@mssm.edu
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Phone |
2128249265
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Organization name |
Icahn School of Medicine at Mount Sinai
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Department |
Oncological Sciences
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Lab |
Emily Bernstein
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Street address |
1470 Madison Ave
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City |
New York |
State/province |
New York |
ZIP/Postal code |
10029 |
Country |
USA |
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Platforms (1) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (13)
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GSM6042893 |
Mouse # 66624 CAF ATAC-seq |
GSM6042894 |
CAF culture from mouse # 66391 H3K27ac ChIP-seq |
GSM6042895 |
CAF culture from mouse # 66383 H3K27ac ChIP-seq |
GSM6042896 |
CAF culture genomic DNA input for ChIP-seq |
GSM6042897 |
CAF culture from mouse # 66391 macroH2A1 CUT&RUN prior to serum stimulation |
GSM6042898 |
CAF culture from mouse # 66391 macroH2A1 CUT&RUN 30 minutes after serum stimulation |
GSM6042899 |
CAF culture from mouse # 66391 IgG background for CUT&RUN |
GSM6042900 |
H3K27ac ChIP-seq in iDF dKO cells |
GSM6042901 |
H3K27ac ChIP-seq in iDF WT cells |
GSM6042902 |
iDF culture genomic DNA input for ChIP-seq |
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This SubSeries is part of SuperSeries: |
GSE200751 |
MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts. |
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Relations |
BioProject |
PRJNA826452 |