Epigenetic analysis of murine normal mammary gland fibroblasts (mNFs) and MMTV-PyMT cancer-associated fibroblasts (mCAF1) (H3K27ac ChIP-seq)

TGFβ suppresses ASPA expression in fibroblasts, whereas ASPA restrains TGFβ-dependent myofibroblast conversion, ECM remodelling, angiogenesis and pro-tumoral macrophage phenotypes. TGFβ/SMAD3-dependent transcriptional repression may require the activity of histone deacetylases (HDACs), which participate in epigenetic rearrangements modulating gene expression. Epigenomic analysis of the 3’ regulatory regions at the Aspa locus in murine MMTV-PyMT-derived breast cancer CAFs (mCAF1) as compared to normal murine mammary gland fibroblasts (mNFs), revealed a selective loss of H3K27Ac, an epigenetic mark of active enhancers.

As expected, bona fide CAF marker genes such as Acta2, Fap, Lrrc15 and others presented increased H3K27Ac signal at regulatory regions in mCAF1, whereas peaks at NF marker genes (Cxcl1 and Pi16) were decreased. Our findings unveil ASPA expression in fibroblasts as a previously unknown gatekeeper of TGFβ responses and activation in cancer progression.