Epigenetic mechanisms underlie the crosstalk between growth factors and a steroid hormone [HCT RNA-Seq]

Growth factors (GFs) suppression by steroid hormones recurs in embryology and is co-opted in pathology. While studying mammary cell migration, which is stimulated by GFs and antagonized by glucocorticoids (GCs), we found that GCs inhibit positive feedback loops activated by GFs and stimulate the reciprocal negative loops. Although no alterations in DNA methylation accompany the transcriptional events instigated by either stimulus, forced demethylation of distal regions broadened the repertoire of inducible genes. Our data indicate that the crosstalk involve transcription factors like p53 and NF-kB, along with reduced pausing (and traveling) of RNA polymerase II (RNAPII) at the promoters (and bodies) of GF-inducible genes. In addition, while GFs hyper-acetylated chromatin at unmethylated promoters and enhancers of genes involved in motility, GCs hypo-acetylated the corresponding regions. In conclusion, stably unmethylated genomic regions that encode feedback regulatory modules and differentially recruit RNAPII and acetylases/deacetylases underlie suppression of growth factor signaling by glucocorticoids. Overall design: RNA-Seq – EGF treatemnt for 60 min of WT and DNMT1a and DNMT3b double-knockout HCT116 cells

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Enuka Y, Feldman ME, Chowdhury A, Srivastava S, Lindzen M, Sas-Chen A, Massart R, Cheishvili D, Suderman MJ, Zaltsman Y, Mazza CA, Shukla K, Körner C, Furth N, Lauriola M, Oren M, Wiemann S, Szyf M, Yarden Y