Nucleosome-scale p53-hormone receptor grammar distributed by Alu elements

The tumor suppressor p53 and the transcription factors estrogen receptor and androgen receptor regulate growth in a sex-dependent hormone-responsive manner, as in breast and prostate tumors and muscle tissue. Using a model of transcriptional regulation, we investigated co-regulation between p53 and hormone receptors in different cellular contexts and highlight an enrichment in mammary and muscle cell types. Sequence, structural and epigenomic evidence demonstrate a broadly distributed functional 73-bp p53-estrogen receptor grammar spanning nucleosome entry/exit to dyad, while p53-androgen receptor grammar spans 146 bp. At a functional breast cancer enhancer regulating Cyclin D, varied spacing led to lower predicted p53 binding. Genome-wide analysis found a major role of Alu sequences in distributing this grammar, in particular in mTORC1 pathway genes, with an evolutionary association of primate body-size sexual dimorphism and muscle aging.