HMGN1 modulates estrogen-mediated transcriptional activation through interactions with specific DNA-binding transcription factors.

HMGN1, an abundant nucleosomal binding protein, can affect both the chromatin higher order structure and the modification of nucleosomal histones, but it alters the expression of only a subset of genes. We investigated specific gene targeting by HMGN1 in the context of estrogen induction of gene expression. Knockdown and overexpression experiments indicated that HMGN1 limits the induction of several estrogen-regulated genes, including TFF1 and FOS, which are induced by estrogen through entirely distinct mechanisms. HMGN1 specifically interacts with estrogen receptor alpha (ER alpha), both in vitro and in vivo. At the TFF1 promoter, estrogen increases HMGN1 association through recruitment by the ER alpha. HMGN1 S20E/S24E, although deficient in binding nucleosomal DNA, still interacts with ER alpha and, strikingly, still represses estrogen-driven activation of the TFF1 gene. On the FOS promoter, which lacks the ER alpha binding sites, constitutively bound serum response factor (SRF) mediates estrogen stimulation. HMGN1 also interacts specifically with SRF, but HMGN1 S20E/S24E does not. Consistent with the protein interactions, only wild-type HMGN1 significantly inhibits the estrogen-driven activation of the FOS gene. Mechanistically, the inhibition of estrogen induction of several ER alpha-associated genes, including TFF1, by HMGN1 correlates with decreased levels of acetylation of Lys9 on histone H3. Together, these findings indicate that HMGN1 regulates the expression of particular genes via specific protein-protein interactions with transcription factors at target gene regulatory regions.