Histone Demethylase JARID1B Controls Mammary Gland Development by Regulating Key Developmental Genes

The jmjC-domain containing H3K4 histone demethylase JARID1B/KDM5B/PLU1 is over-expressed in human breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed a new strain of Jarid1b knockout mice and characterized the phenotypes in detail. Unlike previously reported knockout strains, the majority of our Jarid1b knockout mice are viable beyond embryonic and neonatal stages. Nonetheless, these mice exhibit decreased body weight, higher incidence of adult mortality and decreased female fertility. Furthermore, Jarid1b knockout mice show delayed mammary gland development. Mechanistically, loss of JARID1B leads to decreased serum estrogen levels and reduced proliferation of mammary epithelial cells in early puberty. In addition, in mammary epithelial cells, loss of JARID1B diminishes the expression of key regulators of mammary morphogenesis, including FOXA1, estrogen receptor (ER), and GATA3. Taken together, these results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms.

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Zou MR, Cao J, Liu Z, Huh SJ, Polyak K, Yan Q