Histone Demethylase Jumonji AT-Rich Interactive Domain 1B (JARID1B) Controls Mammary Gland Development by Regulating Key Developmental and Lineage Specification Genes [Developmental Biology]

May 6th, 2014 by Zou, M. R., Cao, J., Liu, Z., Huh, S. J., Polyak, K., Yan, Q.

The JmjC-domain containing H3K4 histone demethylase JARID1B (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b-/- mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b-/- strains, the majority of these Jarid1b-/- mice are viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy. These Jarid1b-/- mice exhibit decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreases serum estrogen level and reduces mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminishes the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor α (ERα). Mechanistically, JARID1B is required for GATA3 recruitment to the Foxa1 promoter to activate Foxa1 expression. These results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms.
  • Posted in Journal of Biological Chemistry, Publications
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