Abstract
The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (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 were 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 exhibited decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreased serum estrogen level and reduced mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminished the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor α. Mechanistically, JARID1B was 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.
Highlights
Histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) is a potential oncoprotein, but its in vivo roles are not well understood
These results indicate that deletion of Jarid1b using this strategy results in the loss of full-length JARID1B mRNA and protein
Consistent with a previous study showing that the master luminal lineage regulator GATA3 binds the Foxa1 promoter to enhance Foxa1 expression in mammary glands [32], we identified several potential GATA3 binding sites near 1.6 kb and another at 0.77 kb upstream of Foxa1 transcriptional start site (TSS) based on the known GATA3 DNA binding motif (Fig. 8A)
Summary
Histone demethylase JARID1B is a potential oncoprotein, but its in vivo roles are not well understood. A strain of Jarid1bϪ/Ϫ mice generated using a different targeting construct showed neonatal lethality due to abnormal respiratory function as well as skeletal and neuronal development defects [19] These defects were linked to the accumulation of H3K4me and activation of neural master regulators like Pax and Otx2 [19]. Another mouse strain that expresses JARID1B with ARID deletion (⌬ARID) exhibited a largely normal phenotype with the exception of delayed mammary gland development [12]. We showed that JARID1B facilitated GATA3 recruitment to the promoter of genes involved in mammary development and activated their transcription These findings revealed the critical roles of an epigenetic regulator in modulating the female reproductive system and maturation of the mammary epithelium during pubertal development
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