PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells

Abstract

Abstract. The four members of the JARID1/KDM5 family of proteins, a sub-group of the larger ARID (AT rich DNA binding domain) family, have been shown to demethylate trimethylated lysine 4 on histone 3 (H3K4me3), a chromatin mark associated with actively transcribed genes. In some lower organisms a single homologue of JARID1 is found, and functions of the four proteins found in mice and humans may be specific or overlapping. To investigate the function of the JARID1B protein we examined the effects of deletion of the gene in mice. Systemic knock out of Jarid1b resulted in early embryonic lethality, whereas mice not expressing the related Jarid1A gene are viable and fertile. A second mouse strain expressing a Jarid1b gene with the ARID domain deleted was viable and fertile but displayed a mammary phenotype, where terminal end bud development and side branching was delayed at puberty and in early pregnancy. Since development of terminal end buds are completely dependent on signalling from the estrogen receptor (ERα), we investigated the expression of a target gene (progesterone receptor) in the ∆ARID mouse and found levels to be reduced as compared to wild-type. JARID1B is widely expressed in ER + breast cancers and breast cancer cell lines, and interaction with ERα was demonstrated by co-immunoprecipitations in cells transfected with tagged ERα and JARID1B genes. Down-regulation of expression of JARID1B using shRNAi in MCF-7 cells resulted in a dramatic decrease in E2 stimulated tumour growth in nude mice. The data demonstrate a specific role for Jarid1B in early embryonic development, in the development and differentiation of the normal mammary gland, and in estrogen induced growth of ER + breast cancer.

Epigenomics of mammary gland development

“…Complete and functional JARID1B knock-out mice have defects in pubertal mammary gland development, including a reduced number of TEBs, less side branching, and impaired ductal elongation [57, 58]. JARID1B mRNA is expressed in both murine basal and luminal lineages (Holliday et al, unpublished data) and seems to be important for rapid epithelial cell proliferation during puberty but not in alveolar development during pregnancy since JARID1B knock-out mice are able to produce milk [58].…”

“…Zou et al [58] observed co-binding of JARID1B and the luminal transcription factor GATA3 at the Foxa1 and Stat5a promoters and loss of GATA3 binding in JARID1B knock-out mammary epithelial cells, arguing that JARID1B and GATA3 can act co-operatively to mediate transcription. JARID1B has also been shown to interact with oestrogen receptor (ER)α in the COS-7 cell line [57]. However, this has not been validated in mammary epithelial cells.…”

Disrupted Intricacy of Histone H3K4 Methylation in Neurodevelopmental Disorders

“…Knockdown of KDM5B in mESCs resulted in failure to differentiate to neurons, whereas knockout in mouse neural stem cells (mNSCs) revealed that loss of KDM5B at this later stage does not affect differentiation to mature neurons [91,92]. Knockout of KDM5B in mouse is embryonic lethal [93], and, remarkably, overexpression also leads to impaired neural differentiation [90]. This suggests tight control of this demethylase is critical for cell fate determination.…”

Cancer and Altered Metabolism: Potential Importance of Hypoxia-Inducible Factor and 2-Oxoglutarate-Dependent Dioxygenases

“…PLU-1 is frequently overexpressed in breast cancer and downregulation of PLU-1 impairs breast cancer growth in vivo (Barrett et al 2002; Catchpole et al 2011). Similarly, PLU-1 is overexpressed in bladder and lung cancer where its inhibition leads to apoptosis (Hayami et al 2010).…”