The histone demethylase KDM6A controls the mammary luminal lineage through enzyme-independent mechanisms

Mammary ducts and alveoli are composed of basal and luminal cells, with the fate and differentiation of secreting cells being controlled by hormones through specific transcription factors. This study establishes the essential role of the histone H3 lysine 27 trimethylation (H3K27me3) demethylase KDM6A (UTX) in a balanced basal and luminal cell compartment. Disproportionate formation of basal cells in the absence of KDM6A resulted in disorganized mammary ducts and alveoli and lactation failure. Mutant luminal progenitors lost their distinctive transcription factor expression pattern and acquired basal characteristics leading to a preferential expansion of this lineage. The structure of mammospheres obtained from mutant progenitors suggested they were derived from basal progenitors. The genomic H3K27me3 landscape was unaltered in the absence of KDM6A suggesting demethylase-independent mechanisms. In support of this, mammary tissue developed normally in mice expressing a catalytically inactive KDM6A. This study demonstrated that mammary luminal progenitor cells rely on UTX to stably maintain their identity and thereby establish a balance of basal and luminal cells required for a functional mammary gland. Overall design: mRNA-seq in WT;MMTV-Cre (Control) and Kdm6af/f;MMTV-Cre(Kdm6a KO) at virgin. ChIP-seq for KDM6A, and NFIB in mammary tissues at virgin and KDM6A KO H3K27me3, H3K4me1, PR, and ER in mammary tissues at p13.