Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration

Abstract

The transcription factors Signal Transducer and Activator of Transcription (STAT) 5A/B mediate prolactin-induced mammary development during pregnancy. However, it is not clear how the different processes, expansion and maturation of alveolar precursor cells and the differential induction of milk protein genes are regulated on a molecular level. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts mammary epithelial development during pregnancy and the regulation of target genes. The presence of only a single Stat5a or Stat5b allele was sufficient for the establishment of histologically undifferentiated alveolar units and two alleles permitted the execution of a differentiation program similar to that found with all four alleles. While one copy of Stat5 induced limited expression of target genes, two copies activated a lactation-like gene signature. Using ChIP-seq analyses on intact tissue under physiological conditions, we found that highly expressed and regulated genes were bound by STAT5 in their promoter proximal regions, whereas upstream binding had minor biological consequences. Remarkably, 80% of the genes bound by STAT5 in vivo were not under STAT5 control. RNA polymerase II intensity was directly proportional to STAT5 concentration only on STAT5 regulated genes providing mechanistic insight by which STAT5 activates mammary specific genes.

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

“…The expression of LALBA is also induced by increased milking frequency in bovine and caprine (21,154) and by the AA Lys and Met in primary bovine mammary cells (155), but it is decreased by mastitis in dairy cow and yak (126,150) and by feed restriction in the cow (62). It is well established that the promoter region of LALBA contains a STAT5 binding site, and the presence of STAT5 is essential for the expression of LALBA in mouse (178,245).…”

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

“…The trimmed single-end reads were mapped to the mouse reference genome mm9 using STAR aligner software (37). Transcript abundance was estimated using the Tuxedo tools (Cufflinks, Cuffmerge, Cuffquant, Cuffnorm, and Cuffdiff) as described earlier (38). Differential transcript expression between JAK1-knockout and control mice during the two developmental stages was determined by estimation of the number of fragments per kilobase of transcript per million mapped reads (FPKM).…”

Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms

“…Basal or luminal cells from the three mice were combined. Total RNA was extracted from the combined cells, and RNA-seq was performed and analyzed as previously described (36). A Star aligner was used to map RNA-seq data to the mouse reference genome mm9 (37).…”