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A cytokine-responsive promoter is required for distal enhancer function mediating the hundreds-fold increase in milk protein gene expression during lactation

Research Square
2023
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Article Description

During lactation, specialized cells in the mammary gland produce milk to nourish the young. Milk protein genes are controlled by distal enhancers activating expression several hundred-fold during lactation. However, the role of promoter elements is not understood. We addressed this issue using the Csn2 gene, which accounts for 10% of mRNA in mammary tissue. We identified STAT5 and other mammary transcription factors binding to three distal candidate enhancers and a cytokine-response promoter element. While deletion of the enhancers or the introduction of an inactivating mutation in a single promoter element had a marginable effect, their combined loss led to a 99.99% reduction of Csn2 expression. Our findings reveal the essential role of a promoter element in the exceptional activation of a milk protein gene and highlight the importance of analyzing regulatory elements in their native genomic context to fully understand the multifaceted functions of enhancer clusters and promoters.

Bibliographic Details

Lothar Hennighausen; Hye Kyung Lee; Chengyu Liu

Research Square Platform LLC

Biochemistry, Genetics and Molecular Biology; Immunology and Microbiology; Medicine; Neuroscience; Psychology; Dentistry

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