Mammary genetic islands: permission denied to cross the border

Authors

• KH Yoo
• CM Yang
• S Oh
• L Hennighausen

Abstract

A most astounding feature of mammary-specific genetic islands is their absolute insulation from neighboring loci. The premier Wap locus contains a single gene encoding 15% of the RNA in lactating tissue. This extraordinary high expression level is governed by enhancers that are controlled by common transcription factors, most notable the cytokine-inducible STAT5. However, the dominance of these TFs does not spread beyond the borders of the Wap island as outside genes are not significantly expressed in mammary tissue. Moreover, regulatory switches governing outside genes do not cross over to the Wap locus, as evidenced by its complete silence in non-mammary cells. Chromatin loops have been invoked in explaining controlled gene regulation, but genetic evidence is scarce. In particular, CTCF has been proposed as an insulator protein that contributes to the establishment of functional three-dimensional chromatin structures. This study has tested the possibility that the establishment and function of mammary genetic loci is dependent CTCF sites and the formation of chromatin loops to also prevents spillover of transcriptional control to neighboring genes. The Wap island is characterized by key mammary-specific enhancers that are activated during pregnancy, low H3K27me3 occupancy and six CTCF binding sites, four of which are between tissues and two specific to mammary tissue. Moreover, ChIA-pet experiments suggest the presence of a chromatin loop initiating at the 5’ end of the Wap gene. The importance of CTCF sites in the establishment and regulation of the Wap island was investigated in mice from which they were deleted using CRISPR/CAS9.

Scientific Focus Area: Genetics and Genomics

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