Do chromatin loops and CTCF binding sites control hormone-regulated mammary-specific genetic islands?

Authors

• CM YANG
• KH Yoo
• S Oh
• C Wang
• L Hennighausen

Abstract

We are addressing the question whether chromatin loops induced by CTCF are critical for the extraordinary hormone-regulated expression of mammary-specific genetic loci in mice. The casein locus with its five genes accounts for ~80% of the entire mRNA population in lactating mammary tissue. In addition to an unprecedented transcriptional activation during pregnancy, this locus also displays extremely tight cell specificity. Neighboring genes are not active in mammary tissue and casein genes are not expressed in other cell types at any significant levels. This suggests the presence of genetic boundaries and chromatin features that isolate this island from outside influences and also prevent spillover to neighboring genes. Expression of genes is not only regulated by transcription factors (TFs), but also by the establishment of permissive chromatin. CCCTC-binding factor (CTCF) has been identified as a transcriptional regulator and a core architectural protein in establishing chromatin loops. It can control chromatin organization with structural maintenance of chromosomes (SMC) proteins that possibly influence the expression of tissue specific genes. In a quest to understand the significance of an ordered, and possibly cell-specific, chromatin structures in the regulation of the casein island, we used ChIP-seq and identified five CTCF binding sites, three specific to mammary tissue and two shared with other cell types. To understand their functions in regulating the mammary-specific and the juxtaposed salivary-specific loci, we employed CRISPR/CAS9 gene editing to eliminate individual CTCF binding sites. Structural consequences and their significance on the tissue-specific and hormone regulation of these loci were examined.

Scientific Focus Area: Genetics and Genomics

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