Abstract
AbstractRegulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication and contains eight genes and 20 candidate regulatory elements, including one super-enhancer.Caseingenes (Csn1s1,Csn2,Csn1s2a,Csn1s2b,Csn3) are expressed in mammary glands, induced 10,000-fold during pregnancy and account for 50% of mRNAs during lactation,Prr27andFdcspare salivary-specific andOdamhas dual specificity. We probed the function of 12 candidate regulatory elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression ofCsn3, Csn1s2b,OdamandFdcspbut largely dispensable forCsn1s1,Csn2andCsn1s2a.Csn3activation also requires its own local enhancer. Synergism between local enhancers and cytokine-responsive promoter elements facilitates activation ofCsn2during pregnancy. Our work identifies the regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements unique to mammary tissue.
Funder
Intramural Research Programs (IRPs) of National Institute of Diabetes and Digestive and Kidney Diseases
Intramural Research Programs (IRPs) of National Heart, Lung, and Blood Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Cited by
5 articles.
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