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A genomic address code directs assembly and function of NKX2‐3:COUP‐TFII complexes that drive organotypic expression of the mucosal vascular addressin
Author(s) -
Dinh Theresa
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02535
Subject(s) - addressin , microbiology and biotechnology , transcription factor , biology , notch signaling pathway , homeobox , high endothelial venules , cancer research , genetics , gene , signal transduction , cell adhesion , endothelium , cell
The m ucosal vascular ad dressin c ell‐ a dhesion m olecule 1 (MAdCAM1) is selectively displayed by intestinal postcapillary and high endothelial venule sites of immune cell recruitment from the blood. It serves as a gatekeeper for lymphocyte entry and is a therapeutic target for inflammatory bowel disease, yet the molecular mechanisms underlying its targeted expression remain unclear. We describe a phylogenetically conserved genomic element within the Madcam1 promoter that integrates intestinal (homeodomain protein Nkx2‐3), capillary/arterial (repressive effector proteins of the Notch signaling pathway), and venule‐selective (COUP‐TFII) transcription regulatory mechanisms with inflammatory (NfkB‐dependent) signals to direct MAdCAM1 expression. The regulatory motif cooperatively binds Nkx2‐3 and COUP‐TFII to activate transcription from the Madcam1 promoter. Heterodimer formation is DNA dependent and is mediated by the Nkx2‐3 tinman domain. The Notch downstream repressor Hey1 competes for binding of NKX2‐3, and Notch signaling and Hey1 overexpression suppress promoter activity and Madcam1 induction in endothelial cells. Pan‐endothelial overexpression of COUP‐TFII counters Hey1 repression and drives ectopic MAdCAM1 in Nkx2‐3+ intestinal capillaries. The results define a genomic address code for MAdCAM1 expression and control of lymphocyte homing via intestinal venules. Finally, we identify similar composite elements in genes involved in cardiovascular and neuronal development, suggesting a mechanism for combinatorial regulation of organogenesis by COUP‐TFII and NXK2 family members.