An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression

Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelia...

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Published in:	Nature communications Vol. 13; no. 1; p. 7448
Main Authors:	Dinh, Thanh Theresa, Xiang, Menglan, Rajaraman, Anusha, Wang, Yongzhi, Salazar, Nicole, Zhu, Yu, Roper, Walter, Rhee, Siyeon, Brulois, Kevin, O’Hara, Ed, Kiefel, Helena, Dinh, Truc M., Bi, Yuhan, Gonzalez, Dalila, Bao, Evan P., Red-Horse, Kristy, Balogh, Peter, Gábris, Fanni, Gaszner, Balázs, Berta, Gergely, Pan, Junliang, Butcher, Eugene C.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-12-2022 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/106 13/109 13/31 13/51 13/89 14/19 38/15 38/90 49/39 49/88 49/91 631/136/16/1993 631/250/1619 631/337/572/2102 64/110 82/29 82/80 Arteries Basic Medicine Binding sites Biology Blood vessels Capillaries Carbohydrates Cell and Molecular Biology Cell Movement Cell- och molekylärbiologi Deoxyribonucleic acid DNA Drug dosages Endothelial Cells Endothelium Gene expression Homeobox Homing Homing behavior Humanities and Social Sciences Immunity Immunology Inflammation Intestine Leukocyte migration Lymphocytes Medical and Health Sciences Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper Morphogenesis Morphogenesis - genetics Mucosa multidisciplinary Mutation Nkx2.3 protein Phylogeny Proteins Regulatory sequences Science Science (multidisciplinary) Specialization Transcription factors Veins
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Summary:	Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelial venules (HEV), providing a prototypical example of organ- and segment-specific endothelial specialization. We identify conserved NKX-COUP-TFII composite elements (NCCE) in regulatory regions of Madcam1 and St6gal1 that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription. The Madcam1 element also integrates repressive signals from arterial/capillary Notch effectors. Pan-endothelial COUP-TFII overexpression induces ectopic addressin expression in NKX2-3 + capillaries, while NKX2-3 deficiency abrogates expression by HEV. Phylogenetically conserved NCCE are enriched in genes involved in neuron migration and morphogenesis of the heart, kidney, pancreas and other organs. Our results define an NKX-COUP-TFII morphogenetic code that targets expression of mucosal vascular addressins. Vascular addressins control lymphocyte homing, thus regulating immunity and inflammation, but how addressin expression is patterned remains unknown. Here the authors identify composite DNA elements (NCCEs) that bind NKX2 homeodomain proteins cooperatively with COUP-TFII to define a morphogenetic code that targets transcription of mucosal vascular addressins.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-34991-2