title: Required enhancer-matrin-3 network interactions for a homeodomain transcription program.
abstract: Homeodomain proteins, described 30 years ago, exert essential roles in development as regulators of target gene expression; however, the molecular mechanisms underlying transcriptional activity of homeodomain factors remain poorly understood. Here investigation of a developmentally required POU-homeodomain transcription factor, Pit1 (also known as Pou1f1), has revealed that, unexpectedly, binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture is a key event in effective activation of the Pit1-regulated enhancer/coding gene transcriptional program. Pit1 association with Satb1 (ref. 8) and β-catenin is required for this tethering event. A naturally occurring, dominant negative, point mutation in human PIT1(R271W), causing combined pituitary hormone deficiency, results in loss of Pit1 association with β-catenin and Satb1 and therefore the matrin-3-rich network, blocking Pit1-dependent enhancer/coding target gene activation. This defective activation can be rescued by artificial tethering of the mutant R271W Pit1 protein to the matrin-3 network, bypassing the pre-requisite association with β-catenin and Satb1 otherwise required. The matrin-3 network-tethered R271W Pit1 mutant, but not the untethered protein, restores Pit1-dependent activation of the enhancers and recruitment of co-activators, exemplified by p300, causing both enhancer RNA transcription and target gene activation. These studies have thus revealed an unanticipated homeodomain factor/β-catenin/Satb1-dependent localization of target gene regulatory enhancer regions to a subnuclear architectural structure that serves as an underlying mechanism by which an enhancer-bound homeodomain factor effectively activates developmental gene transcriptional programs.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Dorota
authors.initials: D
authors.lastname: Skowronska-Krawczyk
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA [2] The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Schwartz
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Scully
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Havilah
authors.initials: H
authors.lastname: Taylor
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tollkuhn
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Ohgi
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Dimple
authors.initials: D
authors.lastname: Notani
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kohwi
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
authors.forename: Terumi
authors.initials: T
authors.lastname: Kohwi-Shigematsu
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism; D051379:Mice; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D010902:Pituitary Gland / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism*; D050817:Transcription Factor Pit-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D036961:Matrix Attachment Region Binding Proteins; D034521:Nuclear Matrix-Associated Proteins; D016601:RNA-Binding Proteins; D050817:Transcription Factor Pit-1; D051176:beta Catenin; C494187:POU1F1 protein, human; C494185:Pou1f1 protein, mouse; C469541:Satb1 protein, mouse; C573692:matrin-3 protein, mouse