Required enhancer-matrin-3 network interactions for a homeodomain transcription program

Skowronska-Krawczyk, D., Ma, Q., Schwartz, M., Scully, K., Li, W., Liu, Z., Taylor, H., Tollkuhn, J., Ohgi, K. A., Notani, D., Kohwi, Y., Kohwi-Shigematsu, T., Rosenfeld, M. G. (2014) Required enhancer-matrin-3 network interactions for a homeodomain transcription program. Nature, 514 (7521). pp. 257-61. ISSN 1476-4687 (Electronic)0028-0836 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/25119036
DOI: 10.1038/nature13573

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 beta-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 beta-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 beta-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/beta-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.

Item Type: Paper
Uncontrolled Keywords: Animals Cells, Cultured Enhancer Elements, Genetic/ genetics Gene Expression Regulation, Developmental Homeodomain Proteins/genetics/ metabolism Humans Matrix Attachment Region Binding Proteins/metabolism Mice Nuclear Matrix-Associated Proteins/ metabolism Pituitary Gland/embryology/metabolism Protein Binding RNA-Binding Proteins/ metabolism Transcription Factor Pit-1/genetics/metabolism Transcription, Genetic/genetics beta Catenin/metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > homeodomain protein
CSHL Authors:
Communities: CSHL labs > Tollkuhn lab
Depositing User: Matt Covey
Date Deposited: 23 Jul 2015 19:17
Last Modified: 23 Jul 2015 19:17
PMCID: PMC4358797
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31654

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