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

Dorota Skowronska-Krawczyk, Qi Ma, Michal Schwartz, Kathleen Scully, Wenbo Li, Zhijie Liu, Havilah Taylor, Jessica Tollkuhn, Kenneth A. Ohgi, Dimple Notani, Yoshinori Kohwi, Terumi Kohwi-Shigematsu, Michael G. Rosenfeld

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)257-261
Number of pages5
JournalNature
Volume514
Issue number7521
DOIs
StatePublished - Oct 9 2014

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Required enhancer-matrin-3 network interactions for a homeodomain transcription program'. Together they form a unique fingerprint.

Cite this