TY - JOUR
T1 - Required enhancer-matrin-3 network interactions for a homeodomain transcription program
AU - Skowronska-Krawczyk, Dorota
AU - Ma, Qi
AU - Schwartz, Michal
AU - Scully, Kathleen
AU - Li, Wenbo
AU - Liu, Zhijie
AU - Taylor, Havilah
AU - Tollkuhn, Jessica
AU - Ohgi, Kenneth A.
AU - Notani, Dimple
AU - Kohwi, Yoshinori
AU - Kohwi-Shigematsu, Terumi
AU - Rosenfeld, Michael G.
N1 - Funding Information:
Acknowledgements We thank M. Ghassemian for assistance with mass spectrometry; C. Nelson for cell culture assistance; J. Hightower for assistance with figures and manuscript preparation; T. Suter for help with images analysis. We acknowledge J. Santini and the UCSD Neuroscience Microscopy Shared Facility (Grant P30 NS047101) for imaging. These studies were supported by grants NS034934, DK039949, DK018477, HL065445, CA173903 to M.G.R. from NIH. D.S.-K. was supported by EMBO Long Term Fellowship, The Swiss National Science Foundation and The San Diego Foundation. M.G.R. is an Investigator with HHMI.
PY - 2014/10/9
Y1 - 2014/10/9
N2 - 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.
AB - 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.
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U2 - 10.1038/nature13573
DO - 10.1038/nature13573
M3 - Article
C2 - 25119036
AN - SCOPUS:84908318367
VL - 514
SP - 257
EP - 261
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7521
ER -