Publication Date:
2014-08-15
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358797/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358797/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Skowronska-Krawczyk, Dorota -- Ma, Qi -- Schwartz, Michal -- Scully, Kathleen -- Li, Wenbo -- Liu, Zhijie -- Taylor, Havilah -- Tollkuhn, Jessica -- Ohgi, Kenneth A -- Notani, Dimple -- Kohwi, Yoshinori -- Kohwi-Shigematsu, Terumi -- Rosenfeld, Michael G -- CA173903/CA/NCI NIH HHS/ -- DK018477/DK/NIDDK NIH HHS/ -- DK039949/DK/NIDDK NIH HHS/ -- HL065445/HL/NHLBI NIH HHS/ -- NS034934/NS/NINDS NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P30 NS047101/NS/NINDS NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS048243/NS/NINDS NIH HHS/ -- R37 CA039681/CA/NCI NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 9;514(7521):257-61. doi: 10.1038/nature13573. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; 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. ; Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119036" target="_blank"〉PubMed〈/a〉
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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