Interplay between transcription regulators RUNX1 and FUBP1 activates an enhancer of the oncogene c-KIT and amplifies cell proliferation

  • Runt-related transcription factor 1 (RUNX1) is a well-known master regulator of hematopoietic lineages but its mechanisms of action are still not fully understood. Here, we found that RUNX1 localizes on active chromatin together with Far Upstream Binding Protein 1 (FUBP1) in human B-cell precursor lymphoblasts, and that both factors interact in the same transcriptional regulatory complex. RUNX1 and FUBP1 chromatin localization identified c-KIT as a common target gene. We characterized two regulatory regions, at +700 bp and +30 kb within the first intron of c-KIT, bound by both RUNX1 and FUBP1, and that present active histone marks. Based on these regions, we proposed a novel FUBP1 FUSE-like DNA-binding sequence on the +30 kb enhancer. We demonstrated that FUBP1 and RUNX1 cooperate for the regulation of the expression of the oncogene c-KIT. Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. These results reveal a new mechanism of action of RUNX1 that implicates FUBP1, as a facilitator, to trigger transcriptional regulation of c-KIT and to regulate cell proliferation. Deregulation of this regulatory mechanism may explain some oncogenic function of RUNX1 and FUBP1.

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Author:Lydie Debaize, Hélène Jakobczyk, Stéphane Avner, Jérémie Gaudichon, Anne-Gaëlle Rio, Aurélien A. Sérandour, Lena Dorsheimer, Frédéric Chalmel, Jason S. Carroll, Martin Zörnig, Michael A. RiegerORCiDGND, Olivier Delalande, Gilles Salbert, Marie-Dominique Galibert, Virginie Gandemer, Marie-Bérengère Troadec
URN:urn:nbn:de:hebis:30:3-485781
DOI:https://doi.org/10.1093/nar/gky756
ISSN:1362-4962
ISSN:0305-1048
ISSN:1362-4954
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30500954
Parent Title (English):Nucleic acids research
Publisher:Oxford Univ. Press
Place of publication:Oxford
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/11/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/12/27
Tag:Chromatin and Epigenetics; Gene Regulation
Volume:46
Issue:21
Page Number:15
First Page:11214
Last Page:11228
Note:
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
HeBIS-PPN:44648931X
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (English):License LogoCreative Commons - Namensnennung-Nicht kommerziell 4.0