RUNX1 isoforms regulate RUNX1 and target genes differentially in platelets-megakaryocytes: association with clinical cardiovascular events.

Autor:	Guan L; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA., Voora D; Department of Medicine, Duke University, Durham, North Carolina, USA., Myers R; Duke Clinical Research Unit, Duke University School of Medicine, Durham, North Carolina, USA., Del Carpio-Cano F; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA., Rao AK; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA; Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA. Electronic address: koneti@temple.edu.
Jazyk:	angličtina
Zdroj:	Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2024 Dec; Vol. 22 (12), pp. 3581-3598. Date of Electronic Publication: 2024 Aug 23.
DOI:	10.1016/j.jtha.2024.07.032
Abstrakt:	Background: Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoters to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream gene regulation in megakaryocytes and platelets are unknown. Objectives: To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms. Methods: We performed studies on RUNX1 isoforms in megakaryocytic human erythroleukemia (HEL) cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD). Results: In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells, RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes (MYL9, F13A1, PCTP, PDE5A, and others) differentially in HEL cells. In platelets, RUNX1B transcripts (by RNA sequencing) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with F13A1, PCTP, PDE5A, RAB1B, and others, and negatively with MYL9. In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets F13A1 and RAB31 associated with acute events. Conclusion: RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner, and this is associated with acute events in CVD. Competing Interests: Declaration of competing interests There are no competing interests to disclose. (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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