Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation.

Blood
Yueying LiQian-Fei Wang

Abstract

Megakaryocytes (MKs) in adult marrow produce platelets that play important roles in blood coagulation and hemostasis. Monoallelic mutations of the master transcription factor gene RUNX1 lead to familial platelet disorder (FPD) characterized by defective MK and platelet development. However, the molecular mechanisms of FPD remain unclear. Previously, we generated human induced pluripotent stem cells (iPSCs) from patients with FPD containing a RUNX1 nonsense mutation. Production of MKs from the FPD-iPSCs was reduced, and targeted correction of the RUNX1 mutation restored MK production. In this study, we used isogenic pairs of FPD-iPSCs and the MK differentiation system to identify RUNX1 target genes. Using integrative genomic analysis of hematopoietic progenitor cells generated from FPD-iPSCs, and mutation-corrected isogenic controls, we identified 2 gene sets the transcription of which is either up- or downregulated by RUNX1 in mutation-corrected iPSCs. Notably, NOTCH4 expression was negatively controlled by RUNX1 via a novel regulatory DNA element within the locus, and we examined its involvement in MK generation. Specific inactivation of NOTCH4 by an improved CRISPR-Cas9 system in human iPSCs enhanced megakaryopoiesis. Moreove...Continue Reading

References

Apr 30, 1999·Science·S Artavanis-TsakonasR J Lake
Mar 3, 2004·Nature Medicine·Brenda J Irvin, Scott W Hiebert
Sep 17, 2005·Genes & Development·Caroline Erter BurnsLeonard I Zon
Jan 29, 2008·Blood·Kenneth Kaushansky
Aug 9, 2008·The Journal of Biological Chemistry·Yusuke SatohYuzuru Kanakura
Sep 13, 2008·Cell Stem Cell·Thomas MercherD Gary Gilliland
Sep 19, 2008·Genome Biology·Yong ZhangX Shirley Liu
Nov 18, 2008·Experimental Hematology·Brent SullenbargerLarry C Lasky
Jul 28, 2009·Journal of Thrombosis and Haemostasis : JTH·Y Ikeda, Y Miyakawa
Aug 17, 2010·The International Journal of Developmental Biology·Gemma SwiersNancy A Speck
Aug 17, 2010·The International Journal of Developmental Biology·Anna BigasLluís Espinosa
Sep 11, 2010·Blood·Sonia Poirault-ChassacEvelyne Lauret
Aug 15, 2012·Proceedings of the National Academy of Sciences of the United States of America·Anthony E BoitanoPeter G Schultz
Sep 8, 2012·Nature·UNKNOWN ENCODE Project Consortium
Sep 8, 2012·Nature·Shane NephJohn A Stamatoyannopoulos
Apr 19, 2013·British Journal of Haematology·Varda R Deutsch, Aaron Tomer
Jun 12, 2013·Nature Biotechnology·Ken Garber
Jun 25, 2013·Cell Stem Cell·Philmo OhIannis Aifantis

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Citations

Apr 17, 2018·Human Molecular Genetics·Cui ZhangJinfu Wang
May 3, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Leila J NoetzliKellie R Machlus
Jul 28, 2019·Current Opinion in Hematology·Fred G Pluthero, Walter H A Kahr
Jan 13, 2018·Blood·Samir Taoudi
Dec 20, 2020·Cell Stem Cell·Hongtao WangJiaxi Zhou
Jul 21, 2021·Genomics, Proteomics & Bioinformatics·Zijuan XinXiangdong Fang

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