Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation
Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F.
American Society of Hematology (ASH)
Published 2018
American Society of Hematology (ASH)
Published 2018
| Publication Date: |
2018-01-12
|
|---|---|
| Publisher: |
American Society of Hematology (ASH)
|
| Print ISSN: |
0006-4971
|
| Electronic ISSN: |
1528-0020
|
| Topics: |
Biology
Medicine
|
| Keywords: |
Hematopoiesis and Stem Cells, Platelets and Thrombopoiesis
|
| Published by: |
| _version_ | 1836398746172129281 |
|---|---|
| autor | Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. |
| beschreibung | 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. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34 + hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets. |
| citation_standardnr | 6136845 |
| datenlieferant | ipn_articles |
| feed_id | 310 |
| feed_publisher | American Society of Hematology (ASH) |
| feed_publisher_url | http://www.hematology.org/ |
| insertion_date | 2018-01-12 |
| journaleissn | 1528-0020 |
| journalissn | 0006-4971 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | American Society of Hematology (ASH) |
| quelle | Blood |
| relation | http://www.bloodjournal.org/cgi/content/short/131/2/191?rss=1 |
| schlagwort | Hematopoiesis and Stem Cells, Platelets and Thrombopoiesis |
| search_space | articles |
| shingle_author_1 | Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. |
| shingle_author_2 | Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. |
| shingle_author_3 | Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. |
| shingle_author_4 | Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. |
| shingle_catch_all_1 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation Hematopoiesis and Stem Cells, Platelets and Thrombopoiesis 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. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34 + hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets. Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_2 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation Hematopoiesis and Stem Cells, Platelets and Thrombopoiesis 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. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34 + hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets. Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_3 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation Hematopoiesis and Stem Cells, Platelets and Thrombopoiesis 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. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34 + hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets. Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_4 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation Hematopoiesis and Stem Cells, Platelets and Thrombopoiesis 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. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34 + hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets. Li, Y., Jin, C., Bai, H., Gao, Y., Sun, S., Chen, L., Qin, L., Liu, P. P., Cheng, L., Wang, Q.-F. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_title_1 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation |
| shingle_title_2 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation |
| shingle_title_3 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation |
| shingle_title_4 | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation |
| timestamp | 2025-06-30T23:31:58.128Z |
| titel | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation |
| titel_suche | Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation |
| topic | W WW-YZ |
| uid | ipn_articles_6136845 |