TY - JOUR
T1 - The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance
AU - Agger, Karl
AU - Nishimura, Koutarou
AU - Miyagi, Satoru
AU - Messling, Jan-Erik
AU - Rasmussen, Kasper Dindler
AU - Helin, Kristian
N1 - Copyright © 2019 American Society of Hematology.
PY - 2019/10/3
Y1 - 2019/10/3
N2 - KDM4/JMJD2 are H3K9- and H3K36-specific demethylases, which are considered promising therapeutic targets for the treatment of acute myeloid leukemia (AML) harboring MLL translocations. Here, we investigate the long-term effects of depleting KDM4 activity on normal hematopoiesis to probe potential side effects of continuous inhibition of these enzymes. Utilizing conditional Kdm4a/Kdm4b/Kdm4c triple-knockout mice, we show that KDM4 activity is required for hematopoietic stem cell (HSC) maintenance in vivo. The knockout of the KDM4 demethylases leads to accumulation of H3K9me3 on transcription start sites and the corresponding downregulation of expression of several genes in HSCs. We show that 2 of these genes, Taf1b and Nom1, are essential for the maintenance of hematopoietic cells. Taken together, our results show that the KDM4 demethylases are required for the expression of genes essential for the long-term maintenance of normal hematopoiesis.
AB - KDM4/JMJD2 are H3K9- and H3K36-specific demethylases, which are considered promising therapeutic targets for the treatment of acute myeloid leukemia (AML) harboring MLL translocations. Here, we investigate the long-term effects of depleting KDM4 activity on normal hematopoiesis to probe potential side effects of continuous inhibition of these enzymes. Utilizing conditional Kdm4a/Kdm4b/Kdm4c triple-knockout mice, we show that KDM4 activity is required for hematopoietic stem cell (HSC) maintenance in vivo. The knockout of the KDM4 demethylases leads to accumulation of H3K9me3 on transcription start sites and the corresponding downregulation of expression of several genes in HSCs. We show that 2 of these genes, Taf1b and Nom1, are essential for the maintenance of hematopoietic cells. Taken together, our results show that the KDM4 demethylases are required for the expression of genes essential for the long-term maintenance of normal hematopoiesis.
UR - http://www.scopus.com/inward/record.url?scp=85072945022&partnerID=8YFLogxK
U2 - 10.1182/blood.2019000855
DO - 10.1182/blood.2019000855
M3 - Article
C2 - 31434704
SN - 0006-4971
VL - 134
SP - 1154
EP - 1158
JO - Blood
JF - Blood
IS - 14
ER -