The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

Karl Agger; Koutarou Nishimura; Satoru Miyagi; Jan-Erik Messling; Kasper Dindler Rasmussen; Kristian Helin

doi:10.1182/blood.2019000855

The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

Karl Agger, Koutarou Nishimura, Satoru Miyagi, Jan-Erik Messling, Kasper Dindler Rasmussen, Kristian Helin^*

^*Corresponding author af dette arbejde

DanStem

14 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Blood
Vol/bind	134
Udgave nummer	14
Sider (fra-til)	1154-1158
Antal sider	5
ISSN	0006-4971
DOI	https://doi.org/10.1182/blood.2019000855
Status	Udgivet - 3 okt. 2019

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10.1182/blood.2019000855

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title = "The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance",

abstract = "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.",

author = "Karl Agger and Koutarou Nishimura and Satoru Miyagi and Jan-Erik Messling and Rasmussen, {Kasper Dindler} and Kristian Helin",

note = "Copyright {\textcopyright} 2019 American Society of Hematology.",

year = "2019",

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doi = "10.1182/blood.2019000855",

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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

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.

U2 - 10.1182/blood.2019000855

DO - 10.1182/blood.2019000855

M3 - Journal article

C2 - 31434704

SN - 0006-4971

VL - 134

SP - 1154

EP - 1158

JO - Blood

JF - Blood

IS - 14

ER -

The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

Abstract

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