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

Karl Agger (Lead / Corresponding author), Koutarou Nishimura, Satoru Miyagi, Jan-Erik Messling, Kasper Dindler Rasmussen, Kristian Helin (Lead / Corresponding author)

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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 hematopoietic stem cells. We show that two of these genes, Taf1band 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.

Original languageEnglish
Number of pages14
JournalBlood
Early online date21 Aug 2019
DOIs
Publication statusE-pub ahead of print - 21 Aug 2019

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Histone Demethylases
Hematopoiesis
Hematopoietic Stem Cells
Stem cells
Genes
Maintenance
Gene Expression
Transcription Initiation Site
Essential Genes
Acute Myeloid Leukemia
Knockout Mice
Down-Regulation
Enzymes
Therapeutics

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Agger, Karl ; Nishimura, Koutarou ; Miyagi, Satoru ; Messling, Jan-Erik ; Rasmussen, Kasper Dindler ; Helin, Kristian. / The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance. In: Blood. 2019.
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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 hematopoietic stem cells. We show that two of these genes, Taf1band 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.",
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The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance. / Agger, Karl (Lead / Corresponding author); Nishimura, Koutarou; Miyagi, Satoru; Messling, Jan-Erik; Rasmussen, Kasper Dindler; Helin, Kristian (Lead / Corresponding author).

In: Blood, 21.08.2019.

Research output: Contribution to journalArticle

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T1 - The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

AU - Agger, Karl

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AU - Helin, Kristian

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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 hematopoietic stem cells. We show that two of these genes, Taf1band 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.

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