The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance
The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance
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DOI：
10.1182/blood.2019000855
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发表时间：
2019-10-03
期刊：
影响因子：
20.3
通讯作者：
Helin, Kristian
中科院分区：
文献类型：
--
作者：
Agger, Karl;Nishimura, Koutarou;Helin, Kristian
KDM 4/JMJD 2是H3 K9和H3 K36特异性脱甲基酶，其被认为是治疗携带MLL易位的急性髓性白血病（AML）的有前景的治疗靶点。在这里，我们研究了消耗KDM 4活性对正常造血的长期影响，以探索连续抑制这些酶的潜在副作用。利用条件Kdm 4a/Kdm 4 b/Kdm 4c三重敲除小鼠，我们表明，KDM 4的活性所需的造血干细胞（HSC）的维持在体内。敲除KDM 4脱甲基酶导致H3 K9 me 3在转录起始位点上的积累和HSC中几个基因表达的相应下调。我们发现，这些基因中的2个，Taf 1b和Nom 1，是维持造血细胞所必需的。两者合计，我们的研究结果表明，KDM 4脱甲基酶的基因表达所需的长期维持正常的造血。
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.