Vitamin C–dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

Zhang, Tian; Huang, Ke; Zhu, Yanling; Wang, Tianyu; Shan, Yongli; Liang, Bing; Li, Yuhang; Chen, Qianyu; Wang, Pengtao; Zhao, Songqing; Li, Dongwei; Wu, Chuman; Kang, Baoqiang; Gu, Jiaming; Mai, Yuchan; Wang, Qing; Li, Jinbing; Zhang, Yanqi; Liang, Zechuan; Guo, Lin; Wu, Fang; Su, Shuquan; Wang, Junwei; Gao, Minghui; Zhong, Xiaofen; Liao, Baojian; Chen, Jiekai; Zhang, Xiao; Shu, Xiaodong; Pei, Duanqing; Nie, Jinfu; Pan, Guoshun

doi:10.1074/jbc.ra119.009757

Cited by 40 publications

(47 citation statements)

References 48 publications

(52 reference statements)

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“…However, VC restored these abnormal epigenetic alterations in MC-LR-exposed oocytes. This confirmed that VC can act as an epigenetic regulator to enhance cell functions ( Zhang T. et al, 2019 ). Moreover, considering that changes in ATP levels correlate with the dysfunction of mitochondria present in MC-LR-exposed oocytes ( Yu et al, 2010 ), we concluded that disturbed cytoskeleton, abnormal epigenetics, and dysfunctional mitochondria were the reasons for the meiosis failure in MC-LR-exposed oocytes.…”

Section: Discussionsupporting

confidence: 65%

Vitamin C Protects Porcine Oocytes From Microcystin-LR Toxicity During Maturation

Zhang

Zhou

et al. 2020

Front. Cell Dev. Biol.

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Microcystin-leucine arginine (MC-LR) is the most toxic cyanotoxin found in water bodies. Microcystins are produced as secondary products of cyanobacteria metabolism. They have a stable structure, and can bioaccumulate in living organisms. Humans and livestock who drink fresh water containing MC-LR can be poisoned. However, few studies have reported the effects of MC-LR exposure on livestock or human reproduction. In this study, we used porcine oocytes as a model to explore the effects of MC-LR on oocyte maturation, and studied the impact of vitamin C (VC) administration on MC-LR-induced meiosis defects. Exposure to MC-LR significantly restricted cumulus cell expansion and decreased first polar body extrusion. Further studies showed that MC-LR exposure led to meiosis arrest by disturbing cytoskeleton dynamics with MC-LR exposed oocytes displaying aberrant spindle organization, low levels of acetylate α-tubulin, and disturbed actin polymerization. Additionally, MC-LR exposure impaired cytoplasmic maturation by inducing mitochondria dysfunction. Moreover, MC-LR also produced abnormal epigenetic modifications, and induced high levels of oxidative stress, caused DNA damage and early apoptosis. The administration of VC provided partial protection from all of the defects observed in oocytes exposed to MC-LR. These results demonstrate that MC-LR has a toxic effect on oocyte meiosis through mitochondrial dysfunction-induced ROS, DNA damage and early apoptosis. Supplementation of VC is able to protect against MC-LR-induced oocyte damage and represents a potential therapeutic strategy to improve the quality of MC-LR-exposed oocytes.

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Section: Discussionsupporting

confidence: 65%

Vitamin C Protects Porcine Oocytes From Microcystin-LR Toxicity During Maturation

Zhang

Zhou

et al. 2020

Front. Cell Dev. Biol.

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“…Given the therapeutic potential of blood and the immune cells such as NK and T cells, the generation of definitive multi-potent HSPCs in vitro, particularly from human PSCs has been a long-sought goal. However, HPCs derived from hPSCs have very limited potential in generating multiple blood lineages, particularly a very limited lymphoid potential 23,24,27,28 . During early hematopoietic development, the lymphoid lineages are mainly generated through definitive hematopoiesis [14][15][16] .…”

Section: Discussionmentioning

confidence: 99%

“…In hPSC differentiation, hemogenic endothelial cells (HECs) express CD34 and CD31 and then show upregulated CD43 on the commitment of hematopoietic fate 22,[24][25][26] . CD43 has served as a marker to indicate hPSC-derived hematopoietic progenitors in many studies 23,24,27,28 . However, even though these CD43 + hPSC-derived HPCs could form various blood CFUs (colony-forming units), they have very limited definitive potency to give rise to immune cells 23,25 .…”

Section: Introductionmentioning

confidence: 99%

Characterization and generation of human definitive multipotent hematopoietic stem/progenitor cells

Zhu

Wang

et al. 2020

Cell Discov

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Definitive hematopoiesis generates hematopoietic stem/progenitor cells (HSPCs) that give rise to all mature blood and immune cells, but remains poorly defined in human. Here, we resolve human hematopoietic populations at the earliest hematopoiesis stage by single-cell RNA-seq. We characterize the distinct molecular profiling between early primitive and definitive hematopoiesis in both human embryonic stem cell (hESC) differentiation and early embryonic development. We identify CD44 to specifically discriminate definitive hematopoiesis and generate definitive HSPCs from hESCs. The multipotency of hESCs-derived HSPCs for various blood and immune cells is validated by single-cell clonal assay. Strikingly, these hESCs-derived HSPCs give rise to blood and lymphoid lineages in vivo. Lastly, we characterize gene-expression dynamics in definitive and primitive hematopoiesis and reveal an unreported role of ROCK-inhibition in enhancing human definitive hematopoiesis. Our study provides a prospect for understanding human early hematopoiesis and a firm basis for generating blood and immune cells for clinical purposes.

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“…in vitro 91 high expression of TET3 may be in cell culture 53,92 a positive prognostic marker. 97 in vitro 71 correlated with adverse outcome in cell culture 70 in male AML patients. Mutations in KDM6A associated with cytarabine resistance.…”

Section: Context 1 Heterozygous Mutations In Tet2mentioning

confidence: 93%

“…Mutations in KDM6A associated with cytarabine resistance. 68 in cell culture 70,94 involved in the regulation of HSC self-renewal, knockout impairs self-renewal. 114 DNA demethylation, and 5hmC may be an epigenetic mark with its own reader.…”

Section: Context 1 Heterozygous Mutations In Tet2mentioning

confidence: 99%

Emerging epigenetic therapeutics for myeloid leukemia: modulating demethylase activity with ascorbate

2020

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The past decade has seen a proliferation of drugs that target epigenetic pathways. Many of these drugs were developed to treat acute myeloid leukemia, a condition in which dysregulation of the epigenetic landscape is well established. While these drugs have shown promise, critical issues persist. Specifically, patients with the same mutations respond quite differently to treatment. This is true even with highly specific drugs that are designed to target the underlying oncogenic driver mutations. Furthermore, patients who do respond may eventually develop resistance. There is now evidence that epigenetic heterogeneity contributes, in part, to these issues. Cancer cells also have a remarkable capacity to ‘rewire’ themselves at the epigenetic level in response to drug treatment, and thereby maintain expression of key oncogenes. This epigenetic plasticity is a promising new target for drug development. It is therefore important to consider combination therapy in cases in which both driver mutations and epigenetic plasticity are targeted. Using ascorbate as an example of an emerging epigenetic therapeutic, we review the evidence for its potential use in both of these modes. We provide an overview of 2-oxoglutarate dependent dioxygenases with DNA, histone and RNA demethylase activity, focusing on those which require ascorbate as a cofactor. We also evaluate their role in the development and maintenance of acute myeloid leukemia. Using this information, we highlight situations in which the use of ascorbate to restore 2-oxoglutarate dependent dioxygenase activity could prove beneficial, in contrast to contexts in which targeted inhibition of specific enzymes might be preferred. Finally, we discuss how these insights could be incorporated into the rational design of future clinical trials.

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Vitamin C–dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

Abstract: The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1-S6 and Tables S1 and S2. The RNA-seq, ATAC-seq, and ChIP-seq data reported in this paper can be assessed under GEO GSE132970.

Cited by 40 publications

References 48 publications

Vitamin C Protects Porcine Oocytes From Microcystin-LR Toxicity During Maturation

Vitamin C Protects Porcine Oocytes From Microcystin-LR Toxicity During Maturation

Characterization and generation of human definitive multipotent hematopoietic stem/progenitor cells

Emerging epigenetic therapeutics for myeloid leukemia: modulating demethylase activity with ascorbate

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