Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells

Wei, Yue; Chen, Rui; Dimicoli, Sophie; Bueso‐Ramos, Carlos E.; Neuberg, Donna; Pierce, Sherry; Wang, Hui; Yang, Hui; Jia, Yu; Zheng, Hong; Fang, Zhihong; Nguyen, Martin; Gañán-Gómez, Irene; Ebert, Benjamin L.; Levine, Ross L.; Kantarjian, Hagop M.; Garcia‐Manero, Guillermo

doi:10.1038/leu.2013.91

Cited by 79 publications

(94 citation statements)

References 61 publications

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“…Similarly, previous work of a large-scale reverse genetic screen found that knockdown of jmjd3 promotes mature erythrocyte markers β-E3 expression at 17 hpf [55]. Consistently, Peripheral blood CD34+ progenitor cells in patients with lower-risk MDS (myelodysplastic syndromes) have increased expression of JMJD3 and an increased ability to form erythroid colonies upon inhibition of JMJD3 [56]. This suggests that Jmjd3 is intimately involved in erythroid lineage determination.…”

Section: Discussionsupporting

confidence: 58%

The histone demethylase Jmjd3 regulates zebrafish myeloid development by promoting spi1 expression

Zhu

Zhang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The histone demethylase Jmjd3 plays a critical role in in cell lineage specification and differentiation at various stages of development. However, its function during normal myeloid development remains poorly understood. Here, we carried out a systematic in vivo screen of epigenetic factors for their function in hematopoiesis and identified Jmjd3 as a new epigenetic factor that regulates myelopoiesis in zebrafish. We demonstrated that jmjd3 was essential for zebrafish primitive and definitive myelopoiesis, knockdown of jmjd3 suppressed the myeloid commitment and enhanced the erythroid commitment. Only overexpression of spi1 but not the other myeloid regulators rescued the myeloid development in jmjd3 morphants. Furthermore, preliminary mechanistic studies demonstrated that Jmjd3 could directly bind to the spi1 regulatory region to alleviate the repressive H3K27me3 modification and activate spi1 expression. Thus, our studies highlight that Jmjd3 is indispensable for early zebrafish myeloid development by promoting spi1 expression.

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Section: Discussionsupporting

confidence: 58%

The histone demethylase Jmjd3 regulates zebrafish myeloid development by promoting spi1 expression

Zhu

Zhang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…Consistent with the hypothesis that reduced A20 expression and increased innate immune function is associated with MDS 144 , empirical data revealed A20 mRNA is significantly reduced in CD34+ cells isolated from the BM of MDS patients 145 . Moreover, miR-125a, which targets A20, is overexpressed in MDS CD34+ cells 16,146 .…”

Section: Negative Regulators Of Innate Immune Signaling In Mdssupporting

confidence: 62%

Deconstructing innate immune signaling in myelodysplastic syndromes

Varney¹,

Melgar²,

Niederkorn³

et al. 2015

Experimental Hematology

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Overexpression of immune-related genes is widely reported in Myelodysplastic syndromes (MDS), and chronic immune stimulation increases the risk for developing MDS. Aberrant innate immune activation, such as due to increased Toll-like receptor (TLR) signaling, in MDS can contribute to systemic effects on hematopoiesis in addition to cell-intrinsic defects on hematopoietic stem/progenitor cell (HSPC) function. This review will deconstruct aberrant function of TLR signaling mediators within MDS HSPC that may contribute to cell intrinsic consequences on hematopoiesis and disease pathogenesis. We will discuss the contribution of chronic TLR signaling to the pathogenesis of MDS based on evidence from patients and mouse genetic models.

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“…We recently performed a genome-wide CHIP-Seq analysis of H3K4me3 in MDS. 2 This analysis identified multiple genes marked by increased H3K4me3 in BM CD34+ cells. A large majority of the genes identified are known to be involved in Toll-like receptor (TLR) mediated innate immunity signaling and NF-kB activation.…”

Section: Introductionmentioning

confidence: 96%

Toll-like receptor alterations in myelodysplastic syndrome

et al. 2013

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Recent studies have implicated the innate immunity system in the pathogenesis of myelodysplastic syndromes (MDS). Toll-like receptor (TLR) genes encode key innate immunity signal initiators. We recently identified multiple genes, known to be regulated by TLRs, to be overexpressed in MDS bone marrow (BM) CD34+ cells, and hypothesized that TLR signaling is abnormally activated in MDS. We analyzed a large cohort of MDS cases and identified that TLR1, 2 and 6 to be significantly overexpressed in MDS BM CD34+ cells. Deep-sequencing followed by Sanger-resequencing of TLR1, 2, 4 and 6 genes uncovered a recurrent genetic variant, TLR2-F217S, in 11% of 149 patients. Functionally, TLR2-F217S results in enhanced activation of downstream signaling including NF-kB activity after TLR2 agonist treatment. In cultured primary BM CD34+ cells of normal donors, TLR2 agonists induced histone demethylase JMJD3 and interleukin-8 gene expression. Inhibition of TLR2 in BM CD34+ cells from patients with lower-risk MDS using shRNA resulted in increased erythroid colony formation. Finally, RNA expression levels of TLR2 and 6 as well as presence of TLR2-F217S are associated with distinct prognosis and clinical characteristics. These findings indicate that TLR2-centered signaling is deregulated in MDS and that its targeting may have potential therapeutic benefit in MDS.

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Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells

Cited by 79 publications

References 61 publications

The histone demethylase Jmjd3 regulates zebrafish myeloid development by promoting spi1 expression

The histone demethylase Jmjd3 regulates zebrafish myeloid development by promoting spi1 expression

Deconstructing innate immune signaling in myelodysplastic syndromes

Toll-like receptor alterations in myelodysplastic syndrome

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