Identification of a PRMT5-dependent repressor complex linked to silencing of human fetal globin gene expression

Rank, Gerhard; Cerruti, Loretta; Simpson, Richard J.; Moritz, Robert L.; Jane, Stephen M.; Zhao, Quan

doi:10.1182/blood-2009-10-251116

Cited by 83 publications

(99 citation statements)

References 42 publications

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“…12,13 Recently, we have shown that the NuRD complex-associated protein PRMT5 can mediate the histone repressive mark, symmetric dimethyl H4R3 (H4R3me2s), which subsequently recruits DNMT3A, culminating in DNA methylation on the γ-globin promoter and gene silencing. 14,15 In this study, we demonstrate that WDR5 binds the γ-globin promoter in a PRMT5-dependent manner and plays a role in γ-globin gene silencing.…”

Section: Introductionmentioning

confidence: 99%

“…Xu et al 1634 haematologica | 2012; 97(11) KD) using a short hairpin (sh) RNA approach. 15 These cells demonstrated a reduction in PRMT5 levels to less than 20% of a scrambled (Scr) control shRNA transduced K562 cell line ( Figure 2C). As expected, immunoprecipitation with anti-NF-E4 antisera resulted in 8-fold less PRMT5 in the precipitate from the PRMT5-kd cells compared with control ( Figure 2C).…”

Section: Wdr5 Binding On γ-Promoter Is Prmt5-dependentmentioning

confidence: 99%

“…15 For BM culture conditions, isolated CD34 + cells were grown in StemSpan SFEM medium with 1X CC100 cytokine mix for six days, and then reseeded into the same medium supplemented with stem cell factor (SCF) (20 ng/mL), erythropoietin (EPO) (1 U/mL), IL-3 (5 ng/mL), dexamethasone (2 mM) and β-estradiol (1 mM) for two more weeks. Cell surface marker analyses with CD71 and glycophorin A indicated that cultured cells were greater than 90% erythroid lineage.…”

Section: Cell Culturementioning

confidence: 99%

“…Both WDR5 and ING2 could be co-eluted with PRMT5, although the peak of the elution profiles did not exactly overlap, suggesting that PRMT5 also participates in another complex in these cells. 15 To determine whether the interaction of ING2 and HDAC1 with WDR5 occurred on the γ-promoter, ChIP experiments with specific antibodies were performed in WDR5-OE K562 cells. We found that ING2 and HDAC1 binding to the γ-promoter were markedly increased in the overexpression line compared to the vector control cells ( Figure 4F).…”

Section: Wdr5 Interacts With Ing2-hdac1 Enhancing Their Binding At Thmentioning

confidence: 99%

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The role of WDR5 in silencing human fetal globin gene expression

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundHistone H3 lysine 4 (K4) methylation has been linked with transcriptional activity in mammalian cells. The WD40-repeat protein, WDR5, is an essential component of the MLL complex that induces histone H3 K4 methylation, but the role of WDR5 in human globin gene regulation has not yet been established. Design and MethodsTo study the role of WDR5 in human globin gene regulation, we performed knockdown experiments in both K562 cells and primary human bone marrow erythroid progenitor cells (BMC). The effects of WDR5 knockdown on γ-globin gene expression were determined. Biochemical approaches were also employed to investigate WDR5 interaction molecules. Chromosomal marks in the globin locus were analyzed by ChIP. ResultsWe found that WDR5 interacted with protein arginine methyltransferase 5 (PRMT5), a known repressor of γ-globin gene expression, and was essential for generating tri-methylated H3K4 (H3K4me3) at the γ-globin promoter in K562 cells. Enforced expression of WDR5 in K562 cells reduced γ-globin gene expression, whereas knockdown of WDR5 increased γ-globin gene expression in both K562 cells and primary human bone marrow erythroid progenitor cells. Consistent with this, both histone H3 and H4 acetylation at the γ-globin promoter were increased, while histone H4R3 and H3K9 methylation were decreased, in WDR5 knockdown cells compared to controls. We found that WDR5 interacted with HDAC1 and a PHD domaincontaining protein, ING2 (inhibitor of growth), an H3K4me3 mark reader, to enhance γ-globin gene transcriptional repression. In human BMC, levels of WDR5 were highly enriched on the γ-promoter relative to levels on other globin promoters and compared to the γ-promoter in cord blood erythroid progenitors, suggesting that WDR5 is important in the developmental globin gene expression program. ConclusionsOur data are consistent with a model in which WDR5 binds the γ-globin promoter in a PRMT5-dependent manner; H3K4me3 induced at the γ-globin promoter by WDR5 may result in the recruitment of the ING2-associated HDAC1 component and consequent silencing of γ-globin gene expression.

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Section: Introductionmentioning

confidence: 99%

Section: Wdr5 Binding On γ-Promoter Is Prmt5-dependentmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Wdr5 Interacts With Ing2-hdac1 Enhancing Their Binding At Thmentioning

confidence: 99%

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The role of WDR5 in silencing human fetal globin gene expression

et al. 2012

Haematologica

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“…28 We suggest that the tight repression of the g-globin genes in mice provides a window of opportunity for identification of additional factors involved in the silencing mechanism at the adult stage. Enforcement of repression of the embryonic/fetal program in adult erythropoiesis may be executed by, for instance, the transcription factors MYB 46 and SOX6, 47 the chromatin-bound FOP/CHTOP protein 27 and NuRD complex, 48 the orphan nuclear receptors TR2/ TR4, 49 and the protein arginine methyl transferase PRMT5, 50 and is likely to include additional epigenetic mechanisms such as PcG complex recruitment and DNA methylation. Future work will be aimed at further elucidating the multilayered, repressive network of the embryonic/fetal program in the adult erythroid environment.…”

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confidence: 99%

Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice

Esteghamat

Gillemans

Bilić

et al. 2013

Blood

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Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21^CIP1 in human breast cancer cell lines

2019

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The epigenetic enzymes catalyze posttranslational modifications (PTMs) of histones, which functionally determine gene expression at the chromatin level. Resveratrol (RVT) a much studied anti‐cancer natural molecule is known for restoration of BRCA1, p53, and p21 in cancer cells. We aimed to investigate the role of histone methylation and acetylation on upregulation of these tumor suppressor genes. Our results suggest RVT significantly increase expression of BRCA1, p53, and p21, while decreased expression of protein arginine methyltransferase 5 (PRMT5) and enhancer of Zeste homolog 2 (EZH2) at a 20 μM concentration by 48 hr in both MCF‐7 and MDA‐MB‐231 breast cancer cells. Also, there was an overall loss of H4R3me2s (catalytic product of PRMT5) and H3K27me3 (catalytic product of PRMT5). In contrast, RVT exposure caused a significant decrease in lysine deacetylase (KDAC) activity and expression of KDAC1‐3, whereas the expression of lysine acetyltransferase KAT2A/3B was increased compared to the unexposed cells. As an outcome, RVT increased global level of H3K9ac and H3K27ac marks. The chromatin immunoprecipitation showed 20 μM RVT exposure significantly reduced the enrichment of repressive histone marks (H4R3me2s and H3K27me3) while the abundance of activating histone marks (H3K9/27ac) within the proximal promoter region of BRCA1, p53, and p21 was increased. We hypothesize RVT by affecting the expression and function of methylation and acetylation enzymes altered the epigenetic modifications on promoter histones that restored expression of these critically important tumor suppressor genes.

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Identification of a PRMT5-dependent repressor complex linked to silencing of human fetal globin gene expression

Cited by 83 publications

References 42 publications

The role of WDR5 in silencing human fetal globin gene expression

The role of WDR5 in silencing human fetal globin gene expression

Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice

Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21^CIP1 in human breast cancer cell lines

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Identification of a PRMT5-dependent repressor complex linked to silencing of human fetal globin gene expression

Cited by 83 publications

References 42 publications

The role of WDR5 in silencing human fetal globin gene expression

The role of WDR5 in silencing human fetal globin gene expression

Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice

Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21CIP1 in human breast cancer cell lines

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Product

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Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21^CIP1 in human breast cancer cell lines