Role of Type II Protein Arginine Methyltransferase 5 in the Regulation of Circadian Per1 Gene

Na, Jungtae; Lee, Sang Hoon; Kim, Hwan-Gon; Shin, Jee-Yoon; Na, Wonho; Jeong, Hayan; Lee, Jongwoo; Cho, Sehyung; Kim, Won-Sun; Ju, Bong‐Gun

doi:10.1371/journal.pone.0048152

Cited by 9 publications

(6 citation statements)

References 55 publications

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“…SKB1 was previously shown to be linked to H4R3sme2 (Fabbrizio et al ., ; Ancelin et al ., ; Wang et al ., ; Na et al ., ; Gurung et al ., ). H4R3sme2 was shown to be a form of epigenetic silencing involved in the regulation of flowering time, vernalization, and in the responses to salt stress and ABA (Wang et al ., ; Schmitz et al ., ; Deng et al ., ; Zhang et al ., ).…”

Section: Resultsmentioning

confidence: 99%

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SKB1/PRMT5‐mediated histone H4R3 dimethylation of Ib subgroup bHLH genes negatively regulates iron homeostasis in Arabidopsis thaliana

et al. 2013

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These authors contributed equally to this work. SUMMARYHistone modifications play critical roles in the perception of environmental cues by plants. Here, we report that Shk1 binding protein 1 (SKB1/AtPRMT5), which catalyzes the symmetric dimethylation of histone H4R3 (H4R3sme2), is involved in iron homeostasis in Arabidopsis. The SKB1 lesion mutant exhibited higher iron accumulation in shoots and greater tolerance to iron deficiency than the wild type. The expression of SKB1 was not affected by iron, but the level of H4R3sme2 mediated by SKB1 was related to iron status in plants. We showed by chromatin immunoprecipitation (ChIP) and genome-wide ChIP-seq that SKB1 associated with the chromatin of the Ib subgroup bHLH genes (AtbHLH38, AtbHLH39, AtbHLH100 and AtbHLH101), and symmetrically dimethylated histone H4R3. The quantity of SKB1 that associated with chromatin of the Ib subgroup bHLH genes and the level of H4R3sme2 corresponded to the iron status of plants (higher with increased iron supply and lower when iron was removed). We conclude that SKB1-mediated H4R3sme2 regulates iron homeostasis in Arabidopsis in the context of increasing or decreasing expression of Ib subgroup bHLH genes. Iron deficiency may cause an increase in the disassociation of SKB1 from chromatin of the bHLH genes and a decrease in the level of H4R3sme2, thereby elevating their transcription and enhancing iron uptake. Our findings provide new insight into the molecular mechanisms of iron homeostasis in strategy I plants.

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Section: Resultsmentioning

confidence: 99%

“…SKB1 was previously shown to be linked to H4R3sme2 (Fabbrizio et al, 2002;Ancelin et al, 2006;Wang et al, 2007b;Na et al, 2012;Gurung et al, 2013). H4R3sme2 was (a) Figure 3.…”

Section: Skb1-mediated H4r3sme2 Is Related To Iron Statusmentioning

confidence: 97%

SKB1/PRMT5‐mediated histone H4R3 dimethylation of Ib subgroup bHLH genes negatively regulates iron homeostasis in Arabidopsis thaliana

et al. 2013

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“…For mutation of RBP-J binding sites (TGTGGGAA → TGACGCTA and TTCACACG → TAGAGTCG) on Hes1 gene promoter, PCR was performed 87 . After transfection of luciferase reporter containing gene and control renilla luciferase expression vector, cells were scratched and reporter activity was determined as described previously 88 .…”

Section: Methodsmentioning

confidence: 99%

JMJD3 and NF-κB-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing

Shin

Jeong

et al. 2017

Sci Rep

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It has been shown that epigenetic regulation plays an important role in skin wound healing. We previously found that histone H3K27me3 demethylase JMJD3 regulates inflammation and cell migration in keratinocyte wound healing. In this study, we identified Notch1 as a direct target of JMJD3 and NF-κB in wounded keratinocytes using in vitro cell and in vivo animal models. We found that Notch1 is up-regulated in the wound edge and its expression is dependent on JMJD3 and NF-κB in wounded keratinocytes. We also found that Notch1 activates the expression of RhoU and PLAU gene, which are critical regulators of cell migration. Consistently, depletion or inactivation of Notch1 resulted in decreased filopodia formation, increased focal adhesion and actin stress fiber, leading to reduced keratinocyte migration and skin wound healing. Thus, our findings provide the molecular mechanism involving JMJD3/NF-κB-Notch pathway in keratinocyte wound healing.

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“…PRMT5 is an important epigenetic enzyme [14][15][16] because of its critical roles in regulating gene transcription 17 , cell signaling 18 , RNA splicing 19 , DNA repair 20 , chromatin remodeling 21 and cell cycle 22 . It is overexpressed in different types of human cancer [23][24][25][26][27][28] , and its inhibition causes tumor suppression or cell death 29,30 , especially in cancer cells lacking methylthioadenosine phosphorylase (MTAP) activity.…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM Structure-guided Selection of Computed Ligand Poses to Enhance Potency in MTA-synergic Inhibition of Human Protein Arginine Methyltransferase 5

Yadav

Zhou

Yang

et al. 2021

Preprint

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The potential of using cryo-electron microscopic (cryo-EM) structures of 2.5-4.0 Å resolutions for structure-based drug design was proposed recently, but is yet to be materialized. Here we show that a 3.1 Å cryo-EM structure of protein arginine methyltransferase 5 (PRMT5) is sufficient to guide the selection of computed poses of a bound inhibitor and its redesign for much higher potency. PRMT5 is an oncogenic target and its multiple inhibitors are in clinical trials for various cancer types. However, all these PRMT5 inhibitors manifest negative cooperativity with a metabolic co-factor analog --- 2-methylthioadenosine (MTA), which is accumulated substantially in cancer patients carrying defective MTA phosphorylase (MTAP). To achieve MTA-synergetic inhibition, we obtained a pharmacophore from virtual screen and synthesized a specific inhibitor (11-2F). Cryo-EM structures of the 11-2F/MTA-bound human PRMT5: MEP50 complex and its apo form together showed that the inhibitor binding in the catalytic pocket causes a shift of the cofactor-binding site by 1.5 – 2.0 Å, disfavoring cofactor-binding and resulting in positive cooperativity between 11-2F and MTA. Coarse-grained and full-atomistic MD simulations of the ligands in their binding pockets were performed to compare computed poses of 11-2F and its redesigned analogs. Three new analogs were predicted to have much better potency. One of them, after synthesis, was ~4 fold more efficient in PRMT5 inhibition in the presence of MTA than 11-2F itself. Computational analysis also suggests strong subtype specificity of 11-2F among PRMTs. These data demonstrate the feasibility of using cryo-EM structures of near-atomic resolutions and computational analysis of ligand poses for better small molecule therapeutics.

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Role of Type II Protein Arginine Methyltransferase 5 in the Regulation of Circadian Per1 Gene

Cited by 9 publications

References 55 publications

SKB1/PRMT5‐mediated histone H4R3 dimethylation of Ib subgroup bHLH genes negatively regulates iron homeostasis in Arabidopsis thaliana

SKB1/PRMT5‐mediated histone H4R3 dimethylation of Ib subgroup bHLH genes negatively regulates iron homeostasis in Arabidopsis thaliana

JMJD3 and NF-κB-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing

Cryo-EM Structure-guided Selection of Computed Ligand Poses to Enhance Potency in MTA-synergic Inhibition of Human Protein Arginine Methyltransferase 5

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