Publications by authors named "She Chen"

238 Publications

Phosphorylation of Ago2 is required for its role in DNA double-strand break repair.

J Genet Genomics 2021 Apr 24. Epub 2021 Apr 24.

Department of Rehabilitation Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China. Electronic address:

Repair of DNA double-strand break (DSB) is critical for the maintenance of genome integrity. A class of DSB-induced small RNAs (diRNAs) has been shown to play an important role in DSB repair. In humans, diRNAs are associated with Ago2 and guide the recruitment of Rad51 to DSB sites to facilitate repair by homologous recombination (HR). Ago2 activity has been reported to be regulated by phosphorylation under normal and hypoxic conditions. However, the role of Ago2 phosphorylation in DNA damage repair is unexplored. Here, we show that S672, S828, T830, and S831 of human Ago2 are phosphorylated in response to ionizing radiation (IR). S672A mutation of Ago2 leads to significant reduction in Rad51 foci formation and HR efficiency. We further show that defective association of Ago2 S672A variant with DSB sites, instead of defects in diRNA and Rad51 binding, may account for decreased Rad51 foci formation and HR efficiency. Our study reveals a novel regulatory mechanism for the function of Ago2 in DNA repair.
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http://dx.doi.org/10.1016/j.jgg.2021.03.011DOI Listing
April 2021

A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin-induced corpus luteum regression.

Elife 2021 May 24;10. Epub 2021 May 24.

National Institute of Biological Sciences, Beijing, China.

Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knock-in mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.
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http://dx.doi.org/10.7554/eLife.67409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143796PMC
May 2021

Loss of polarity protein Par3 is mediated by transcription factor Sp1 in breast cancer.

Biochem Biophys Res Commun 2021 Jul 21;561:172-179. Epub 2021 May 21.

NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Road, Xuhui District, Shanghai, 200032, PR China. Electronic address:

Loss of polarity protein Par3 promotes breast cancer tumorigenesis and metastasis. The underlying molecular mechanisms of Par3 down-regulation and related prognostic significance in breast cancer remain unclear. Here, we discovered that Par3 down-regulation was associated with shorter relapse-free survival in Luminal A subtype of breast cancer. Par3 knockdown promoted breast cancer cells migration and invasion. Importantly, we identified that transcription factor Sp1 bound to PARD3 promoter region and induced Par3 expression. Breast cancer patients with low Sp1 showed significantly worse RFS and low expression level of Par3. Par3 over-expression partially reversed Sp1 knockdown induced migration and invasion. Together, decreased Sp1 level mediates Par3 down-regulation, which correlated with poor prognosis of ER + breast cancer patients, via reduced binding with PARD3 promoter.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.025DOI Listing
July 2021

FACT interacts with Set3 HDAC and fine-tunes GAL1 transcription in response to environmental stimulation.

Nucleic Acids Res 2021 06;49(10):5502-5519

State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.

The histone chaperone facilitates chromatin transactions (FACT) functions in various DNA transactions. How FACT performs these multiple functions remains largely unknown. Here, we found, for the first time, that the N-terminal domain of its Spt16 subunit interacts with the Set3 histone deacetylase complex (Set3C) and that FACT and Set3C function in the same pathway to regulate gene expression in some settings. We observed that Spt16-G132D mutant proteins show defects in binding to Set3C but not other reported FACT interactors. At the permissive temperature, induction of the GAL1 and GAL10 genes is reduced in both spt16-G132D and set3Δ cells, whereas transient upregulation of GAL10 noncoding RNA (ncRNA), which is transcribed from the 3' end of the GAL10 gene, is elevated. Mutations that inhibit GAL10 ncRNA transcription reverse the GAL1 and GAL10 induction defects in spt16-G132D and set3Δ mutant cells. Mechanistically, set3Δ and FACT (spt16-G132D) mutants show reduced histone acetylation and increased nucleosome occupancy at the GAL1 promoter under inducing conditions and inhibition of GAL10 ncRNA transcription also partially reverses these chromatin changes. These results indicate that FACT interacts with Set3C, which in turn prevents uncontrolled GAL10 ncRNA expression and fine-tunes the expression of GAL genes upon a change in carbon source.
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http://dx.doi.org/10.1093/nar/gkab312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191775PMC
June 2021

MRCKβ links Dasm1 to actin rearrangements to promote dendrite development.

J Biol Chem 2021 Apr 29:100730. Epub 2021 Apr 29.

NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;. Electronic address:

Proper dendrite morphogenesis and synapse formation are essential for neuronal development and function. Dasm1, a member of the immunoglobulin superfamily, is known to promote dendrite outgrowth and excitatory synapse maturation in vitro. However, the in vivo function of Dasm1 in neuronal development and the underlying mechanisms are not well understood. To learn more, Dasm1 knockout mice were constructed and employed to confirm that Dasm1 regulates dendrite arborization and spine formation in vivo. We performed a yeast two-hybrid screen using Dasm1, revealing MRCKβ as a putative partner; additional lines of evidence confirmed this interaction and identified cytoplasmic proline-rich region (823-947 aa) of Dasm1 and MRCKβ self-activated kinase domain (CC1, 410-744 aa) as necessary and sufficient for binding. Using co-immunoprecipitation assay, auto-phosphorylation assay and BS3 cross-linking assay, we show that Dasm1 binding triggers a change in MRCKβ's conformation and subsequent dimerization, resulting in auto-phosphorylation and activation. Activated MRCKβ in turn phosphorylates a class 2 regulatory myosin light chain (MLC2), which leads to enhanced actin rearrangement, causing the dendrite outgrowth and spine formation observed before. Removal of Dasm1 in mice leads to behavioral abnormalities. Together, these results reveal a crucial molecular pathway mediating cell surface and intracellular signaling communication to regulate actin dynamics and neuronal development in the mammalian brain.
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http://dx.doi.org/10.1016/j.jbc.2021.100730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191314PMC
April 2021

Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis.

Cancer Sci 2021 May 1. Epub 2021 May 1.

NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Bladder cancer (BLCA) remains the leading cause of cancer-related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2-box (CAGGTG) of PARD3 promoter-proximal. Inhibition of GSK-3β promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936-1356 aa) and ZO-1 (1372-1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK-3β/Snail/Par3/ZO-1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA.
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http://dx.doi.org/10.1111/cas.14920DOI Listing
May 2021

The role of Sphingomyelin synthase 2 (SMS2) in platelet activation and its clinical significance.

Thromb J 2021 Apr 28;19(1):27. Epub 2021 Apr 28.

Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.

Background: Sphingomyelin (SM) is an essential component of biological lipid rafts, and it plays an indispensable role in maintaining plasma membrane stability and in mediating signal transduction. The ultimate biosynthesis of SM is catalyzed by two sphingomyelin synthases (SMSs) namely SMS1 and SMS2, which are selectively distributed in the trans-Golgi apparatus and the plasma membrane. It has been demonstrated that SMS2 acts as an irreplaceable molecule in the regulation of transmembrane signaling, and loss of SMS2 has been reported to worsen atherosclerosis and liver steatosis. However, the function of SMS2 in platelet activation and its association with the pathological process of thrombosis in acute coronary syndrome (ACS) and portal hypertension (PH) remain unclear.

Methods: In this study, we tested the role of SMS2 in platelet activation and thrombosis using SMS2 knockout (SMS2 -/-) mice and SMS2-specific inhibitor, D609. Furthermore, we detected SMS2 expression in patients with ACS and PH.

Results: SMS2 -/- platelets showed significant reduction in platelet aggregation, spreading, clot retraction and in vivo thrombosis. Similar inhibitory effects on platelet activation were detected in D609-treated wild-type platelets. PLCγ/PI3K/Akt signaling pathway was inhibited in SMS2 -/- platelets and D609-treated wild-type platelets. In addition, we discovered that platelet SMS2 expression was remarkably increased in patients with ACS and PH, compared with healthy subjects.

Conclusions: Our study indicates that SMS2 acts as a positive regulator of platelet activation and thrombosis, and provides a theoretical basis for the potential use of D609 in anti-thrombosis treatment.
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http://dx.doi.org/10.1186/s12959-021-00282-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082820PMC
April 2021

Three functionally redundant plant-specific paralogs are core subunits of the SAGA histone acetyltransferase complex in Arabidopsis.

Mol Plant 2021 Mar 15. Epub 2021 Mar 15.

College of Life Sciences, Beijing Normal University, Beijing, China; National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 10084, China. Electronic address:

The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is an evolutionarily conserved histone acetyltransferase complex that has a critical role in histone acetylation, gene expression, and various developmental processes in eukaryotes. However, little is known about the composition and function of the SAGA complex in plants. In this study, we found that the SAGA complex in Arabidopsis thaliana contains not only conserved subunits but also four plant-specific subunits: three functionally redundant paralogs, SCS1, SCS2A, and SCS2B (SCS1/2A/2B), and a TAF-like subunit, TAFL. Mutations in SCS1/2A/2B lead to defective phenotypes similar to those caused by mutations in the genes encoding conserved SAGA subunits HAG1 and ADA2B, including delayed juvenile-to-adult phase transition, late flowering, and increased trichome density. Furthermore, we demonstrated that SCS1/2A/2B are required for the function of the SAGA complex in histone acetylation, thereby promoting the transcription of development-related genes. These results together suggest that SCS1/2A/2B are core subunits of the SAGA complex in Arabidopsis. Compared with SAGA complexes in other eukaryotes, the SAGA complexes in plants have evolved unique features that are necessary for normal growth and development.
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http://dx.doi.org/10.1016/j.molp.2021.03.014DOI Listing
March 2021

OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential.

EMBO Rep 2021 04 3;22(4):e51606. Epub 2021 Mar 3.

Graduate School of Peking Union Medical College, Beijing, China.

Reduction of mitochondrial membrane potential (Δψ ) is a hallmark of mitochondrial dysfunction. It activates adaptive responses in organisms from yeast to human to rewire metabolism, remove depolarized mitochondria, and degrade unimported precursor proteins. It remains unclear how cells maintain Δψ , which is critical for maintaining iron-sulfur cluster (ISC) synthesis, an indispensable function of mitochondria. Here, we show that yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA, respectively, exhibit activated stress responses and progressive reduction of Δψ . Extensive omics analyses of these mutants show that these mutants progressively activate adaptive responses, including transcriptional downregulation of ATP synthase inhibitor Inh1 and OXPHOS subunits, Puf3-mediated upregulation of import receptor Mia40 and global mitochondrial biogenesis, Snf1/AMPK-mediated upregulation of glycolysis and repression of ribosome biogenesis, and transcriptional upregulation of cytoplasmic chaperones. These adaptations disinhibit mitochondrial ATP hydrolysis, remodel mitochondrial proteome, and optimize ATP supply to mitochondria to convergently maintain Δψ , ISC biosynthesis, and cell proliferation.
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http://dx.doi.org/10.15252/embr.202051606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025004PMC
April 2021

Visualizing the Calcitonin Gene-Related Peptide Immunoreactive Innervation of the Rat Cranial Dura Mater with Immunofluorescence and Neural Tracing.

J Vis Exp 2021 01 6(167). Epub 2021 Jan 6.

Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences;

The aim of this study was to examine the distribution and origin of the calcitonin gene-related peptide (CGRP)-immunoreactive sensory nerve fibers of the cranial dura mater using immunofluorescence, three-dimensional (3D) reconstruction and retrograde tracing technique. Here, the nerve fibers and blood vessels were stained using immunofluorescence and histochemistry techniques with CGRP and fluorescent phalloidin, respectively. The spatial correlation of dural CGRP-immuoreactive nerve fibers and blood vessels were demonstrated by 3D reconstruction. Meanwhile, the origin of the CGRP-immunoreactive nerve fibers were detected by neural tracing technique with fluorogold (FG) from the area around middle meningeal artery (MMA) in the cranial dura mater to the trigeminal ganglion (TG) and cervical (C) dorsal root ganglia (DRGs). In addition, the chemical characteristics of FG-labeled neurons in the TG and DRGs were also examined together with CGRP using double immunofluorescences. Taking advantage of the transparent whole-mount sample and 3D reconstruction, it was shown that CGRP-immunoreactive nerve fibers and phalloidin-labeled arterioles run together or separately forming a dural neurovascular network in a 3D view, while the FG-labeled neurons were found in the ophthalmic, maxillary, and mandibular branches of TG, as well as the C2-3 DRGs ipsilateral to the side of tracer application in which some of FG-labeled neurons presented with CGRP-immunoreactive expression. With these approaches, we demonstrated the distributional characteristics of CGRP-immunoreactive nerve fibers around the blood vessels in the cranial dura mater, as well as the origin of these nerve fibers from TG and DRGs. From the perspective of methodology, it may provide a valuable reference for understanding the complicated neurovascular structure of the cranial dura mater under the physiological or pathological condition.
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http://dx.doi.org/10.3791/61742DOI Listing
January 2021

A histone H3K27me3 reader cooperates with a family of PHD finger-containing proteins to regulate flowering time in Arabidopsis.

J Integr Plant Biol 2021 Apr 4;63(4):787-802. Epub 2021 Mar 4.

National Institute of Biological Sciences, Beijing, 102206, China.

Trimethylated histone H3 lysine 27 (H3K27me3) is a repressive histone marker that regulates a variety of developmental processes, including those that determine flowering time. However, relatively little is known about the mechanism of how H3K27me3 is recognized to regulate transcription. Here, we identified BAH domain-containing transcriptional regulator 1 (BDT1) as an H3K27me3 reader. BDT1 is responsible for preventing flowering by suppressing the expression of flowering genes. Mutation of the H3K27me3 recognition sites in the BAH domain disrupted the binding of BDT1 to H3K27me3, leading to de-repression of H3K27me3-enriched flowering genes and an early-flowering phenotype. We also found that BDT1 interacts with a family of PHD finger-containing proteins, which we named PHD1-6, and with CPL2, a Pol II carboxyl terminal domain (CTD) phosphatase responsible for transcriptional repression. Pull-down assays showed that the PHD finger-containing proteins can enhance the binding of BDT1 to the H3K27me3 peptide. Mutations in all of the PHD genes caused increased expression of flowering genes and an early-flowering phenotype. This study suggests that the binding of BDT1 to the H3K27me3 peptide, which is enhanced by PHD proteins, is critical for preventing early flowering.
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http://dx.doi.org/10.1111/jipb.13067DOI Listing
April 2021

Hepatic NOD2 promotes hepatocarcinogenesis via a RIP2-mediated proinflammatory response and a novel nuclear autophagy-mediated DNA damage mechanism.

J Hematol Oncol 2021 01 7;14(1). Epub 2021 Jan 7.

Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.

Background: Key hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (-) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis.

Methods: NOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2-knockout (Nod2), Rip2-knockout (Rip2), Lamin A/C-knockout (Lamn) and Rip2/Lamin A/C double-knockout (Rip2/Lamn) mice models of diethylnitrosamine (DEN)/CCl-induced HCC.

Results: NOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCC patients. Hepatic NOD2 deletion in vivo decreased DEN/CCl-induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability.

Conclusions: We reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.
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http://dx.doi.org/10.1186/s13045-020-01028-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791875PMC
January 2021

The CBP/p300 histone acetyltransferases function as plant-specific MEDIATOR subunits in Arabidopsis.

J Integr Plant Biol 2021 Apr 8;63(4):755-771. Epub 2021 Mar 8.

National Institute of Biological Sciences, Beijing, 102206, China.

In eukaryotes, MEDIATOR is a conserved multi-subunit complex that links transcription factors and RNA polymerase II and that thereby facilitates transcriptional initiation. Although the composition of MEDIATOR has been well studied in yeast and mammals, relatively little is known about the composition of MEDIATOR in plants. By affinity purification followed by mass spectrometry, we identified 28 conserved MEDIATOR subunits in Arabidopsis thaliana, including putative MEDIATOR subunits that were not previously validated. Our results indicated that MED34, MED35, MED36, and MED37 are not Arabidopsis MEDIATOR subunits, as previously proposed. Our results also revealed that two homologous CBP/p300 histone acetyltransferases, HAC1 and HAC5 (HAC1/5) are in fact plant-specific MEDIATOR subunits. The MEDIATOR subunits MED8 and MED25 (MED8/25) are partially responsible for the association of MEDIATOR with HAC1/5, MED8/25 and HAC1/5 co-regulate gene expression and thereby affect flowering time and floral development. Our in vitro observations indicated that MED8 and HAC1 form liquid-like droplets by phase separation, and our in vivo observations indicated that these droplets co-localize in the nuclear bodies at a subset of nuclei. The formation of liquid-like droplets is required for MED8 to interact with RNA polymerase II. In summary, we have identified all of the components of Arabidopsis MEDIATOR and revealed the mechanism underlying the link of histone acetylation and transcriptional regulation.
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http://dx.doi.org/10.1111/jipb.13052DOI Listing
April 2021

Casein kinase 1G2 suppresses necroptosis-promoted testis aging by inhibiting receptor-interacting kinase 3.

Elife 2020 11 18;9. Epub 2020 Nov 18.

National Institute of Biological Sciences, Beijing, China.

Casein kinases are a large family of intracellular serine/threonine kinases that control a variety of cellular signaling functions. Here we report that a member of casein kinase 1 family, casein kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting kinase 3, RIPK3, thereby attenuating RIPK3-mediated necroptosis. The binding of CSNK1G2 to RIPK3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and premature aging of their testis, a phenotype that was rescued by either double knockout of the gene or feeding the animal with a RIPK1 kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIPK3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIPK3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.
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http://dx.doi.org/10.7554/eLife.61564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673785PMC
November 2020

SCF controls protein turnover of unfoldase CDC48A to promote plant immunity.

New Phytol 2021 03 4;229(5):2795-2811. Epub 2020 Dec 4.

Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.

The unfoldase CDC48 (Cell Division Cycle 48) is highly conserved in eukaryotes, serving as an AAA + ATPase to extract ubiquitinated proteins from large protein complexes and membranes. Although its biochemical properties have been studied extensively in yeast and animal systems, the biological roles and regulations of the plant CDC48s have been explored only recently. Here we describe the identification of a novel E3 ligase from the SNIPER (snc1-influencing plant E3 ligase reverse genetic) screen, which contributes to plant defense regulation by targeting CDC48A for degradation. SNIPER7 encodes an F-box protein and its overexpression leads to autoimmunity. We identified CDC48s as interactors of SNIPER7 through immunoprecipitation followed by mass spectrometry proteomic analysis. SNIPER7 overexpression lines phenocopy the autoimmune mutant Atcdc48a-4. Furthermore, CDC48A protein levels are reduced or stabilized when SNIPER7 is overexpressed or inhibited, respectively, suggesting that CDC48A is the ubiquitination substrate of SCF . Taken together, this study reveals a new mechanism where a SCF complex regulates CDC48 unfoldase levels and modulates immune output.
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http://dx.doi.org/10.1111/nph.17071DOI Listing
March 2021

Expression and Clinical Prognostic Value of Platelet in Acute Coronary Syndrome.

Int J Gen Med 2020 9;13:791-802. Epub 2020 Oct 9.

Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China.

Purpose: Little is known about the relationship between the level of platelet NOD-like receptor protein 3 (NLRP3) and the severity of acute coronary syndrome (ACS) or the prognostic value of platelet NLRP3 for percutaneous coronary intervention (PCI).

Methods: Platelets collected from 25 healthy subjects, 23 patients with stable angina pectoris (SAP), and 72 patients with ACS were analyzed by Western blotting and real-time fluorescence quantitative PCR (qPCR). A total of 152 patients with ACS who had undergone PCI were included in this study to evaluate the prognostic value of platelet .

Results: The levels of platelet in both the healthy and SAP groups were clearly lower than in the ACS group (<0.001). According to the Pearson correlation analysis, the expression of platelet was closely related to the mean platelet volume (MPV), left ventricular ejection fraction (LVEF), the Gensini score, and the Global Registry of Acute Coronary Events (GRACE) score (all <0.001). Multivariate logistic regression analysis identified as an independent risk factor for adverse cardiovascular events (ACEs) after PCI (=0.004). The proportion of patients with high expression (the -high group) remaining free of adverse events for 3 years was remarkably lower than that in patients with low expression (the -low group; =0.024). The -high group had a significantly higher proportion of patients with interleukin-1β-expressing (20.4%±6.1%) platelets than the -low group (10.7%±3.5%, <0.001). Moreover, the -high group exhibited higher platelet activity, as indicated by increased PAC-1 binding and CD62P expression, compared with the -low group (<0.001).

Conclusion: These results indicated that platelet was a novel potential prognostic factor for patients with ACS that underwent PCI.
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http://dx.doi.org/10.2147/IJGM.S275481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555296PMC
October 2020

Author Correction: Genetically encoded tags for direct synthesis of EM-visible gold nanoparticles in cells.

Nat Methods 2020 Nov;17(11):1167

National Institute of Biological Sciences, Beijing, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41592-020-00996-2DOI Listing
November 2020

[Microstructural characteristics of lymphatic vessels in skin tissues of acupoints "Taichong" and "Yongquan" in the rat].

Zhen Ci Yan Jiu 2020 Sep;45(9):731-4

Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.

Objective: To provide a new method for investigating the histological characteristics of acupoints by obser-ving the microstructure of the lymphatic vessels in the skin tissue of "Taichong" (LR3) and "Yongquan" (KI1) regions.

Methods: Six male SD rats were used in the present study. The skin tissue of LR3 and KI1 from the hind foot were taken following transcardial perfusion with 4% paraformaldehyde. The skin tissues were cut into sagittal sections with a freezing microtome and stained by fluorescent immunohistochemistry with lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), calcitonin gene-related peptide (CGRP), and phalloidin for displaying the lymphatic vessels, nerve fibers, and blood vessels, separately. The samples were viewed and recorded using fluorescent microscope and laser scanning confocal microscope.

Results: In the skin tissue of LR3 and KI1 regions, the lymphatic vessels, nerve fibers, and blood vessels were labeled with LYVE-1, CGRP and phalloidin, respectively. The lymphatic capillaries were found to start from the enlarged blind end and distribute in the dermis and subcutaneous tissues with various forms, crisscrossing. Abundant blood capillaries at various thickness distributed around the lymphatic capillaries in a parallel or crossed pattern, intermingled with free nerve fibers.

Conclusion: The lymphatic capillaries, blood capillaries and nerve fibers extensively distribute in the skin tissues of LR3 and KI1 regions in rats, suggesting an involvement of the immunomodulation in the effects of acupuncture in pathological conditions, despite being not limited to the acupoint regions in the distribution of lymphatic capillaries.
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http://dx.doi.org/10.13702/j.1000-0607.190769DOI Listing
September 2020

Myofiber necroptosis promotes muscle stem cell proliferation via releasing Tenascin-C during regeneration.

Cell Res 2020 12 24;30(12):1063-1077. Epub 2020 Aug 24.

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.

Necroptosis, a form of programmed cell death, is characterized by the loss of membrane integrity and release of intracellular contents, the execution of which depends on the membrane-disrupting activity of the Mixed Lineage Kinase Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers committed MLKL-dependent necroptosis after muscle injury. Either pharmacological inhibition of the necroptosis upstream kinase Receptor Interacting Protein Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to significant muscle regeneration defects. By releasing factors into the muscle stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to be critical for MuSC proliferation. The temporary expression of TNC in myofibers is tightly controlled by necroptosis; the extracellular release of TNC depends on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR) signaling pathway in MuSCs through its N-terminus assembly domain together with the EGF-like domain. These findings indicate that necroptosis plays a key role in promoting MuSC proliferation to facilitate muscle regeneration.
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http://dx.doi.org/10.1038/s41422-020-00393-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784988PMC
December 2020

A new approach for examining the neurovascular structure with phalloidin and calcitonin gene-related peptide in the rat cranial dura mater.

J Mol Histol 2020 Oct 13;51(5):541-548. Epub 2020 Aug 13.

Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

The neurovascular structures in the cranial dura mater have been studied with various histological techniques in the past years. In order to obtain a proper approach to reveal the detailed structures, different labeling methods for the cranial vessels and nerve fibers were tested in this study. Firstly, the labeling characteristics of phalloidin, alpha smooth muscle actin (α-SMA), and CD31 were compared in rat whole-mount cranial dura mater by using fluorescent immunohistochemistry or histochemistry. Secondly, according to their properties, phalloidin and α-SMA were selected to combine with calcitonin gene-related peptide (CGRP) to further demonstrate the cranial neurovascular structure. By these approaches, a three-dimensional map of blood vessels and nerve fibers within the whole-mount rat cranial dura mater was obtained. The results showed that phalloidin, α-SMA, and CD31 were preferably expressed in the wall of cranial vessels, corresponding to the arteriors, venules, and capillaries, respectively. Additionally, CGRP + nerve fibers were clearly demonstrated together with phalloidin + or α-SMA + vessels, forming a delicate neurovascular network in the cranial dura mater. The thick nerve bundles ran closely to the phalloidin + or α-SMA + vessels in parallel pattern, while the thin nerve fibers branched off from the bundles tending to surround the phalloidin + arterioles rather than α-SMA + venules. These findings suggest that phalloidin could be an appropriate biochemical maker to be effectively used together with CGRP for experiments examining the detailed spatial correlation of cranial blood vessels and nerve fibers in a three-dimensional view, which may provide clues for understanding the underlying mechanisms of cranial neurovascular disorders.
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http://dx.doi.org/10.1007/s10735-020-09903-7DOI Listing
October 2020

Genetically encoded tags for direct synthesis of EM-visible gold nanoparticles in cells.

Nat Methods 2020 09 10;17(9):937-946. Epub 2020 Aug 10.

National Institute of Biological Sciences, Beijing, China.

Genetically encoded tags for single-molecule imaging in electron microscopy (EM) are long-awaited. Here, we report an approach for directly synthesizing EM-visible gold nanoparticles (AuNPs) on cysteine-rich tags for single-molecule visualization in cells. We first uncovered an auto-nucleation suppression mechanism that allows specific synthesis of AuNPs on isolated tags. Next, we exploited this mechanism to develop approaches for single-molecule detection of proteins in prokaryotic cells and achieved an unprecedented labeling efficiency. We then expanded it to more complicated eukaryotic cells and successfully detected the proteins targeted to various organelles, including the membranes of endoplasmic reticulum (ER) and nuclear envelope, ER lumen, nuclear pores, spindle pole bodies and mitochondrial matrices. We further implemented cysteine-rich tag-antibody fusion proteins as new immuno-EM probes. Thus, our approaches should allow biologists to address a wide range of biological questions at the single-molecule level in cellular ultrastructural contexts.
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http://dx.doi.org/10.1038/s41592-020-0911-zDOI Listing
September 2020

DREAM complex suppresses DNA methylation maintenance genes and precludes DNA hypermethylation.

Nat Plants 2020 08 13;6(8):942-956. Epub 2020 Jul 13.

National Institute of Biological Sciences, Beijing, China.

The DNA methyltransferases MET1 and CMT3 are known to be responsible for maintenance of DNA methylation at symmetric CG and CHG sites, respectively, in Arabidopsis thaliana. However, it is unknown how the expression of methyltransferase genes is regulated in different cell states and whether change in expression affects DNA methylation at the whole-genome level. Using a reverse genetic screen, we identified TCX5, a tesmin/TSO1-like CXC domain-containing protein, and demonstrated that it is a transcriptional repressor of genes required for maintenance of DNA methylation, which include MET1, CMT3, DDM1, KYP and VIMs. TCX5 functions redundantly with its paralogue TCX6 in repressing the expression of these genes. In the tcx5 tcx6 double mutant, expression of these genes is markedly increased, thereby leading to markedly increased DNA methylation at CHG sites and, to a lesser extent, at CG sites at the whole-genome level. Furthermore, our whole-genome DNA methylation analysis indicated that the CG and CHG methylation level is lower in differentiated quiescent cells than in dividing cells in the wild type but is comparable in the tcx5/6 mutant, suggesting that TCX5/6 are required for maintenance of the difference in DNA methylation between the two cell types. We identified TCX5/6-containing multi-subunit complexes, which are known as DREAM in other eukaryotes, and demonstrated that the Arabidopsis DREAM components function as a whole to preclude DNA hypermethylation. Given that the DREAM complexes are conserved from plants to animals, the preclusion of DNA hypermethylation by DREAM complexes may represent a conserved mechanism in eukaryotes.
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http://dx.doi.org/10.1038/s41477-020-0710-7DOI Listing
August 2020

Comparative Treatment Patterns and Outcomes of Fulvestrant versus Everolimus Plus Exemestane for Postmenopausal Metastatic Breast Cancer Resistant to Aromatase Inhibitors in Real-World Experience.

Ther Clin Risk Manag 2020 30;16:607-615. Epub 2020 Jun 30.

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.

Background: Fulvestrant (FUL) and the combination of everolimus and exemestane (EVE-EXE) were the options to treat hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) patients who were refractory to aromatase inhibitors (AIs). The practical knowledge of treatment patterns and outcomes between the two regimens is essential for improving treatment decisions.

Methods: HR+/HER2- MBC patients, who were refractory to AI, were treated with FUL or EVE-EXE from June 2013 to June 2016 were included. Treatment patterns, progression-free survival (PFS), overall survival (OS), and toxicity were reported. Propensity score matching (PSM) was used to minimize potential confounders.

Results: A total of 168 patients were enrolled. Of 168 patients, 124 patients were treated with FUL and 44 patients received EVE-EXE. Patients who were treated with EVE-EXE were younger, more likely to have visceral, liver, multiple sites of metastases, and had received more prior chemotherapy. After adjusting for propensity score matching (PSM), no significant difference in PFS was found between two groups (=0.419). However, in the subgroup of multiple metastatic sites, the median PFS was significantly improved in the EVE-EXE arm compared with FUL arm (6.1 vs 3.2 months, respectively, =0.012). More patients in EVE-EXE arm discontinued treatment due to adverse events than in the FUL arm.

Conclusion: A substantial difference in treatment patterns was observed between the two arms. Clinical outcomes were comparable after PSM.

Clinicaltrialsgov Identifier: NCT03695341 (May 14, 2018).
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http://dx.doi.org/10.2147/TCRM.S255365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335268PMC
June 2020

Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma.

J Hepatol 2020 12 28;73(6):1446-1459. Epub 2020 Jun 28.

NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address:

Background & Aims: Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying causes of this aberrant activation remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor that acts via the mTORC1 axis.

Methods: We performed quantitative reverse-transcription PCR (92 pairs), western blot (30 pairs), and immunostaining (225 cases) assays in HCC tissue samples to evaluate VEPH1 expression. We explored the functional effects of VEPH1 on tumor growth and metastasis. Molecular and biochemical strategies were used to gain insight into mechanisms underlying the tumor-suppressive function of VEPH1.

Results: VEPH1 is frequently silenced in HCC tissues, primarily resulting from let-7d upregulation. Decreased VEPH1 expression is associated with poor prognosis and aggressive tumor phenotypes in patients with HCC. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion in vitro and in vivo. The VEPH1 fragments 580-625aa and 447-579 aa bind directly to TSC1 (719-1,164aa) and TSC2 (1-420 aa), respectively, enhancing TSC1/TCS2 binding and promoting translocation of TSC2 to the membrane, which leads to increased TSC2 Ser phosphorylation. Subsequently, Rheb is inactivated by the GTPase activity of TSC2, inhibiting mTORC1 signaling and contributing to changes in HCC carcinogenesis and metastasis. Rapamycin, the mTOR inhibitor, can inhibit the pro-tumorigenic effect of VEPH1 knockdown. Loss of VEPH1 correlates with decreased TSC2 Ser phosphorylation and increased mTOR activity in HCC specimens.

Conclusions: The loss of VEPH1 leads to aberrantly activated mTORC1 signaling in HCC; rapamycin (or rapalogs) may serve as an effective treatment option for patients with HCC and dampened VEPH1 expression.

Lay Summary: Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression.
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http://dx.doi.org/10.1016/j.jhep.2020.06.027DOI Listing
December 2020

Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape.

PLoS Genet 2020 06 1;16(6):e1008836. Epub 2020 Jun 1.

Department of Physiology, The University of Texas Southwestern Medical Center,Harry Hines Blvd., Dallas, Texas, United States of America.

Codon usage bias is a universal feature of all genomes and plays an important role in regulating protein expression levels. Modification of adenosine to inosine at the tRNA anticodon wobble position (I34) by adenosine deaminases (ADATs) is observed in all eukaryotes and has been proposed to explain the correlation between codon usage and tRNA pool. However, how the tRNA pool is affected by I34 modification to influence codon usage-dependent gene expression is unclear. Using Neurospora crassa as a model system, by combining molecular, biochemical and bioinformatics analyses, we show that silencing of adat2 expression severely impaired the I34 modification levels for the ADAT-related tRNAs, resulting in major ADAT-related tRNA profile changes and reprogramming of translation elongation kinetics on ADAT-related codons. adat2 silencing also caused genome-wide codon usage-biased ribosome pausing on mRNAs and proteome landscape changes, leading to selective translational repression or induction of different mRNAs. The induced expression of CPC-1, the Neurospora ortholog of yeast GCN4p, mediates the transcriptional response after adat2 silencing and amino acid starvation. Together, our results demonstrate that the tRNA I34 modification by ADAT plays a major role in driving codon usage-biased translation to shape proteome landscape.
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http://dx.doi.org/10.1371/journal.pgen.1008836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289440PMC
June 2020

FAD-dependent enzyme-catalysed intermolecular [4+2] cycloaddition in natural product biosynthesis.

Nat Chem 2020 07 25;12(7):620-628. Epub 2020 May 25.

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

The Diels-Alder reaction is one of the most powerful and widely used methods in synthetic chemistry for the stereospecific construction of carbon-carbon bonds. Despite the importance of Diels-Alder reactions in the biosynthesis of numerous secondary metabolites, no naturally occurring stand-alone Diels-Alderase has been demonstrated to catalyse intermolecular Diels-Alder transformations. Here we report a flavin adenine dinucleotide-dependent enzyme, Morus alba Diels-Alderase (MaDA), from Morus cell cultures, that catalyses an intermolecular [4+2] cycloaddition to produce the natural isoprenylated flavonoid chalcomoracin with a high efficiency and enantioselectivity. Density functional theory calculations and preliminary measurements of the kinetic isotope effects establish a concerted but asynchronous pericyclic pathway. Structure-guided mutagenesis and docking studies demonstrate the interactions of MaDA with the diene and dienophile to catalyse the [4+2] cycloaddition. MaDA exhibits a substrate promiscuity towards both dienes and dienophiles, which enables the expedient syntheses of structurally diverse natural products. We also report a biosynthetic intermediate probe (BIP)-based target identification strategy used to discover MaDA.
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http://dx.doi.org/10.1038/s41557-020-0467-7DOI Listing
July 2020

The CCR4-NOT complex component NOT1 regulates RNA-directed DNA methylation and transcriptional silencing by facilitating Pol IV-dependent siRNA production.

Plant J 2020 08 25;103(4):1503-1515. Epub 2020 Jun 25.

National Institute of Biological Sciences, Beijing, 102206, China.

Small interfering RNAs (siRNAs) are responsible for establishing and maintaining DNA methylation through the RNA-directed DNA methylation (RdDM) pathway in plants. Although siRNA biogenesis is well known, it is relatively unclear about how the process is regulated. By a forward genetic screen in Arabidopsis thaliana, we identified a mutant defective in NOT1 and demonstrated that NOT1 is required for transcriptional silencing at RdDM target genomic loci. We demonstrated that NOT1 is required for Pol IV-dependent siRNA accumulation and DNA methylation at a subset of RdDM target genomic loci. Furthermore, we revealed that NOT1 is a constituent of a multi-subunit CCR4-NOT deadenylase complex by immunoprecipitation combined with mass spectrometry and demonstrated that the CCR4-NOT components can function as a whole to mediate chromatin silencing. Therefore, our work establishes that the CCR4-NOT complex regulates the biogenesis of Pol IV-dependent siRNAs, and hence facilitates DNA methylation and transcriptional silencing in Arabidopsis.
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http://dx.doi.org/10.1111/tpj.14818DOI Listing
August 2020

FHA2 is a plant-specific ISWI subunit responsible for stamen development and plant fertility.

J Integr Plant Biol 2020 Nov 15;62(11):1703-1716. Epub 2020 Jun 15.

National Institute of Biological Sciences, Beijing, 102206, China.

Imitation Switch (ISWI) chromatin remodelers are known to function in diverse multi-subunit complexes in yeast and animals. However, the constitution and function of ISWI complexes in Arabidopsis thaliana remain unclear. In this study, we identified forkhead-associated domain 2 (FHA2) as a plant-specific subunit of an ISWI chromatin-remodeling complex in Arabidopsis. By in vivo and in vitro analyses, we demonstrated that FHA2 directly binds to RLT1 and RLT2, two redundant subunits of the ISWI complex in Arabidopsis. The stamen filament is shorter in the fha2 and rlt1/2 mutants than in the wild type, whereas their pistil lengths are comparable. The shorter filament, which is due to reduced cell size, results in insufficient pollination and reduced fertility. The rlt1/2 mutant shows an early-flowering phenotype, whereas the phenotype is not shared by the fha2 mutant. Consistent with the functional specificity of FHA2, our RNA-seq analysis indicated that the fha2 mutant affects a subset of RLT1/2-regulated genes that does not include genes involved in the regulation of flowering time. This study demonstrates that FHA2 functions as a previously uncharacterized subunit of the Arabidopsis ISWI complex and is exclusively involved in regulating stamen development and plant fertility.
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http://dx.doi.org/10.1111/jipb.12945DOI Listing
November 2020

Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals.

Sci Transl Med 2020 05;12(542)

National Institute of Biological Sciences, Beijing 102206, China.

Transcriptional regulation lies at the core of the circadian clockwork, but how the clock-related transcription machinery controls the circadian phase is not understood. Here, we show both in human cells and in mice that RuvB-like ATPase 2 (RUVBL2) interacts with other known clock proteins on chromatin to regulate the circadian phase. Pharmacological perturbation of RUVBL2 with the adenosine analog compound cordycepin resulted in a rapid-onset 12-hour clock phase-shift phenotype at human cell, mouse tissue, and whole-animal live imaging levels. Using simple peripheral injection treatment, we found that cordycepin penetrated the blood-brain barrier and caused rapid entrainment of the circadian phase, facilitating reduced duration of recovery in a mouse jet-lag model. We solved a crystal structure for human RUVBL2 in complex with a physiological metabolite of cordycepin, and biochemical assays showed that cordycepin treatment caused disassembly of an interaction between RUVBL2 and the core clock component BMAL1. Moreover, we showed with spike-in ChIP-seq analysis and binding assays that cordycepin treatment caused disassembly of the circadian super-complex, which normally resides at E-box chromatin loci such as , , and Mathematical modeling supported that the observed type 0 phase shifts resulted from derepression of E-box clock gene transcription.
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http://dx.doi.org/10.1126/scitranslmed.aba0769DOI Listing
May 2020

Dual Recognition of H3K4me3 and DNA by the ISWI Component ARID5 Regulates the Floral Transition in Arabidopsis.

Plant Cell 2020 07 30;32(7):2178-2195. Epub 2020 Apr 30.

National Institute of Biological Sciences, Beijing 102206, China

Chromatin remodeling and histone modifications are important for development and floral transition in plants. However, it is largely unknown whether and how these two epigenetic regulators coordinately regulate the important biological processes. Here, we identified three types of Imitation Switch (ISWI) chromatin-remodeling complexes in Arabidopsis (). We found that AT-RICH INTERACTING DOMAIN5 (ARID5), a subunit of a plant-specific ISWI complex, can regulate development and floral transition. The ARID-PHD dual domain cassette of ARID5 recognizes both the H3K4me3 histone mark and AT-rich DNA. We determined the ternary complex structure of the ARID5 ARID-PHD cassette with an H3K4me3 peptide and an AT-containing DNA. The H3K4me3 peptide is combinatorially recognized by the PHD and ARID domains, while the DNA is specifically recognized by the ARID domain. Both PHD and ARID domains are necessary for the association of ARID5 with chromatin. The results suggest that the dual recognition of AT-rich DNA and H3K4me3 by the ARID5 ARID-PHD cassette may facilitate the association of the ISWI complex with specific chromatin regions to regulate development and floral transition.
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http://dx.doi.org/10.1105/tpc.19.00944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346560PMC
July 2020