Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells
Abstract
:1. Introduction
2. Results
2.1. EZH2 Is a Transcriptional Node Controlling Genes Regulated by GLT and HDAC3 Inhibition
2.2. EZH2 Attenuation Protects Against GLT-Induced Apoptosis
2.3. EZH2 Attenuation Protects the β-Cell against GLT-Induced ER Stress
2.4. EZH2 Attenuation Does Not Protect against GLT-Induced Insulin-Secretory Dysfunction
2.5. EZH2 KD Prevents Downregulation of the Non-Canonical NFκB Pathway
3. Discussion
4. Materials and Methods
4.1. Cell Culture and Reagents
4.2. Small Molecule Inhibitors
4.3. Lentiviral shRNA-Mediated EZH2 Knockdown
4.4. Generation of CRISPR/Cas9-Mediated Heterozygous EZH2 Expressing Cells
4.5. Human Islets
4.6. Mouse Islets
4.7. mRNA Microarray
4.8. Quantitative Real-Time PCR
4.9. Apoptosis
4.10. Immunoblotting
4.11. Insulin Secretion
4.12. Data Analysis
4.13. Data and Resource Availability
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ATF | Activating transcription factor |
Bcl2 | B-cell lymphoma 2 |
Bcl-xL | B-cell lymphoma-extra large |
BiP | Binding immunoglobulin protein |
CHOP | C/EBP homologous protein |
EED | Embryonic ectoderm development |
ER | Endoplasmic reticulum |
EZH2 | Enhancer of zeste homolog 2 |
FOS | Fos Proto-Oncogene |
GLT | Glucolipotoxicity |
HDAC | Histone deacetylase |
HMT | Histone-lysine N-methyltransferase |
ID1 | Inhibitor of DNA Binding 1 |
IκBα | Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha |
JNK | c-Jun N-terminal kinase |
IRE1 | Serine/threonine-protein kinase/endoribonuclease |
MSI2 | Musashi RNA Binding Protein 2 |
NEFA | Non-esterified fatty acid |
NFkB | Nuclear factor of kappa light polypeptide gene enhancer in B-cells |
PERK | Protein kinase RNA-like endoplasmic reticulum kinase |
PRC2 | Polycomb repressive complex 2 |
RbAp48 | Histone-Binding Protein Retinoblastoma-Binding Protein 4 |
SAM | S-adenosyl methionine |
SUZ12 | Suppressor of Zeste 12 |
T2D | Type 2 diabetes |
TNFRSF11B | Tumor Necrosis Factor Receptor Superfamily Member 11b |
sXBP1 | Spliced X-box-binding protein-1 |
References
- DeFronzo, R.A. Pathogenesis of type 2 diabetes mellitus. Med. Clin. N. Am. 2004, 88, 787–835. [Google Scholar] [CrossRef] [PubMed]
- Ling, C.; Groop, L. Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes 2009, 58, 2718–2725. [Google Scholar] [CrossRef] [Green Version]
- Maedler, K.; Spinas, G.A.; Dyntar, D.; Moritz, W.; Kaiser, N.; Donath, M.Y. Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function. Diabetes 2001, 50, 69–76. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cunha, D.A.; Hekerman, P.; Ladriere, L.; Bazarra-Castro, A.; Ortis, F.; Wakeham, M.C.; Moore, F.; Rasschaert, J.; Cardozo, A.K.; Bellomo, E.; et al. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J. Cell Sci. 2008, 121, 2308–2318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, Y.P.; Grill, V.E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J. Clin. Investig. 1994, 93, 870–876. [Google Scholar] [CrossRef] [Green Version]
- Carpentier, A.; Mittelman, S.D.; Lamarche, B.; Bergman, R.N.; Giacca, A.; Lewis, G.F. Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. Am. J. Physiol. 1999, 276, E1055–E1066. [Google Scholar] [CrossRef]
- Michaliszyn, S.F.; Bonadonna, R.C.; Sjaarda, L.A.; Lee, S.; Farchoukh, L.; Arslanian, S.A. Beta-Cell lipotoxicity in response to free fatty acid elevation in prepubertal youth: African American versus Caucasian contrast. Diabetes 2013, 62, 2917–2922. [Google Scholar] [CrossRef] [Green Version]
- Leahy, J.L.; Cooper, H.E.; Deal, D.A.; Weir, G.C. Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions. J. Clin. Investig. 1986, 77, 908–915. [Google Scholar] [CrossRef] [Green Version]
- Briaud, I.; Rouault, C.; Reach, G.; Poitout, V. Long-term exposure of isolated rat islets of Langerhans to supraphysiologic glucose concentrations decreases insulin mRNA levels. Metab. Clin. Exp. 1999, 48, 319–323. [Google Scholar] [CrossRef]
- Federici, M.; Hribal, M.; Perego, L.; Ranalli, M.; Caradonna, Z.; Perego, C.; Usellini, L.; Nano, R.; Bonini, P.; Bertuzzi, F.; et al. High glucose causes apoptosis in cultured human pancreatic islets of Langerhans: A potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes 2001, 50, 1290–1301. [Google Scholar] [CrossRef] [Green Version]
- Malmgren, S.; Spegel, P.; Danielsson, A.P.; Nagorny, C.L.; Andersson, L.E.; Nitert, M.D.; Ridderstrale, M.; Mulder, H.; Ling, C. Coordinate changes in histone modifications, mRNA levels, and metabolite profiles in clonal INS-1 832/13 beta-cells accompany functional adaptations to lipotoxicity. J. Biol. Chem. 2013, 288, 11973–11987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lundby, A.; Lage, K.; Weinert, B.T.; Bekker-Jensen, D.B.; Secher, A.; Skovgaard, T.; Kelstrup, C.D.; Dmytriyev, A.; Choudhary, C.; Lundby, C.; et al. Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep. 2012, 2, 419–431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mosley, A.L.; Ozcan, S. The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose. J. Biol. Chem. 2004, 279, 54241–54247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Christensen, D.P.; Dahllof, M.; Lundh, M.; Rasmussen, D.N.; Nielsen, M.D.; Billestrup, N.; Grunnet, L.G.; Mandrup-Poulsen, T. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol. Med. (Camb. Mass.) 2011, 17, 378–390. [Google Scholar] [CrossRef] [PubMed]
- Plaisance, V.; Rolland, L.; Gmyr, V.; Annicotte, J.S.; Kerr-Conte, J.; Pattou, F.; Abderrahmani, A. The class I histone deacetylase inhibitor MS-275 prevents pancreatic beta cell death induced by palmitate. J. Diabetes Res. 2014, 2014, 195739. [Google Scholar] [CrossRef] [PubMed]
- Wagner, F.F.; Lundh, M.; Kaya, T.; McCarren, P.; Zhang, Y.L.; Chattopadhyay, S.; Gale, J.P.; Galbo, T.; Fisher, S.L.; Meier, B.C.; et al. An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in beta-Cell Protection. ACS Chem. Biol. 2016, 11, 363–374. [Google Scholar] [CrossRef] [PubMed]
- Lundh, M.; Galbo, T.; Poulsen, S.S.; Mandrup-Poulsen, T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes. Metab. 2015, 17, 703–707. [Google Scholar] [CrossRef]
- Larsen, L.; Tonnesen, M.; Ronn, S.G.; Storling, J.; Jorgensen, S.; Mascagni, P.; Dinarello, C.A.; Billestrup, N.; Mandrup-Poulsen, T. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia 2007, 50, 779–789. [Google Scholar] [CrossRef]
- Lundh, M.; Christensen, D.P.; Rasmussen, D.N.; Mascagni, P.; Dinarello, C.A.; Billestrup, N.; Grunnet, L.G.; Mandrup-Poulsen, T. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines. Diabetologia 2010, 53, 2569–2578. [Google Scholar] [CrossRef] [Green Version]
- Christensen, D.P.; Gysemans, C.; Lundh, M.; Dahllof, M.S.; Noesgaard, D.; Schmidt, S.F.; Mandrup, S.; Birkbak, N.; Workman, C.T.; Piemonti, L.; et al. Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and beta-cell protection. Proc. Natl. Acad. Sci. USA 2014, 111, 1055–1059. [Google Scholar] [CrossRef] [Green Version]
- Di Croce, L.; Helin, K. Transcriptional regulation by Polycomb group proteins. Nat. Struct. Amp. Mol. Biol. 2013, 20, 1147. [Google Scholar] [CrossRef]
- Kim, E.; Kim, M.; Woo, D.H.; Shin, Y.; Shin, J.; Chang, N.; Oh, Y.T.; Kim, H.; Rheey, J.; Nakano, I.; et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 2013, 23, 839–852. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, J.M.; Lee, J.S.; Kim, H.; Kim, K.; Park, H.; Kim, J.Y.; Lee, S.H.; Kim, I.S.; Kim, J.; Lee, M.; et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol. Cell 2012, 48, 572–586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shi, B.; Liang, J.; Yang, X.; Wang, Y.; Zhao, Y.; Wu, H.; Sun, L.; Zhang, Y.; Chen, Y.; Li, R.; et al. Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol. Cell. Biol. 2007, 27, 5105–5119. [Google Scholar] [CrossRef] [Green Version]
- Xu, K.; Wu, Z.J.; Groner, A.C.; He, H.H.; Cai, C.; Lis, R.T.; Wu, X.; Stack, E.C.; Loda, M.; Liu, T.; et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 2012, 338, 1465–1469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, S.T.; Li, Z.; Wu, Z.; Aau, M.; Guan, P.; Karuturi, R.K.; Liou, Y.C.; Yu, Q. Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol. Cell 2011, 43, 798–810. [Google Scholar] [CrossRef] [PubMed]
- Hamid, T.; Guo, S.Z.; Kingery, J.R.; Xiang, X.; Dawn, B.; Prabhu, S.D. Cardiomyocyte NF-kappaB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc. Res. 2011, 89, 129–138. [Google Scholar] [CrossRef]
- Xu, C.; Bailly-Maitre, B.; Reed, J.C. Endoplasmic reticulum stress: Cell life and death decisions. J. Clin. Investig. 2005, 115, 2656–2664. [Google Scholar] [CrossRef] [Green Version]
- Shao, C.; Lawrence, M.C.; Cobb, M.H. Regulation of CCAAT/enhancer-binding protein homologous protein (CHOP) expression by interleukin-1 beta in pancreatic beta cells. J. Biol. Chem. 2010, 285, 19710–19719. [Google Scholar] [CrossRef] [Green Version]
- Xu, C.R.; Li, L.C.; Donahue, G.; Ying, L.; Zhang, Y.W.; Gadue, P.; Zaret, K.S. Dynamics of genomic H3K27me3 domains and role of EZH2 during pancreatic endocrine specification. Embo J. 2014, 33, 2157–2170. [Google Scholar] [CrossRef] [Green Version]
- Lu, T.T.; Heyne, S.; Dror, E.; Casas, E.; Leonhardt, L.; Boenke, T.; Yang, C.H.; Sagar; Arrigoni, L.; Dalgaard, K.; et al. The Polycomb-Dependent Epigenome Controls beta Cell Dysfunction, Dedifferentiation, and Diabetes. Cell Metab. 2018, 27, 1294–1308.e1297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Y.; Sun, J.; Ni, Q.; Nie, A.; Gu, Y.; Wang, S.; Zhang, W.; Ning, G.; Wang, W.; Wang, Q. Dual Effect of Raptor on Neonatal beta-Cell Proliferation and Identity Maintenance. Diabetes 2019, 68, 1950–1964. [Google Scholar] [CrossRef]
- Chen, H.; Gu, X.; Su, I.H.; Bottino, R.; Contreras, J.L.; Tarakhovsky, A.; Kim, S.K. Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 2009, 23, 975–985. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Auerbach, R.K.; Chen, B.; Butte, A.J. Relating genes to function: Identifying enriched transcription factors using the ENCODE ChIP-Seq significance tool. Bioinform. (Oxf. Engl.) 2013, 29, 1922–1924. [Google Scholar] [CrossRef] [Green Version]
- Tan, J.; Yang, X.; Zhuang, L.; Jiang, X.; Chen, W.; Lee, P.L.; Karuturi, R.K.; Tan, P.B.; Liu, E.T.; Yu, Q. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007, 21, 1050–1063. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, Z.L.; Zheng, S.S.; Li, Z.M.; Qiao, Y.Y.; Aau, M.Y.; Yu, Q. Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell Death Differ. 2010, 17, 801–810. [Google Scholar] [CrossRef] [Green Version]
- Viatour, P.; Bentires-Alj, M.; Chariot, A.; Deregowski, V.; de Leval, L.; Merville, M.P.; Bours, V. NF- kappa B2/p100 induces Bcl-2 expression. Leukemia 2003, 17, 1349–1356. [Google Scholar] [CrossRef] [Green Version]
- Bujisic, B.; De Gassart, A.; Tallant, R.; Demaria, O.; Zaffalon, L.; Chelbi, S.; Gilliet, M.; Bertoni, F.; Martinon, F. Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth. Blood 2017, 129, 2420–2428. [Google Scholar] [CrossRef] [Green Version]
- Wan, J.; Zhan, J.; Li, S.; Ma, J.; Xu, W.; Liu, C.; Xue, X.; Xie, Y.; Fang, W.; Chin, Y.E.; et al. PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression. Nucleic Acids Res. 2015, 43, 3591–3604. [Google Scholar] [CrossRef] [Green Version]
- Gregoire, S.; Xiao, L.; Nie, J.; Zhang, X.; Xu, M.; Li, J.; Wong, J.; Seto, E.; Yang, X.J. Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2. Mol. Cell. Biol. 2007, 27, 1280–1295. [Google Scholar] [CrossRef] [Green Version]
- Zhang, X.; Zhao, X.; Fiskus, W.; Lin, J.; Lwin, T.; Rao, R.; Zhang, Y.; Chan, J.C.; Fu, K.; Marquez, V.E.; et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 2012, 22, 506–523. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Takashina, T.; Kinoshita, I.; Kikuchi, J.; Shimizu, Y.; Sakakibara-Konishi, J.; Oizumi, S.; Nishimura, M.; Dosaka-Akita, H. Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells. Cancer Sci. 2016, 107, 955–962. [Google Scholar] [CrossRef] [PubMed]
- Dinarello, C.A.; Fossati, G.; Mascagni, P. Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol. Med. (Camb. Mass.) 2011, 17, 333–352. [Google Scholar] [CrossRef]
- Akerfeldt, M.C.; Laybutt, D.R. Inhibition of Id1 augments insulin secretion and protects against high-fat diet-induced glucose intolerance. Diabetes 2011, 60, 2506–2514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Szabat, M.; Kalynyak, T.B.; Lim, G.E.; Chu, K.Y.; Yang, Y.H.; Asadi, A.; Gage, B.K.; Ao, Z.; Warnock, G.L.; Piret, J.M.; et al. Musashi expression in beta-cells coordinates insulin expression, apoptosis and proliferation in response to endoplasmic reticulum stress in diabetes. Cell Death Dis. 2011, 2, e232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lundh, M.; Christensen, D.P.; Damgaard Nielsen, M.; Richardson, S.J.; Dahllöf, M.S.; Skovgaard, T.; Berthelsen, J.; Dinarello, C.A.; Stevenazzi, A.; Mascagni, P.; et al. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children. Diabetologia 2012, 55, 2421–2431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Glauser, D.A.; Brun, T.; Gauthier, B.R.; Schlegel, W. Transcriptional response of pancreatic beta cells to metabolic stimulation: Large scale identification of immediate-early and secondary response genes. BMC Mol. Biol. 2007, 8, 54. [Google Scholar] [CrossRef] [Green Version]
- Schrader, J.; Rennekamp, W.; Niebergall, U.; Schoppet, M.; Jahr, H.; Brendel, M.D.; Hörsch, D.; Hofbauer, L.C. Cytokine-induced osteoprotegerin expression protects pancreatic beta cells through p38 mitogen-activated protein kinase signalling against cell death. Diabetologia 2007, 50, 1243–1247. [Google Scholar] [CrossRef] [Green Version]
- O’Carroll, D.; Erhardt, S.; Pagani, M.; Barton, S.C.; Surani, M.A.; Jenuwein, T. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 2001, 21, 4330–4336. [Google Scholar] [CrossRef] [Green Version]
- McCabe, M.T.; Ott, H.M.; Ganji, G.; Korenchuk, S.; Thompson, C.; Van Aller, G.S.; Liu, Y.; Graves, A.P.; Della Pietra, A., III; Diaz, E.; et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012, 492, 108–112. [Google Scholar] [CrossRef]
- Verma, S.K.; Tian, X.; LaFrance, L.V.; Duquenne, C.; Suarez, D.P.; Newlander, K.A.; Romeril, S.P.; Burgess, J.L.; Grant, S.W.; Brackley, J.A.; et al. Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med. Chem. Lett. 2012, 3, 1091–1096. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Janjic, D.; Maechler, P.; Sekine, N.; Bartley, C.; Annen, A.S.; Wolheim, C.B. Free radical modulation of insulin release in INS-1 cells exposed to alloxan. Biochem. Pharmacol. 1999, 57, 639–648. [Google Scholar] [CrossRef]
- Merglen, A.; Theander, S.; Rubi, B.; Chaffard, G.; Wollheim, C.B.; Maechler, P. Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells. Endocrinology 2004, 145, 667–678. [Google Scholar] [CrossRef]
- Ghiasi, S.M.; Dahlby, T.; Hede Andersen, C.; Haataja, L.; Petersen, S.; Omar-Hmeadi, M.; Yang, M.; Pihl, C.; Bresson, S.E.; Khilji, M.S.; et al. Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential for Proinsulin Handling. Diabetes 2019, 68, 747–760. [Google Scholar] [CrossRef] [PubMed]
- Okonechnikov, K.; Golosova, O.; Fursov, M. Unipro UGENE: A unified bioinformatics toolkit. Bioinformatics 2012, 28, 1166–1167. [Google Scholar] [CrossRef] [Green Version]
- Gasteiger, E.; Gattiker, A.; Hoogland, C.; Ivanyi, I.; Appel, R.D.; Bairoch, A. ExPASy: The proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res. 2003, 31, 3784–3788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gentleman, R.C.; Carey, V.J.; Bates, D.M.; Bolstad, B.; Dettling, M.; Dudoit, S.; Ellis, B.; Gautier, L.; Ge, Y.; Gentry, J.; et al. Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol. 2004, 5, R80. [Google Scholar] [CrossRef] [Green Version]
- Gautier, L.; Cope, L.; Bolstad, B.M.; Irizarry, R.A. Affy—Analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 2004, 20, 307–315. [Google Scholar] [CrossRef]
- Gentleman, R.; Carey, V.; Huber, W.; Hahne, F. Genefilter: Genefilter: Methods for Filtering Genes from High-Throughput Experiments; R Package Version 1.42.0; Bioconductor: Seattle, WA, USA, 2013. [Google Scholar]
- Gentleman, R. Annotate: Annotation for Microarrays; R Package Version 1.38.0; Bioconductor: Seattle, WA, USA, 2013. [Google Scholar]
- Warnes, G.R.; Bolker, B.; Bonebakker, L.; Gentleman, R.; Liaw, W.H.A.; Lumley, T.; Maechler, M.; Magnusson, A.; Moeller, S.; Schwartz, M.; et al. Gplots: Various R Programming Tools for Plotting Data; R Package Version 2.12.1; Comprehensive R Archive Network: Vienna, Austria, 2013. [Google Scholar]
- Carlson, M. Rat2302.db: Affymetrix Rat Genome 230 2.0 Array Annotation Data (Chip Rat2302); R Package Version 2.9.0; Bioconductor: Seattle, WA, USA, 2013. [Google Scholar]
- Haase, T.N.; Rasmussen, M.; Jaksch, C.A.; Gaarn, L.W.; Petersen, C.K.; Billestrup, N.; Nielsen, J.H. Growth arrest specific protein (GAS) 6: A role in the regulation of proliferation and functional capacity of the perinatal rat beta cell. Diabetologia 2013, 56, 763–773. [Google Scholar] [CrossRef]
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Dahlby, T.; Simon, C.; Backe, M.B.; Dahllöf, M.S.; Holson, E.; Wagner, B.K.; Böni-Schnetzler, M.; Marzec, M.T.; Lundh, M.; Mandrup-Poulsen, T. Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells. Int. J. Mol. Sci. 2020, 21, 8016. https://doi.org/10.3390/ijms21218016
Dahlby T, Simon C, Backe MB, Dahllöf MS, Holson E, Wagner BK, Böni-Schnetzler M, Marzec MT, Lundh M, Mandrup-Poulsen T. Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells. International Journal of Molecular Sciences. 2020; 21(21):8016. https://doi.org/10.3390/ijms21218016
Chicago/Turabian StyleDahlby, Tina, Christian Simon, Marie Balslev Backe, Mattias Salling Dahllöf, Edward Holson, Bridget K. Wagner, Marianne Böni-Schnetzler, Michal Tomasz Marzec, Morten Lundh, and Thomas Mandrup-Poulsen. 2020. "Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells" International Journal of Molecular Sciences 21, no. 21: 8016. https://doi.org/10.3390/ijms21218016