Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome
Abstract
:1. Introduction
2. Results
2.1. Data Pre-Processing and Identification of Common Genes
2.2. Weighted Gene Co-Expression Networks
2.3. Correlation between Modules and Clinical Traits
2.4. Different Brain Tissues/Models Generate Modules of Dysregulated Genes
2.5. Module Analysis
2.6. Key Cellular Pathways Involved in Synapses Dysregulated in Rett Models
2.7. Differential Gene Expression in iPSC Derived Neurons (OH) and Postmortem (MT) Datasets
3. Discussion
3.1. Meta-Analyses Produced Four Significant Modules Correlated to Disease Status
3.2. Meta-Analysis Hub Genes within the Skyblue Module Are Relevant to RTT Pathology
3.3. Meta-Analysis Shows Commonly Dysregulated Synaptic Pathways
3.4. Expression of Overlapping Genes in MT and OH in Comparison to Skyblue
3.5. Hub Gene Expression Comparison across Studies
4. Materials and Methods
4.1. Dataset Selection
4.2. Dataset Pre-Processing
4.3. Weighted Gene Correlation Analysis
4.4. Module Selection
4.5. Module Enrichment
4.6. Module Visualisation and Identification of Hub Genes
4.7. Differential Gene Expression
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Neul, J.L.; Kaufmann, W.E.; Glaze, D.G.; Christodoulou, J.; Clarke, A.J.; Bahi-Buisson, N.; Leonard, H.; Bailey, M.E.S.; Schanen, N.C.; Zappella, M.; et al. Rett syndrome: Revised diagnostic criteria and nomenclature. Ann. Neurol. 2010, 68, 944–950. [Google Scholar] [CrossRef]
- Ward, C.S.; Huang, T.-W.; Herrera, J.A.; Samaco, R.C.; McGraw, C.M.; Parra, D.E.; Arvide, E.M.; Ito-Ishida, A.; Meng, X.; Ure, K.; et al. Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia. Front. Neurol. 2020, 11, 593554. [Google Scholar] [CrossRef]
- Meehan, R.; Lewis, J.D.; Bird, A.P. Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res. 1992, 20, 5085–5092. [Google Scholar] [CrossRef]
- Gabel, H.W.; Kinde, B.Z.; Stroud, H.; Gilbert, C.S.; Harmin, D.A.; Kastan, N.R.; Hemberg, M.; Ebert, D.H.; Greenberg, M.E. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 2015, 522, 89–93. [Google Scholar] [CrossRef] [PubMed]
- Guo, J.U.; Su, Y.; Shin, J.H.; Shin, J.; Li, H.; Xie, B.; Song, H. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat. Neurosci. 2014, 17, 215–222. [Google Scholar] [CrossRef]
- Pietri, T.; Roman, A.C.; Guyon, N.; Romano, S.A.; Washbourne, P.; Moens, C.B.; de Polavieja, G.G.; Sumbre, G. The first mecp2-null zebrafish model shows altered motor behaviors. Front. Neural Circuits 2013, 7, 118. [Google Scholar] [CrossRef]
- Chahrour, M.; Jung, S.Y.; Shaw, C.; Zhou, X.; Wong, S.T.C.; Qin, J.; Zoghbi, H.Y. MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription. Science 2008, 320, 1224–1229. [Google Scholar] [CrossRef]
- Young, J.I.; Hong, E.P.; Castle, J.C.; Crespo-Barreto, J.; Bowman, A.B.; Rose, M.F.; Zoghbi, H.Y. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc. Natl. Acad. Sci. USA 2005, 102, 17551–17558. [Google Scholar] [CrossRef]
- Boxer, L.; Renthal, W.; Greben, A.W.; Whitwam, T.; Silberfeld, A.; Stroud, H.; Li, E.; Yang, M.G.; Kinde, B.; Griffith, E.; et al. MeCP2 Represses the Rate of Transcriptional Initiation of Highly Methylated Long Genes. Mol. Cell 2019, 77, 294–309.e9. [Google Scholar] [CrossRef]
- Li, W. Excitation and Inhibition Imbalance in Rett Syndrome. Front. Neurosci. 2022, 16, 825063. [Google Scholar] [CrossRef]
- Krishnaraj, R.; Haase, F.; Coorey, B.; Luca, E.; Wong, I.; Boyling, A.; Ellaway, C.; Christodoulou, J.; Gold, W.A. Genome-wide transcriptomic and proteomic studies of Rett syndrome mouse models identify common signaling pathways and cellular functions as potential therapeutic targets. Hum. Mutat. 2019, 40, 2184–2196. [Google Scholar] [CrossRef] [PubMed]
- Clowry, G.; Molnár, Z.; Rakic, P. Renewed focus on the developing human neocortex. J. Anat. 2010, 217, 276–288. [Google Scholar] [CrossRef] [PubMed]
- Dolmetsch, R.; Geschwind, D.H. The human brain in a dish: The promise of iPSC-derived neurons. Cell 2011, 145, 831–834. [Google Scholar] [CrossRef]
- Marchetto, M.C.; Carromeu, C.; Acab, A.; Yu, D.; Yeo, G.W.; Mu, Y.; Chen, G.; Gage, F.H.; Muotri, A.R. A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells. Cell 2010, 143, 527–539. [Google Scholar] [CrossRef]
- Takahashi, K.; Yamanaka, S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 2006, 126, 663–676. [Google Scholar] [CrossRef]
- Yamanaka, S. Induced Pluripotent Stem Cells: Past, Present, and Future. Cell Stem Cell 2012, 10, 678–684. [Google Scholar] [CrossRef]
- Hinz, L.; Hoekstra, S.D.; Watanabe, K.; Posthuma, D.; Heine, V.M. Generation of Isogenic Controls for In Vitro Disease Modelling of X-Chromosomal Disorders. Stem Cell Rev. Rep. 2019, 15, 276–285. [Google Scholar] [CrossRef] [PubMed]
- Belichenko, P.V.; Wright, E.E.; Belichenko, N.P.; Masliah, E.; Li, H.H.; Mobley, W.C.; Francke, U. Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of rett syndrome: Evidence for disruption of neuronal networks. J. Comp. Neurol. 2009, 514, 240–258. [Google Scholar] [CrossRef]
- Trujillo, C.; Gao, R.; Negraes, P.; Chaim, I.; Domissy, A.; Vandenberghe, M.; Devor, A.; Yeo, G.; Voytek, B.; Muotri, A. Nested oscillatory dynamics in cortical organoids model early human brain network development. bioRxiv 2018. [Google Scholar] [CrossRef]
- Kim, J.J.; Savas, J.N.; Miller, M.T.; Hu, X.; Carromeu, C.; Lavallée-Adam, M.; Freitas, B.C.G.; Muotri, A.R.; Yates, J.R.; Ghosh, A. Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function. PLoS ONE 2019, 14, e0212553. [Google Scholar] [CrossRef]
- Kim, K.Y.; Hysolli, E.; Park, I.H. Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc. Natl. Acad. Sci. USA 2011, 108, 14169–14174. [Google Scholar] [CrossRef] [PubMed]
- de Souza, J.S.; Carromeu, C.; Torres, L.B.; Araujo, B.H.; Cugola, F.R.; Maciel, R.; Giannocco, G. IGF1 neuronal response in the absence of MECP2 is dependent on TRalpha 3. Hum. Mol. Genet. 2017, 26, 270–281. [Google Scholar] [CrossRef] [PubMed]
- Rodrigues, D.C.; Kim, D.-S.; Yang, G.; Zaslavsky, K.; Ha, K.; Mok, R.S.; Ross, P.; Zhao, M.; Piekna, A.; Wei, W.; et al. MECP2 Is Post-transcriptionally Regulated during Human Neurodevelopment by Combinatorial Action of RNA-Binding Proteins and miRNAs. Cell Rep. 2016, 17, 720–734. [Google Scholar] [CrossRef] [PubMed]
- Chen, R.Z.; Akbarian, S.; Tudor, M.; Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 2001, 27, 327–331. [Google Scholar] [CrossRef] [PubMed]
- Matagne, V.; Borloz, E.; Ehinger, Y.; Saidi, L.; Villard, L.; Roux, J.-C. Severe offtarget effects following intravenous delivery of AAV9-MECP2 in a female mouse model of Rett syndrome. Neurobiol. Dis. 2021, 149, 105235. [Google Scholar] [CrossRef]
- Rodrigues, D.C.; Mufteev, M.; Ellis, J. Regulation, diversity and function of MECP2 exon and 3’UTR isoforms. Hum. Mol. Genet. 2020, 29, R89–R99. [Google Scholar] [CrossRef]
- Pacheco, N.L.; Heaven, M.R.; Holt, L.M.; Crossman, D.K.; Boggio, K.J.; Shaffer, S.A.; Flint, D.L.; Olsen, M.L. RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome. Mol. Autism 2017, 8, 1–24. [Google Scholar] [CrossRef]
- Matagne, V.; Ehinger, Y.; Saidi, L.; Borges-Correia, A.; Barkats, M.; Bartoli, M.; Villard, L.; Roux, J.-C. A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome. Neurobiol. Dis. 2017, 99, 1–11. [Google Scholar] [CrossRef]
- Ohashi, M.; Korsakova, E.; Allen, D.; Lee, P.; Fu, K.; Vargas, B.S.; Cinkornpumin, J.; Salas, C.; Park, J.C.; Germanguz, I. Loss of MECP2 leads to activation of P53 and neuronal senescence. Stem Cell Rep. 2018, 10, 1453–1463. [Google Scholar] [CrossRef]
- Kim, H.J.; Bayarsaikhan, D.; Lee, J.; Bayarsaikhan, G.; Lee, B. Brain-Derived Neurotrophic Factor Secreting Human Mesenchymal Stem Cells Improve Outcomes in Rett Syndrome Mouse Models. Front. Neurosci. 2021, 15, 725398. [Google Scholar] [CrossRef]
- Sun, Y.E.; Wu, H. The Ups and Downs of BDNF in Rett Syndrome. Neuron 2006, 49, 321–323. [Google Scholar] [CrossRef] [PubMed]
- Gold, W.; Williamson, S.; Kaur, S.; Hargreaves, I.; Land, J.; Pelka, G.; Tam, P.; Christodoulou, J. Mitochondrial dysfunction in the skeletal muscle of a mouse model of Rett syndrome (RTT): Implications for the disease phenotype. Mitochondrion 2014, 15, 10–17. [Google Scholar] [CrossRef]
- Kyle, S.M.; Vashi, N.; Justice, M.J. Rett syndrome: A neurological disorder with metabolic components. Open Biol. 2018, 8, 170216. [Google Scholar] [CrossRef] [PubMed]
- Marano, D.; Fioriniello, S.; Fiorillo, F.; Gibbons, R.J.; D’Esposito, M.; Della Ragione, F. ATRX Contributes to MeCP2-Mediated Pericentric Heterochromatin Organization during Neural Differentiation. Int. J. Mol. Sci. 2019, 20, 5371. [Google Scholar] [CrossRef]
- Gibbons, R.J.; Picketts, D.J.; Villard, L.; Higgs, D.R. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome). Cell 1995, 80, 837–845. [Google Scholar] [CrossRef]
- Nan, X.; Hou, J.; Maclean, A.; Nasir, J.; Lafuente, M.J.; Shu, X.; Kriaucionis, S.; Bird, A. Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc. Natl. Acad. Sci. USA 2007, 104, 2709–2714. [Google Scholar] [CrossRef] [PubMed]
- Valenzuela, M.; Amato, R.; Sgura, A.; Antoccia, A.; Berardinelli, F. The Multiple Facets of ATRX Protein. Cancers 2021, 13, 2211. [Google Scholar] [CrossRef]
- Ramamoorthy, M.; Smith, S. Loss of ATRX Suppresses Resolution of Telomere Cohesion to Control Recombination in ALT Cancer Cells. Cancer Cell 2015, 28, 357–369. [Google Scholar] [CrossRef]
- Kim, N.; Kim, K.H.; Lim, W.-J.; Kim, J.; Kim, S.A.; Yoo, H.J. Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder. Genes 2020, 12, 1. [Google Scholar] [CrossRef]
- Neul, J.L. The relationship of Rett syndrome and MECP2 disorders to autism. Dialog. Clin. Neurosci. 2012, 14, 253–262. [Google Scholar] [CrossRef]
- Percy, A.K. Rett syndrome: Exploring the autism link. Arch. Neurol. 2011, 68, 985–989. [Google Scholar] [CrossRef] [PubMed]
- Devasani, K.; Yao, Y. Expression and functions of adenylyl cyclases in the CNS. Fluids Barriers CNS 2022, 19, 23. [Google Scholar] [CrossRef]
- Bedogni, F.; Gigli, C.C.; Pozzi, D.; Rossi, R.L.; Scaramuzza, L.; Rossetti, G.; Pagani, M.; Kilstrup-Nielsen, C.; Matteoli, M.; Landsberger, N. Defects During Mecp2 Null Embryonic Cortex Development Precede the Onset of Overt Neurological Symptoms. Cereb. Cortex 2015, 26, 2517–2529. [Google Scholar] [CrossRef]
- De Felice, C.; Leoncini, S.; Signorini, C.; Cortelazzo, A.; Rovero, P.; Durand, T.; Hayek, J. Rett syndrome: An autoimmune disease? Autoimmun. Rev. 2016, 15, 411–416. [Google Scholar] [CrossRef] [PubMed]
- Fischer, L.R.; Igoudjil, A.; Magrané, J.; Li, Y.; Hansen, J.M.; Manfredi, G.; Glass, J.D. SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse. Brain 2010, 134, 196–209. [Google Scholar] [CrossRef] [PubMed]
- Damaj, L.; Lupien-Meilleur, A.; Lortie, A.; Riou, É.; Ospina, L.H.; Gagnon, L.; Vanasse, C.; Rossignol, E. CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. Eur. J. Hum. Genet. 2015, 23, 1505–1512. [Google Scholar] [CrossRef]
- Epperson, M.V.; Haws, M.E.; Standridge, S.M.; Gilbert, D.L. An Atypical Rett Syndrome Phenotype Due to a Novel Missense Mutation in CACNA1A. J. Child Neurol. 2018, 33, 286–289. [Google Scholar] [CrossRef]
- Minichiello, L.; Calella, A.M.; Medina, D.L.; Bonhoeffer, T.; Klein, R.; Korte, M. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 2002, 36, 121–137. [Google Scholar] [CrossRef]
- Corrêa, T.; Poswar, F.; Feltes, B.C.; Riegel, M. Candidate Genes Associated with Neurological Findings in a Patient with Trisomy 4p16.3 and Monosomy 5p15.2. Front. Genet. 2020, 11, 561. [Google Scholar] [CrossRef]
- Antona, V.; Scalia, F.; Giorgio, E.; Radio, F.; Brusco, A.; Oliveri, M.; Corsello, G.; Celso, F.L.; Vadalà, M.; De Macario, E.C.; et al. A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy. Int. J. Mol. Sci. 2020, 21, 7631. [Google Scholar] [CrossRef]
- Yamada, M.; Suzuki, K.; Mizutani, M.; Asada, A.; Matozaki, T.; Ikeuchi, T.; Hatanaka, H. Analysis of tyrosine phosphorylation-dependent protein-protein interactions in TrkB-mediated intracellular signaling using modified yeast two-hybrid system. J. Biochem. 2001, 130, 157–165. [Google Scholar] [CrossRef]
- Bu, Q.; Wang, A.; Hamzah, H.; Waldman, A.; Jiang, K.; Dong, Q.; Chang, Q. CREB Signaling Is Involved in Rett Syndrome Pathogenesis. J. Neurosci. Off. J. Soc.Neurosci. 2017, 37, 3671–3685. [Google Scholar] [CrossRef] [PubMed]
- Swinehart, B.D.; Bland, K.M.; Holley, Z.L.; Lopuch, A.J.; Casey, Z.O.; Handwerk, C.J.; Vidal, G.S. Integrin β3 organizes dendritic complexity of cerebral cortical pyramidal neurons along a tangential gradient. Mol. Brain 2020, 13, 168. [Google Scholar] [CrossRef]
- Jackson, M.E.; Homayoun, H.; Moghaddam, B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc. Natl. Acad. Sci. USA 2004, 101, 8467–8472. [Google Scholar] [CrossRef] [PubMed]
- Kron, M.; Howell, C.J.; Adams, I.T.; Ransbottom, M.; Christian, D.; Ogier, M.; Katz, D.M. Brain Activity Mapping in Mecp2 Mutant Mice Reveals Functional Deficits in Forebrain Circuits, Including Key Nodes in the Default Mode Network, that are Reversed with Ketamine Treatment. J. Neurosci. 2012, 32, 13860–13872. [Google Scholar] [CrossRef] [PubMed]
- Voituron, N.; Hilaire, G. The benzodiazepine Midazolam mitigates the breathing defects of Mecp2-deficient mice. Respir. Physiol. Neurobiol. 2011, 177, 56–60. [Google Scholar] [CrossRef]
- Dittmer, S.; Kovacs, Z.; Yuan, S.H.; Siszler, G.; Kögl, M.; Summer, H.; Geerts, A.; Golz, S.; Shioda, T.; Methner, A. TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex. J. Cell Sci. 2011, 124, 252–260. [Google Scholar] [CrossRef]
- Schipper, H.M.; Song, W.; Zukor, H.; Hascalovici, J.R.; Zeligman, D. Heme oxygenase-1 and neurodegeneration: Expanding frontiers of engagement. J. Neurochem. 2009, 110, 469–485. [Google Scholar] [CrossRef]
- Pozzo-Miller, L.; Pati, S.; Percy, A.K. Rett Syndrome: Reaching for Clinical Trials. Neurotherapeutics 2015, 12, 631–640. [Google Scholar] [CrossRef]
- Djukic, A.; Holtzer, R.; Shinnar, S.; Muzumdar, H.; Rose, S.A.; Mowrey, W.; Galanopoulou, A.S.; Shinnar, R.; Jankowski, J.J.; Feldman, J.F.; et al. Pharmacologic Treatment of Rett Syndrome with Glatiramer Acetate. Pediatr. Neurol. 2016, 61, 51–57. [Google Scholar] [CrossRef] [PubMed]
- Naegelin, Y.; Kuhle, J.; Schädelin, S.; Datta, A.N.; Magon, S.; Amann, M.; Barro, C.; Ramelli, G.P.; Heesom, K.; Barde, Y.-A.; et al. Fingolimod in children with Rett syndrome: The FINGORETT study. Orphanet J. Rare Dis. 2021, 16, 19. [Google Scholar] [CrossRef]
- Nissenkorn, A.; Kidon, M.; Ben-Zeev, B. A Potential Life-Threatening Reaction to Glatiramer Acetate in Rett Syndrome. Pediatr. Neurol. 2017, 68, 40–43. [Google Scholar] [CrossRef] [PubMed]
- Ritchie, M.E.; Belinda, P.; Wu, D.; Hu, Y.; Law, C.W.; Shi, W.; Smyth, G.K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015, 43, e47. [Google Scholar] [CrossRef]
- Law, C.W.; Chen, Y.; Shi, W.; Smyth, G.K. Voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014, 15, R29. [Google Scholar] [CrossRef] [PubMed]
- Langfelder, P.; Horvath, S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinform. 2008, 9, 559. [Google Scholar] [CrossRef]
- Kanehisa, M.; Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000, 28, 27–30. [Google Scholar] [CrossRef] [PubMed]
- Kanehisa, M.; Sato, Y.; Furumichi, M.; Morishima, K.; Tanabe, M. New approach for understanding genome variations in KEGG. Nucleic Acids Res. 2019, 47, D590–D595. [Google Scholar] [CrossRef]
- Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; von Mering, C. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021, 49, D605–D612. [Google Scholar] [CrossRef]
- Ehrhart, F.; Coort, S.; Cirillo, E.; Smeets, E.; Evelo, C.; Curfs, L. New insights in Rett syndrome using pathway analysis for transcriptomics data. Wien. Med. Wochenschr. 2016, 166, 346–352. [Google Scholar] [CrossRef] [Green Version]
Study | Sample | Age | Gender | Tissue | Disease State | Mutation |
---|---|---|---|---|---|---|
Post-mortem human brain GSE75303 | GSM1949097 | 19y 231d | F | frontal cortex | WT | NA |
GSM1949098 | 17y 28d | F | frontal cortex | WT | NA | |
GSM1949099 | 17y 28d | F | temporal cortex | WT | NA | |
GSM1949100 | 20y 228d | F | temporal cortex | WT | NA | |
GSM1949101 | 18y 138d | F | frontal cortex | WT | NA | |
GSM1949102 | 18y 138d | F | temporal cortex | WT | NA | |
GSM1949103 | 18y 130d | F | frontal cortex | RTT | c.378-2A > G | |
GSM1949104 | 18y 130d | F | temporal cortex | RTT | c.378-2A > G | |
GSM1949105 | 20y 356d | F | frontal cortex | RTT | c.763C > T | |
GSM1949106 | 20y 356d | F | temporal cortex | RTT | c.763C > T | |
GSM1949107 | 19y 280d | F | frontal cortex | RTT | c.451G > T | |
GSM1949108 | 19y 280d | F | temporal cortex | RTT | c.451G > T | |
iPSC-derived neurons GSE123753 | GSM3510829 | NA | F | neurons | WT | isogenic |
GSM3510835 | NA | F | neurons | MT | Exon 3–4 deletion | |
GSM3510857 | NA | F | neurons | WT | isogenic | |
GSM3510863 | NA | F | neurons | MT | Exon 3–4 deletion | |
GSM3510877 | NA | F | neurons | WT | isogenic | |
GSM3510883 | NA | F | neurons | MT | Exon 3–4 deletion | |
Mouse brain GSE96684 | GSM2538276 | P60 | M | cortex | WT | NA |
GSM2538277 | P60 | M | cortex | WT | NA | |
GSM2538278 | P60 | M | cortex | WT | NA | |
GSM2538279 | P60 | M | cortex | WT | NA | |
GSM2538280 | P60 | M | cortex | RTT | R168X | |
GSM2538281 | P60 | M | cortex | RTT | R168X | |
GSM2538282 | P60 | M | cortex | RTT | R168X | |
GSM2538283 | P60 | M | cortex | RTT | R168X |
Gene Symbol | Gene Function |
---|---|
MECP2 | Methyl-CpG-binding protein 2; a chromatin-associated protein that can both activate and repress transcription. It is required for maturation of neurons and is developmentally regulated. |
BDNF | Brain-derived neurotrophic factor; during development, promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the central nervous system (CNS). The versatility of BDNF is emphasised by its contribution to a range of adaptive neuronal responses including long-term potentiation (LTP), long-term depression (LTD), certain forms of short-term synaptic plasticity. |
CCT5 | T-complex protein 1 subunit epsilon; a molecular chaperone that assists the folding of proteins upon ATP hydrolysis. As part of the BBS/CCT protein complex it may play a role in the assembly of BBSome, a complex involved in ciliogenesis, regulating transport vesicles to the cilia. Known to play a role in vitro in the folding of actin and tubulin. |
CACNA1A | Voltage-dependent P/Q-type calcium channel subunit alpha-1A; voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the ‘high-voltage activated’ (HVA) group and are blocked by the funnel toxin (Ftx) and by omega-agatoxin-IVA (omega-Aga-IVA). |
ADCY9 | Adenylate cyclase type 9; an adenylyl cyclase that catalyses the formation of the signalling molecule cAMP in response to activation of G-protein-coupled receptors. Contributes to signalling cascades activated by CRH (corticotropin-releasing factor), corticosteroids and beta-adrenergic receptors. |
ADCY7 | Adenylate cyclase type 7; a membrane-bound, calcium-inhibitable adenylyl cyclase. |
ATRX | Transcriptional regulator ATRX; involved in transcriptional regulation and chromatin remodelling. Facilitates DNA replication in multiple cellular environments and is required for efficient replication of a subset of genomic loci. Binds to DNA tandem repeat sequences in both telomeres and euchromatin, and in vitro binds DNA quadruplex structures. May helpin stabilising G-rich regions into regular chromatin structures by remodelling G4 DNA and incorporating H3.3-containing nucleosomes. Catalytic component of the chromatin remodelling complex ATRX:DAXX, which has ATP-dependent DNA translocase activity. |
RPS9 | Small subunit ribosomal protein s9e; ribosomal protein S9. |
SOD1 | Superoxide dismutase [Cu-Zn]; destroys radicals that are normally produced within the cells and toxic to biological systems. |
PLCG1 | 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1; mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signalling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, FGFR1, FGFR2, FGFR3 and FGFR4. Plays a role in actin reorganisation and cell migration. |
Study | Sample | Gender | Tissue | Disease State | Mutation |
---|---|---|---|---|---|
Post-mortem human brain (MT) GSE6955 | GSM160306 | F | Superior Frontal Gyrus | WT | NA |
GSM160307 | F | Superior Frontal Gyrus | RTT | c.316C > T | |
GSM160308 | F | Superior Frontal Gyrus | WT | NA | |
GSM160309 | F | Superior Frontal Gyrus | RTT | c.316C > T | |
GSM160310 | F | Superior Frontal Gyrus | WT | NA | |
GSM160311 | F | Superior Frontal Gyrus x | WT | NA | |
GSM2866278 | F | neurons | WT | Isogenic (c.1461A > G) | |
GSM2866279 | F | neurons | WT | Isogenic (c.705delG) | |
iPSC-derived neurons (OH) GSE107399 | GSM2866281 | F | neurons | WT | Isogenic (c.705delG) |
GSM2866282 | F | neurons | RTT | c.1461A > G (replicate 1) | |
GSM3510883 | F | neurons | RTT | c.1461A > G (repiclate 2) | |
GSM3510885 | F | neurons | RTT | c.705delG (replicate 1) | |
GSM3510886 | F | neurons | RTT | c.705delG (replicate 2) |
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Haase, F.; Singh, R.; Gloss, B.; Tam, P.; Gold, W. Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome. Int. J. Mol. Sci. 2022, 23, 11125. https://doi.org/10.3390/ijms231911125
Haase F, Singh R, Gloss B, Tam P, Gold W. Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome. International Journal of Molecular Sciences. 2022; 23(19):11125. https://doi.org/10.3390/ijms231911125
Chicago/Turabian StyleHaase, Florencia, Rachna Singh, Brian Gloss, Patrick Tam, and Wendy Gold. 2022. "Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome" International Journal of Molecular Sciences 23, no. 19: 11125. https://doi.org/10.3390/ijms231911125