Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 Feb 2024
08 Feb 2024
Historique:
received:
16
06
2023
accepted:
15
01
2024
medline:
9
2
2024
pubmed:
9
2
2024
entrez:
8
2
2024
Statut:
epublish
Résumé
We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2
Identifiants
pubmed: 38331934
doi: 10.1038/s41467-024-45121-5
pii: 10.1038/s41467-024-45121-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1210Subventions
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : APP1155224
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : APP1163240
Informations de copyright
© 2024. The Author(s).
Références
Amberger, J. S., Bocchini, C. A., Schiettecatte, F., Scott, A. F. & Hamosh, A. OMIM.org: online mendelian inheritance in man (OMIM(R)), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 43, D789–D798 (2015).
pubmed: 25428349
doi: 10.1093/nar/gku1205
Ozlu, C., Bailey, R. M., Sinnett, S. & Goodspeed, K. D. Gene transfer therapy for neurodevelopmental disorders. Dev. Neurosci. 43, 230–240 (2021).
pubmed: 33882495
doi: 10.1159/000515434
Kumar, R. et al. THOC2 mutations implicate mRNA-export pathway in X-linked intellectual disability. Am. J. Hum. Genet. 97, 302–310 (2015).
pubmed: 26166480
pmcid: 4573269
doi: 10.1016/j.ajhg.2015.05.021
Kumar, R. et al. Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. Hum. Mutat. 39, 1126–1138 (2018).
pubmed: 29851191
pmcid: 6481655
doi: 10.1002/humu.23557
Kumar, R. et al. Expanding clinical presentations due to variations in THOC2 mRNA nuclear export factor. Front. Mol. Neurosci. 13, 12 (2020).
pubmed: 32116545
pmcid: 7026477
doi: 10.3389/fnmol.2020.00012
Wang, L. et al. The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming. Cell Stem Cell 13, 676–690 (2013).
pubmed: 24315442
pmcid: 3962795
doi: 10.1016/j.stem.2013.10.008
Heath, C. G., Viphakone, N. & Wilson, S. A. The role of TREX in gene expression and disease. Biochem. J. 473, 2911–2935 (2016).
pubmed: 27679854
doi: 10.1042/BCJ20160010
Folco, E. G., Lee, C. S., Dufu, K., Yamazaki, T. & Reed, R. The proteins PDIP3 and ZC11A associate with the human TREX complex in an ATP-dependent manner and function in mRNA export. PLoS One 7, e43804 (2012).
pubmed: 22928037
pmcid: 3426524
doi: 10.1371/journal.pone.0043804
Viphakone, N. et al. Luzp4 defines a new mRNA export pathway in cancer cells. Nucleic Acids Res. 43, 2353–2366 (2015).
pubmed: 25662211
pmcid: 4344508
doi: 10.1093/nar/gkv070
Pena, A. et al. Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor. EMBO J. 31, 1605–1616 (2012).
pubmed: 22314234
pmcid: 3321177
doi: 10.1038/emboj.2012.10
Puhringer, T. et al. Structure of the human core transcription-export complex reveals a hub for multivalent interactions. Elife 9, e61503 (2020).
pubmed: 33191911
pmcid: 7744094
doi: 10.7554/eLife.61503
Katahira, J. & Yoneda, Y. Roles of the TREX complex in nuclear export of mRNA. RNA Biol. 6, 149–152 (2009).
pubmed: 19229134
doi: 10.4161/rna.6.2.8046
Meinel, D. M. et al. Recruitment of TREX to the transcription machinery by its direct binding to the phospho-CTD of RNA polymerase II. PLoS Genet. 9, e1003914 (2013).
pubmed: 24244187
pmcid: 3828145
doi: 10.1371/journal.pgen.1003914
Cai, S. et al. Knockdown of THOC1 reduces the proliferation of hepatocellular carcinoma and increases the sensitivity to cisplatin. J. Exp. Clin. Cancer Res. 39, 135 (2020).
pubmed: 32669125
pmcid: 7362638
doi: 10.1186/s13046-020-01634-7
Castellano-Pozo, M., Garcia-Muse, T. & Aguilera, A. R-loops cause replication impairment and genome instability during meiosis. EMBO Rep. 13, 923–929 (2012).
pubmed: 22878416
pmcid: 3463965
doi: 10.1038/embor.2012.119
Salas-Armenteros, I. et al. Human THO-Sin3A interaction reveals new mechanisms to prevent R-loops that cause genome instability. EMBO J. 36, 3532–3547 (2017).
pubmed: 29074626
pmcid: 5709763
doi: 10.15252/embj.201797208
Gomez-Gonzalez, B. et al. Genome-wide function of THO/TREX in active genes prevents R-loop-dependent replication obstacles. EMBO J. 30, 3106–3119 (2011).
pubmed: 21701562
pmcid: 3160181
doi: 10.1038/emboj.2011.206
Castellano-Pozo, M., Garcia-Muse, T. & Aguilera, A. The Caenorhabditis elegans THO complex is required for the mitotic cell cycle and development. PLoS One 7, e52447 (2012).
pubmed: 23285047
pmcid: 3527488
doi: 10.1371/journal.pone.0052447
Dominguez-Sanchez, M. S., Barroso, S., Gomez-Gonzalez, B., Luna, R. & Aguilera, A. Genome instability and transcription elongation impairment in human cells depleted of THO/TREX. PLoS Genet. 7, e1002386 (2011).
pubmed: 22144908
pmcid: 3228816
doi: 10.1371/journal.pgen.1002386
Yamazaki, T. et al. The closely related RNA helicases, UAP56 and URH49, preferentially form distinct mRNA export machineries and coordinately regulate mitotic progression. Mol. Biol. Cell 21, 2953–2965 (2010).
pubmed: 20573985
pmcid: 2921121
doi: 10.1091/mbc.e09-10-0913
Rehwinkel, J. et al. Genome-wide analysis of mRNAs regulated by the THO complex in Drosophila melanogaster. Nat. Struct. Mol. Biol. 11, 558–566 (2004).
pubmed: 15133499
doi: 10.1038/nsmb759
Amsterdam, A. et al. Identification of 315 genes essential for early zebrafish development. Proc. Natl. Acad. Sci. USA 101, 12792–12797 (2004).
pubmed: 15256591
pmcid: 516474
doi: 10.1073/pnas.0403929101
Dickinson, M. E. et al. High-throughput discovery of novel developmental phenotypes. Nature 537, 508–514 (2016).
pubmed: 27626380
pmcid: 5295821
doi: 10.1038/nature19356
Chi, B. et al. Aly and THO are required for assembly of the human TREX complex and association of TREX components with the spliced mRNA. Nucleic Acids Res. 41, 1294–1306 (2013).
pubmed: 23222130
doi: 10.1093/nar/gks1188
Di Gregorio, E. et al. A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia. J. Med. Genet. 50, 543–551 (2013).
pubmed: 23749989
doi: 10.1136/jmedgenet-2013-101542
Woerner, A. C. et al. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science 351, 173–176 (2016).
pubmed: 26634439
doi: 10.1126/science.aad2033
Wang, T. et al. Identification and characterization of essential genes in the human genome. Science 350, 1096–1101 (2015).
pubmed: 26472758
pmcid: 4662922
doi: 10.1126/science.aac7041
Cardoso-Moreira, M. et al. Gene expression across mammalian organ development. Nature 571, 505–509 (2019).
pubmed: 31243369
pmcid: 6658352
doi: 10.1038/s41586-019-1338-5
Morris, R. G., Garrud, P., Rawlins, J. N. & O’Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).
pubmed: 7088155
doi: 10.1038/297681a0
Barnes, C. A. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J. Comp. Physiol. Psychol. 93, 74–104 (1979).
pubmed: 221551
doi: 10.1037/h0077579
Kraeuter, A. K., Guest, P. C. & Sarnyai, Z. The Y-maze for assessment of spatial working and reference memory in mice. Methods Mol. Biol. 1916, 105–111 (2019).
pubmed: 30535688
doi: 10.1007/978-1-4939-8994-2_10
Shiotsuki, H. et al. A rotarod test for evaluation of motor skill learning. J. Neurosci. Methods 189, 180–185 (2010).
pubmed: 20359499
doi: 10.1016/j.jneumeth.2010.03.026
Sashindranath, M., Daglas, M. & Medcalf, R. L. Evaluation of gait impairment in mice subjected to craniotomy and traumatic brain injury. Behav Brain Res. 286, 33–38 (2015).
pubmed: 25721743
doi: 10.1016/j.bbr.2015.02.038
Carola, V., D’Olimpio, F., Brunamonti, E., Mangia, F. & Renzi, P. Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behav Brain Res. 134, 49–57 (2002).
pubmed: 12191791
doi: 10.1016/S0166-4328(01)00452-1
Bourin, M. & Hascoet, M. The mouse light/dark box test. Eur. J. Pharmacol. 463, 55–65 (2003).
pubmed: 12600702
doi: 10.1016/S0014-2999(03)01274-3
Luong, T. N., Carlisle, H. J., Southwell, A. & Patterson, P. H. Assessment of motor balance and coordination in mice using the balance beam. J. Vis. Exp. 49, 2376 (2011).
Tennant, K. A. et al. The vermicelli and capellini handling tests: simple quantitative measures of dexterous forepaw function in rats and mice. J. Vis. Exp. 41, 2076 (2010).
Bouet, V. et al. The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nat. Protoc. 4, 1560–1564 (2009).
pubmed: 19798088
doi: 10.1038/nprot.2009.125
Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191–W198 (2019).
pubmed: 31066453
pmcid: 6602461
doi: 10.1093/nar/gkz369
Kochinke, K. et al. Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am. J. Hum. Genet. 98, 149–164 (2016).
pubmed: 26748517
pmcid: 4716705
doi: 10.1016/j.ajhg.2015.11.024
Toma, K., Wang, T. C. & Hanashima, C. Encoding and decoding time in neural development. Dev. Growth Differ. 58, 59–72 (2016).
pubmed: 26748623
doi: 10.1111/dgd.12257
Martinez-Cerdeno, V. & Noctor, S. C. Neural progenitor cell terminology. Front. Neuroanat. 12, 104 (2018).
pubmed: 30574073
pmcid: 6291443
doi: 10.3389/fnana.2018.00104
Liszewska, E. & Jaworski, J. Neural stem cell dysfunction in human brain disorders. Results Probl. Cell Differ. 66, 283–305 (2018).
pubmed: 30209665
doi: 10.1007/978-3-319-93485-3_13
Moortgat, S. et al. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients. Eur. J. Hum. Genet. 26, 64–74 (2018).
pubmed: 29180823
doi: 10.1038/s41431-017-0038-6
Stark, G. R. & Taylor, W. R. Analyzing the G2/M checkpoint. Methods Mol. Biol. 280, 51–82 (2004).
pubmed: 15187249
Mah, L. J., El-Osta, A. & Karagiannis, T. C. gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia 24, 679–686 (2010).
pubmed: 20130602
doi: 10.1038/leu.2010.6
Lu, Y., Liu, Y. & Yang, C. Evaluating in vitro DNA damage using comet assay. J. Vis. Exp. 128, 56450 (2017).
Allison, D. F. & Wang, G. G. R-loops: formation, function, and relevance to cell stress. Cell Stress 3, 38–46 (2019).
pubmed: 31225499
pmcid: 6551709
doi: 10.15698/cst2019.02.175
Hicks, T. et al. R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline. Nucleic Acids Res. 50, 8041–8059 (2022).
pubmed: 35871299
pmcid: 9371901
doi: 10.1093/nar/gkac621
Marabitti, V. et al. ATM pathway activation limits R-loop-associated genomic instability in Werner syndrome cells. Nucleic Acids Res. 47, 3485–3502 (2019).
pubmed: 30657978
pmcid: 6468170
doi: 10.1093/nar/gkz025
Ramirez, P., Crouch, R. J., Cheung, V. G. & Grunseich, C. R-loop analysis by dot-blot. J. Vis. Exp. 167, 62069 (2021).
Homan, C. C. et al. Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth. Am. J. Hum. Genet. 94, 470–478 (2014).
pubmed: 24607389
pmcid: 3951929
doi: 10.1016/j.ajhg.2014.02.004
Kato, M. Genotype-phenotype correlation in neuronal migration disorders and cortical dysplasias. Front. Neurosci. 9, 181 (2015).
pubmed: 26052266
pmcid: 4439546
doi: 10.3389/fnins.2015.00181
Durbec, P., Franceschini, I., Lazarini, F. & Dubois-Dalcq, M. In vitro migration assays of neural stem cells. Methods Mol. Biol. 438, 213–225 (2008).
pubmed: 18369761
doi: 10.1007/978-1-59745-133-8_18
Hardwick, L. J., Ali, F. R., Azzarelli, R. & Philpott, A. Cell cycle regulation of proliferation versus differentiation in the central nervous system. Cell Tissue Res. 359, 187–200 (2015).
pubmed: 24859217
doi: 10.1007/s00441-014-1895-8
Jolly, L. A., Homan, C. C., Jacob, R., Barry, S. & Gecz, J. The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth. Hum. Mol. Genet. 22, 4673–4687 (2013).
pubmed: 23821644
doi: 10.1093/hmg/ddt315
Mincheva-Tasheva, S., Nieto Guil, A. F., Homan, C. C., Gecz, J. & Thomas, P. Q. Disrupted excitatory synaptic contacts and altered neuronal network activity underpins the neurological phenotype in PCDH19-clustering epilepsy (PCDH19-CE). Mol. Neurobiol. 58, 2005–2018 (2021).
pubmed: 33411240
doi: 10.1007/s12035-020-02242-4
Rondon, A. G., Jimeno, S., Garcia-Rubio, M. & Aguilera, A. Molecular evidence that the eukaryotic THO/TREX complex is required for efficient transcription elongation. J. Biol. Chem. 278, 39037–39043 (2003).
pubmed: 12871933
doi: 10.1074/jbc.M305718200
Bai, X. et al. THOC2 and THOC5 regulate stemness and radioresistance in triple-negative breast cancer. Adv. Sci. (Weinh) 8, e2102658 (2021).
pubmed: 34708581
doi: 10.1002/advs.202102658
Gu, X. J., Li, Y. J., Wang, F. & Ye, T. MiR-30e-3p inhibits gastric cancer development by negatively regulating THO complex 2 and PI3K/AKT/mTOR signaling. World J. Gastrointest. Oncol. 14, 2170–2182 (2022).
pubmed: 36438699
pmcid: 9694264
doi: 10.4251/wjgo.v14.i11.2170
Mattioli, F. et al. Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Hum. Mol. Genet. 28, 952–960 (2019).
pubmed: 30476144
doi: 10.1093/hmg/ddy391
Zhou, X. et al. Knockdown THOC2 suppresses the proliferation and invasion of melanoma. Bioengineered 10, 635–645 (2019).
pubmed: 31680623
pmcid: 7567448
doi: 10.1080/21655979.2019.1685727
Alvarez-Mora, M. I. et al. Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders. Orphanet. J. Rare Dis. 17, 60 (2022).
pubmed: 35183220
pmcid: 8858550
doi: 10.1186/s13023-022-02213-z
Kamp, J. A. et al. THO complex deficiency impairs DNA double-strand break repair via the RNA surveillance kinase SMG-1. Nucleic Acids Res. 50, 6235–6250 (2022).
pubmed: 35670662
pmcid: 9226523
doi: 10.1093/nar/gkac472
Guria, A. et al. Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts. RNA 17, 1048–1056 (2011).
pubmed: 21525145
pmcid: 3096037
doi: 10.1261/rna.2607011
Tamhankar, V., Tamhankar, P., Chaubal, R., Chaubal, J. & Chaubal, N. Novel consensus splice site pathogenic variation in THOC2 gene leads to recurrent arthrogryposis multiplex congenita phenotype: a case report. Cureus 13, e19682 (2021).
pubmed: 34976470
pmcid: 8681921
Ye, Z., Bing, A., Zhao, S., Yi, S. & Zhan, X. Comprehensive analysis of spliceosome genes and their mutants across 27 cancer types in 9070 patients: clinically relevant outcomes in the context of 3P medicine. EPMA J. 13, 335–350 (2022).
pubmed: 35719132
pmcid: 9203615
doi: 10.1007/s13167-022-00279-0
Yuan, X. et al. THO complex-dependent posttranscriptional control contributes to vascular smooth muscle cell fate decision. Circ. Res. 123, 538–549 (2018).
pubmed: 30026254
doi: 10.1161/CIRCRESAHA.118.313527
Mancini, A. et al. THOC5/FMIP, an mRNA export TREX complex protein, is essential for hematopoietic primitive cell survival in vivo. BMC Biol. 8, 1 (2010).
pubmed: 20051105
pmcid: 2806247
doi: 10.1186/1741-7007-8-1
Pitzonka, L. et al. The THO ribonucleoprotein complex is required for stem cell homeostasis in the adult mouse small intestine. Mol. Cell Biol. 33, 3505–3514 (2013).
pubmed: 23816884
pmcid: 3753850
doi: 10.1128/MCB.00751-13
Verma, V., Paul, A., Amrapali Vishwanath, A., Vaidya, B. & Clement, J. P. Understanding intellectual disability and autism spectrum disorders from common mouse models: synapses to behaviour. Open Biol. 9, 180265 (2019).
pubmed: 31185809
pmcid: 6597757
doi: 10.1098/rsob.180265
Bourgeron, T. A synaptic trek to autism. Curr. Opin. Neurobiol. 19, 231–234 (2009).
pubmed: 19545994
doi: 10.1016/j.conb.2009.06.003
Robbins, E. M. et al. SynCAM 1 adhesion dynamically regulates synapse number and impacts plasticity and learning. Neuron 68, 894–906 (2010).
pubmed: 21145003
pmcid: 3026433
doi: 10.1016/j.neuron.2010.11.003
Lavi, A., Perez, O. & Ashery, U. Shaping neuronal network activity by presynaptic mechanisms. PLoS Comput. Biol. 11, e1004438 (2015).
pubmed: 26372048
pmcid: 4570815
doi: 10.1371/journal.pcbi.1004438
Lavi, A., Sheinin, A., Shapira, R., Zelmanoff, D. & Ashery, U. DOC2B and Munc13-1 differentially regulate neuronal network activity. Cereb. Cortex 24, 2309–2323 (2014).
pubmed: 23537531
doi: 10.1093/cercor/bht081
Kim, S. Y. et al. Global transcriptional downregulation of TREX and nuclear trafficking machinery as pan-senescence phenomena: evidence from human cells and tissues. Exp. Mol. Med. 52, 1351–1359 (2020).
pubmed: 32859952
pmcid: 8080647
doi: 10.1038/s12276-020-00490-x
Luna, R., Rondon, A. G., Perez-Calero, C., Salas-Armenteros, I. & Aguilera, A. The THO complex as a paradigm for the prevention of cotranscriptional R-loops. Cold Spring Harb. Symp. Quant. Biol. 84, 105–114 (2019).
pubmed: 32493765
doi: 10.1101/sqb.2019.84.039594
Mosler, T. et al. R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability. Nat. Commun. 12, 7314 (2021).
pubmed: 34916496
pmcid: 8677849
doi: 10.1038/s41467-021-27530-y
Skourti-Stathaki, K. & Proudfoot, N. J. A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev. 28, 1384–1396 (2014).
pubmed: 24990962
pmcid: 4083084
doi: 10.1101/gad.242990.114
Crossley, M. P., Bocek, M. & Cimprich, K. A. R-loops as cellular regulators and genomic threats. Mol. Cell 73, 398–411 (2019).
pubmed: 30735654
pmcid: 6402819
doi: 10.1016/j.molcel.2019.01.024
Cuartas, J. & Gangwani, L. R-loop mediated DNA damage and impaired DNA repair in spinal muscular atrophy. Front. Cell Neurosci. 16, 826608 (2022).
pubmed: 35783101
pmcid: 9243258
doi: 10.3389/fncel.2022.826608
Bunting, M. D. et al. Generation of gene drive mice for invasive pest population suppression. Methods Mol. Biol. 2495, 203–230 (2022).
pubmed: 35696035
doi: 10.1007/978-1-0716-2301-5_11
Kito, S. et al. Improved in vitro fertilization and development by use of modified human tubal fluid and applicability of pronucleate embryos for cryopreservation by rapid freezing in inbred mice. Comp. Med. 54, 564–570 (2004).
pubmed: 15575371
Kaech, S. & Banker, G. Culturing hippocampal neurons. Nat. Protoc. 1, 2406–2415 (2006).
pubmed: 17406484
doi: 10.1038/nprot.2006.356
Iggo, R. Lentiviral transduction of mammary epithelial cells. Methods Mol. Biol. 2471, 159–183 (2022).
pubmed: 35175596
doi: 10.1007/978-1-0716-2193-6_8
Douglass, M. L. et al. Is SGSH heterozygosity a risk factor for early-onset neurodegenerative disease? J. Inherit. Metab. Dis. 44, 763–776 (2021).
pubmed: 33423317
doi: 10.1002/jimd.12359
Garcia-Rubio, M., Barroso, S. I. & Aguilera, A. Detection of DNA-RNA hybrids in vivo. Methods Mol. Biol. 1672, 347–361 (2018).
pubmed: 29043635
doi: 10.1007/978-1-4939-7306-4_24
Smolka, J. A., Sanz, L. A., Hartono, S. R. & Chedin, F. Recognition of RNA by the S9.6 antibody creates pervasive artifacts when imaging RNA:DNA hybrids. J. Cell Biol. 220, e202004079 (2021).
pubmed: 33830170
pmcid: 8040515
doi: 10.1083/jcb.202004079
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
pubmed: 22743772
doi: 10.1038/nmeth.2019
Dias, A. P., Dufu, K., Lei, H. & Reed, R. A role for TREX components in the release of spliced mRNA from nuclear speckle domains. Nat. Commun. 1, 97 (2010).
pubmed: 20981025
doi: 10.1038/ncomms1103
Mrozik, K. M. et al. LCRF-0006, a small molecule mimetic of the N-cadherin antagonist peptide ADH-1, synergistically increases multiple myeloma response to bortezomib. FASEB Bioadv. 2, 339–353 (2020).
pubmed: 32617520
pmcid: 7325588
doi: 10.1096/fba.2019-00073
Konca, K. et al. A cross-platform public domain PC image-analysis program for the comet assay. Mutat. Res. 534, 15–20 (2003).
pubmed: 12504751
doi: 10.1016/S1383-5718(02)00251-6
Frega, M. et al. Distinct pathogenic genes causing intellectual disability and autism exhibit a common neuronal network hyperactivity phenotype. Cell Rep. 30, 173–186 e6 (2020).
pubmed: 31914384
doi: 10.1016/j.celrep.2019.12.002
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).
pubmed: 22728672
doi: 10.4161/fly.19695
Cingolani, P. et al. Using drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift. Front. Genet. 3, 35 (2012).
pubmed: 22435069
pmcid: 3304048
doi: 10.3389/fgene.2012.00035
Abyzov, A., Urban, A. E., Snyder, M. & Gerstein, M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 21, 974–984 (2011).
pubmed: 21324876
pmcid: 3106330
doi: 10.1101/gr.114876.110
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).
pubmed: 28263959
pmcid: 5600148
doi: 10.1038/nmeth.4197
Stolarczyk, M., Reuter, V. P., Smith, J. P., Magee, N. E. & Sheffield, N. C. Refgenie: a reference genome resource manager. Gigascience 9, giz149 (2020).
pubmed: 31995185
pmcid: 6988606
doi: 10.1093/gigascience/giz149
Chen, Y., Lun, A. T. & Smyth, G. K. From reads to genes to pathways: differential expression analysis of RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood pipeline. F1000Res 5, 1438 (2016).
pubmed: 27508061
pmcid: 4934518
Supek, F., Bosnjak, M., Skunca, N. & Smuc, T. REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One 6, e21800 (2011).
pubmed: 21789182
pmcid: 3138752
doi: 10.1371/journal.pone.0021800
Ge, S. X., Jung, D. & Yao, R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics 36, 2628–2629 (2020).
pubmed: 31882993
doi: 10.1093/bioinformatics/btz931
Bruderer, R. et al. Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. Mol. Cell. Proteomics 14, 1400–1410 (2015).
pubmed: 25724911
pmcid: 4424408
doi: 10.1074/mcp.M114.044305
Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).
pubmed: 27141961
pmcid: 4987924
doi: 10.1093/nar/gkw377
Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).
pubmed: 23586463
pmcid: 3637064
doi: 10.1186/1471-2105-14-128
RCoreTeam. R: a language and environment for statistical computing. (R Foundation for Statistical Computing, 2021).
Bardou, P., Mariette, J., Escudie, F., Djemiel, C. & Klopp, C. jvenn: an interactive Venn diagram viewer. BMC Bioinformatics 15, 293 (2014).
pubmed: 25176396
pmcid: 4261873
doi: 10.1186/1471-2105-15-293
Sunyer, B., Patil, S., Höger, H. & Lubec, G. Barnes maze, a useful task to assess spatial reference memory in the mice. https://assets.researchsquare.com/files/nprot-349/v1/6d50cbea-4031-4bb6-a009-75e4ef58eb5b.pdf (2007).