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Transcriptomic Changes Resulting from STK32B Overexpression Identifies Pathways Potentially Relevant to Essential Tremor

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Transcriptomic Changes Resulting from STK32B Overexpression Identifies Pathways Potentially Relevant to Essential Tremor bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted May 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Transcriptomic changes resulting from 2 STK$%B overexpression identifies pathways 3 potentially relevant to essential tremor 4 Calwing Liao.,0, Faezeh Sarayloo.,0, Veikko Vuokila0, Daniel Rochefort0, Fulya Akçimen.,0, 5 Simone Diamond0, Alexandre D. Laporte0, Dan Spiegelman0, Qin HeJ, Hélène Catoire0, Patrick A. 6 Dion0,O, Guy A. Rouleau.,0,O 7 8 .Department of Human GeneticS, McGill University, Montréal, Quebec, Canada 9 0Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada. 10 JDepartment of Biomedical ScienceS, Université de Montréal, Montréal, Quebec, Canada 11 ODepartment of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada 12 13 Corresponding Author: 14 Dr. Guy A. Rouleau, MD, PhD, FRCPC, OQ 15 Department of Neurology and Neurosurgery 16 McGill University 17 Montréal, Québec, Canada 18 HJA 0BO 19 E-mail: [email protected] 20 21 Keywords: STK$%B, eSSential tremor, transcriptome, FUS 22 Conflict of Interests: All authors report no conflict of intereStS. 23 Funding Sources: Canadian InstituteS of Health ReSearch 24 bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted May 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 25 Abstract 26 ESSential tremor (ET) iS a common movement diSorder that haS a high heritability. A number of 27 genetic StudieS have aSSociateD different geneS and loci with ET, but few have inveStigated the 28 biology of any of theSe geneS. STK$%B was Significantly aSSociated with ET in a large GWAS 29 Study and waS found to be overexpreSSed in ET cerebellar tiSSue. Here, we overexpreSSeD STK$%B 30 in human cerebellar DAOY cells and used an RNA-Seq approach to identify differentially 31 expreSSed geneS by comparing the transcriptome profile of theSe cellS to the one of control DAOY 32 cells. Pathway and gene ontology enrichment identified axon guidance, olfactory Signalling and 33 calcium-voltage channelS aS Significant. Additionally, we Show that overexpreSSing STK$%B 34 affectS transcript levelS of previously implicated ET geneS Such aS FUS. Our reSultS inveStigate the 35 effectS of overexpreSSed STK$%B and SuggeSt that it may be involved in relevant ET pathways and 36 geneS. 37 Introduc;on 38 ESSential tremor (ET) iS one of the most common movement DiSorderS and iS typically 39 characterized by a kinetic tremor in the hand or armS.. The Severity tends to increaSe with age and 40 may involve different regions Such aS the head, voice or jaw0. Previous StudieS inveStigating the 41 hiStology of post-mortem tiSSue have pinpointed the cerebellum aS a region of intereSt for ETJ. 42 Specifically, abnormalitieS with Purkinje cell axons and dendriteS were found in ET brainSO. 43 Furthermore, the olivocerebellar circuitry haS been implicated in ET pathology and many calcium 44 voltage channelS are highly expreSSed in thiS circuitryj. 45 46 The genetic etiology of ET haS remained largely elusive and most StudieS have focused on common 47 or rare variantS and on looking for genetic overlap with other diSordersk,l. Twin StudieS have Shown 48 that ET haS a concordance of km–mJ% in monozygotic twins and 0l–0m% in dizygotic twins, which 49 SuggeStS that both genetic and environmental factors drive the onset and development of thiS 50 complex traitp. A recent genome-wide aSSociation Study (GWAS) identified a Significant locus in 51 STK$%B and found that ET patientS overexpreSSed STK$%B in cerebellar tiSSue by compariSon to 52 healthy controlSm. STK$%B is transcribeD and translated into YANK0, a Serine/threonine kinaSe, 53 that haS not been well characterizeD. There have been Several exome-wide StudieS that implicated 54 different genetic variantS aS causeS of ET. The first ET-implicated gene found through exome bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted May 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 55 Sequencing waS the Fused in Sarcoma gene (FUS).s. However, it iS unclear whether theSe “ET” 56 geneS interact or have indirect effectS on the expreSSion of each other. 57 58 To understand the effectS of overexpreSSed STK$%B and identify pathways potentially relevant to 59 ET, we overexpreSSed the gene in human cerebellar DAOY cellS and compared transcriptomic 60 changeS in overexpreSSed cellS and empty-vector controlS using RNA Sequencing. Several 61 intereSting pathways Such aS axon guidance, calcium ion transmembrane transport, and olfactory 62 transduction were Significantly enricheD after overexpreSSion of STK$%B. We also identifieD 63 previously implicated ET geneS whose expreSSion iS dySregulated through the overexpreSSion of 64 STK$%B, suggeSting that overexpreSSed STK$%B may have relevant downstream effectS. 65 Results 66 Confirming overexpression of STK$%B 67 The STK$%B Stable cell lineS had higher RNA expreSSion of STK$%B, which waS detected by 68 reVerSe-tranScriptaSe qPCR (Supplementary Figure .). RNA Sequencing (RNA-Seq) alSo 69 confirmeD that the Stable cell lineS have higher STK$%B RNA levelS compared to controlS; it was 70 the most significantly differentially expreSSed gene (Figure .–0). 71 72 Quality control of RNA-seq analyses 73 The QQ-plot for differentially expreSSed geneS did not Show Stratification or potential biaSeS 74 (Supplementary Figure 0). The M-A plot Showed Slight enrichment of downregulated geneS 75 compared to upregulateD geneS (Supplementary Figure J). A principal component (PC) plot 76 Showed Separation of controlS and STK$%B cell lineS (Figure J). Additionally, the dendrogram with 77 heatmap ShowS that controlS and STK$%B cell lineS are diStinct (Supplementary Figure O). The 78 mean-variance plot showS the shrinkage under the sleuth model (Supplementary Figure j). 79 80 Overexpression of STK$%B affects expression of previously iden;fied ET-associated genes 81 A total of J,lmO geneS were found to be differentially expreSSed with a q-value <s.sj. There were 82 O0j geneS with a β > |s.j| and q-value <s.sj. Amongst the O0j geneS, three potentially relevant ET 83 geneS were dysregulateD: FUS (q-value = s.ssl, β=s.p.0) and two calcium voltage channel geneS 84 that are enriched in the olivocerebellar circuitry, CACNA-C (q-value = s.s.., β= s.jsJ) and bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted May 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 85 CACNA-A (q-value = s.sJs, β= s.ls0). Several pathways and gene ontologieS were enriched for 86 differentially expreSSed geneS (DEGS) due to the overexpreSSion of STK$%B, including olfactory 87 transduction (P=0.kpE-Jm), axon guidance (P=m.jsE-Jk), and calcium ion transmembrane 88 transport (P=J.s0E-J.) (Table .). 89 90 Gene network analyses 91 To identify which cluster of DEGS drove the Significant pathways, gene network analysiS baSed 92 on co-expreSSion waS done and identifieD .O different clusters within the differentially expreSSed 93 geneS (Figure O). AnalysiS of the top J largeSt clusters for pathway enrichmentS found Several 94 similar pathways in different databaSeS including axon guidance (P<..smE-.0) in cluster . and 95 calcium signalling pathway in cluster J (0.skE-sj). 96 Discussion 97 The genetic etiology of ET iS complex and likely explained by a combination of copy number 98 variantS, rare variantS, gene-gene interactions and common variant drivers. One of the most 99 Significantly enriched pathways we identified was olfactory Signalling and transduction. Previous 100 reportS have Shown conflicting evidence about olfactory losS in ET..,.0. It may be that ET patientS 101 with dysregulated olfactory Signalling have overexpreSSed STK$%B, which may contribute to the 102 Subset of ET patientS with olfactory losS. 103 104 IntereStingly, FUS waS amongst the geneS dysregulated when STK$%B waS overexpreSSed. In the 105 exome familial ET Study that identified FUS, we alSo found reduced mRNA levelS for FUS.s. 106 Similarly, the expreSSion of FUS is lower when STK$%B iS overexpreSSeD, SuggeSting an indirect 107 relationship between the two geneS. Additionally, two calcium voltage-gated channel geneS, 108 CACNA-C AND CACNA-A were overexpreSSeD. Enrichment analyseS found calcium ion 109 transmembrane transport to be highly Significant in GO ProceSSeS, SuggeSting that STK$%B may 110 play a role upstream of theSe geneS. In the olivocerebellar circuitry, a System implicated in ET, is 111 enriched for both of theSe geneSj,.J. CACNA-A haS been Shown to be predominantly expreSSed in 112 Purkinje cellS, a cell type relevant to ET.J. Another enriched pathway waS axon guidance. A 113 previous Study identified the TENM0 miSSense variant Segregating within ET familieS.O. TENM0 114 iS a regulator of axon guidance and myelination and TenmO knockout mice Showed an ET bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted May 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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