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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 February 18, 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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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$%B overexpression identifies pathways 3 potentially relevant to essential tremor 4 5 Calwing Liao/,1, Faezah Sarayloo/,1, Daniel Rochefort1, Fulya Akçimen/,1, Greer S. Diamond1, 6 Alexandre D. Laporte1, Dan Spiegelman1, Qin HeK, Hélène Catoire1, Patrick A. Dion1,O, Guy A. 7 Rouleau/,1,O 8 9 /Department of Human GeneticS, McGill University, Montréal, Quebec, Canada 10 1Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada. 11 KDepartment of Biomedical ScienceS, Université de Montréal, Montréal, Quebec, Canada 12 ODepartment of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada 13 14 Corresponding Author: 15 Dr. Guy A. Rouleau, MD, PhD, FRCPC, OQ 16 Department of Neurology and Neurosurgery 17 McGill University 18 Montréal, Québec, Canada 19 HKA 1BO 20 E-mail: [email protected] 21 22 Keywords: STK$%B, eSSential tremor, transcriptome, FUS, 23 Conflict of Interests: All authors report no conflict of intereStS. 24 Funding Sources: Canadian InstituteS of Health ReSearch 25 bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted February 18, 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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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. 26 Abstract 27 ESSential tremor (ET) iS a common movement diSorder that haS a high heritability. A number of 28 genetic StudieS have aSSociated different geneS and loci with ET, but few have inveStigated the 29 biology of any of theSe geneS. STK$%B was Significantly aSSociated with ET in a large GWAS 30 Study and waS found to be overexpreSSed in ET cerebellar tiSSue. Here, we overexpreSSed STK$%B 31 in human cerebellar DAOY cells and used an RNA-Seq approach to identify differentially 32 expreSSed geneS by comparing the transcriptome profile of theSe cellS to the one of control DAOY 33 cells. Pathway and gene ontology enrichment identified axon guidance, olfactory Signalling and 34 calcium-voltage channelS aS Significant. Additionally, we Show that overexpreSSing STK$%B 35 affectS transcript levelS of previously implicated ET geneS Such aS FUS. Our reSultS inveStigate the 36 effectS of overexpreSSed STK$%B and SuggeSt that it may be involved in relevant ET pathways and 37 geneS. 38 Introduc;on 39 ESSential tremor (ET) iS one of the most common movement diSorderS and iS typically 40 characterized by a kinetic tremor in the hand or armS/. The Severity tends to increaSe with age and 41 may involve different regions Such aS the head, voice or jaw1. Previous StudieS inveStigating the 42 hiStology of post-mortem tiSSue have pinpointed the cerebellum aS a region of intereSt for ETK. 43 Specifically, abnormalitieS with Purkinje cell axons and dendriteS were found in ET brainSO. 44 Furthermore, the olivocerebellar circuitry haS been implicated in ET pathology and many calcium 45 voltage channelS are highly expreSSed in thiS circuitryi. 46 47 The genetic etiology of ET haS remained largely elusive and most StudieS have focused on common 48 or rare variantS and on looking for genetic overlap with other diSordersj,k. Twin StudieS have Shown 49 that ET haS a concordance of jl–lK% in monozygotic twins and 1k–1l% in dizygotic twins, which 50 SuggeStS that both genetic and environmental factors drive the onset and development of thiS 51 complex traito. A recent genome-wide aSSociation Study (GWAS) identified a Significant locus in 52 STK$%B and found that ET patientS overexpreSSed STK$%B in cerebellar tiSSue by compariSon to 53 healthy controlSl. STK$%B is tranScribed and translated into YANK1, a Serine/threonine kinaSe, 54 that haS not been well characterized. There have been Several exome-wide StudieS that implicated 55 different genetic variantS aS causeS of ET. The first ET-implicated gene found through exome bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted February 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 56 Sequencing waS the Fused in Sarcoma gene (FUS)/r. However, it iS unclear whether theSe “ET” 57 geneS interact or have indirect effectS on the expreSSion of each other. 58 59 To understand the effectS of overexpreSSed STK$%B and identify pathways potentially relevant to 60 ET, we overexpreSSed the gene in human cerebellar DAOY cellS and compared transcriptomic 61 changeS in overexpreSSed cellS and empty-vector controlS using RNA Sequencing. Several 62 intereSting pathways Such aS axon guidance, calcium ion transmembrane transport, and olfactory 63 transduction were Significantly enriched after overexpreSSion of STK$%B. We also identified 64 previously implicated ET geneS whose expreSSion iS dysregulated through the overexpreSSion of 65 STK$%B, suggeSting that overexpreSSed STK$%B may have relevant downstream effectS. 66 Results 67 Confirming overexpression of STK$%B (YANKC protein) 68 The STK$%B Stable cell lineS had higher protein expreSSion of YANK1, which waS detected by 69 WeStern blot (Supplementary Figure /–1). RNA Sequencing (RNA-Seq) confirmed that the Stable 70 cell lineS have higher STK$%B RNA levelS compared to controlS; it waS the most Significantly 71 differentially expreSSed gene (Figure /–1). 72 73 Quality control of RNA-seq analyses 74 The QQ-plot for differentially expreSSed geneS did not Show Stratification or potential biaSeS 75 (Supplementary Figure K). The M-A plot Showed Slight enrichment of downregulated geneS 76 compared to upregulated geneS (Supplementary Figure O). A principal component (PC) plot 77 Showed Separation of controlS and STK$%B cell lineS (Figure K). Additionally, the dendrogram with 78 heatmap ShowS that controlS and STK$%B cell lineS are diStinct (Supplementary Figure i). The 79 mean-variance plot showS the shrinkage under the sleuth model (Supplementary Figure j). 80 81 Overexpression of STK$%B affects expression of previously iden;fied ET-associated genes 82 A total of K,klO geneS were found to be differentially expreSSed with a q-value <r.ri. There were 83 O1i geneS with a β > |r.i| and q-value <r.ri. Amongst the O1i geneS, three potentially relevant ET 84 geneS were dysregulated: FUS (q-value = r.rrk, β=r.o/1) and two calcium voltage channel geneS 85 that are enriched in the olivocerebellar circuitry, CACNA.C (q-value = r.r//, β= r.irK) and bioRxiv preprint doi: https://doi.org/10.1101/552901; this version posted February 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 86 CACNA.A (q-value = r.rKr, β= r.kr1). Several pathways and gene ontologieS were enriched for 87 differentially expreSSed geneS (DEGS) due to the overexpreSSion of STK$%B, including olfactory 88 transduction (P=1.joE-Kl), axon guidance (P=l.irE-Kj), and calcium ion transmembrane 89 transport (P=K.r1E-K/) (Table /). 90 91 Gene network analyses 92 To identify which cluster of DEGS drove the Significant pathways, gene network analysiS baSed 93 on co-expreSSion waS done and identified /O different clusters within the differentially expreSSed 94 geneS (Figure O). AnalysiS of the top K largeSt clusters for pathway enrichmentS found Several 95 similar pathways in different databaSeS including axon guidance (P</.rlE-/1) in cluster / and 96 calcium signalling pathway in cluster K (1.rjE-ri). 97 Discussion 98 The genetic etiology of ET iS complex and likely explained by a combination of copy number 99 variantS, rare variantS, gene-gene interactions and common variant drivers. One of the most 100 Significantly enriched pathways we identified was olfactory Signalling and transduction. Previous 101 reportS have Shown conflicting evidence about olfactory losS in ET//,/1. It may be that ET patientS 102 with dysregulated olfactory Signalling have overexpreSSed STK$%B, which may contribute to the 103 Subset of ET patientS with olfactory losS. 104 105 IntereStingly, FUS waS amongst the geneS dysregulated when STK$%B waS overexpreSSed. In the 106 exome familial ET Study that identified FUS, we alSo found reduced mRNA levelS for FUS/r. 107 Similarly, the expreSSion of FUS is lower when STK$%B iS overexpreSSed, SuggeSting an indirect 108 relationship between the two geneS. Additionally, two calcium voltage-gated channel geneS, 109 CACNA.C AND CACNA.A were overexpreSSed. Enrichment analyseS found calcium ion 110 transmembrane transport to be highly Significant in GO ProceSSeS, SuggeSting that STK$%B may 111 play a role upstream of theSe geneS. In the olivocerebellar circuitry, a System implicated in ET, is 112 enriched for both of theSe geneSi,/K. CACNA.A haS been Shown to be predominantly expreSSed in 113 Purkinje cellS, a cell type relevant to ET/K. Another enriched pathway waS axon guidance. A 114 previous Study identified the TENM1 miSSense variant segregating within ET familieS/O. TENM1 115 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 February 18, 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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