RESSALVA Atendendo solicitação do(a) autor(a), o texto completo desta tese será disponibilizado somente a partir de 08/05/2021. UNIVERSIDADE ESTADUAL PAULISTA - UNESP CÂMPUS DE JABOTICABAL GENOMIC IDENTIFICATION OF MATE, ABC, AND MFS TRANSPORTERS IN Citrus sinensis AND EXPRESSION ANALYSIS OF CITRUS SPECIES INTERACTING WITH Xanthomonas citri subsp. citri Maria Heloisa Moreno Julião Biotecnologista 2020 UNIVERSIDADE ESTADUAL PAULISTA - UNESP CÂMPUS DE JABOTICABAL GENOMIC IDENTIFICATION OF MATE, ABC, AND MFS TRANSPORTERS IN Citrus sinensis AND EXPRESSION ANALYSIS OF CITRUS SPECIES INTERACTING WITH Xanthomonas citri subsp. citri Discente: Maria Heloisa Moreno Julião Orientador: Prof. Dr. Alessandro de Mello Varani Coorientador: Prof. Dr. Jesus Aparecido Ferro 2020 Dissertação apresentada à Faculdade de Ciências Agrárias e Veterinárias – Unesp, Campus de Jaboticabal, como parte das exigências para a obtenção do título de Mestre em Agronomia (Genética e Melhoramento de Plantas). J94g Julião, Maria Heloisa Moreno Genomic identification of MATE, ABC, and MFS Transporters in Citrus sinensis and expression analysis of Citrus species interacting with Xanthomonas citri subsp. citri / Maria Heloisa Moreno Julião. -- Jaboticabal, 2020 84 p. : il., tabs. Dissertação (mestrado) - Universidade Estadual Paulista (Unesp), Faculdade de Ciências Agrárias e Veterinárias, Jaboticabal Orientador: Alessandro de Mello Varani Coorientador: Jesus Aparecido Ferro 1. Genômica Vegetal. 2. Proteínas Transportadoras. 3. Transcriptoma. I. Título. Sistema de geração automática de fichas catalográficas da Unesp. Biblioteca da Faculdade de Ciências Agrárias e Veterinárias, Jaboticabal. Dados fornecidos pelo autor(a). Essa ficha não pode ser modificada. CURRICULAR DATA OF THE AUTHOR Maria Heloisa Moreno Julião – born on January 29, 1997, in Nova Andradina – MS, Brazil. She has a bachelor's degree in Biotechnology from the Federal University of Grande Dourados - UFGD (2014 - 2017). She was a member of the Research Group on Plant Breeding and Biotechnology, participating as a collaborator in research projects. Developed the course conclusion work entitled “Floral biology and in vitro germination of nasturtium pollen grains (Tropaeolum majus L.) in cultivation with chicken litter.” under the guidance of Drª. Lívia Maria Chamma Davide. In the same period, she participated in the coordination of the extension project “Biotechnology for All” under the guidance of Drª. Liliam Silvia Candido. She completed a mandatory internship in 2017 at Fundação MS - Pesquisa e Difusão de Tecnologias Agropecuárias, located in Maracajú - MS. In 2018, he joined the Graduate Program in Agronomy (Genetics and Plant Breeding), Faculty of Agricultural and Veterinary Sciences - Unesp/FCAV, Jaboticabal Campus, at the Laboratory of Biochemistry and Molecular Biology under the guidance of the professors Dr. Alessandro de Mello Varani and Dr. Jesus Aparecido Ferro. The dissertation project was developed as a fellow at the Coordination for the Improvement of Higher Education Personnel (CAPES). “The task is not so much to see what no one has seen yet, but to think what nobody has thought yet, about what everybody sees.” (Arthur Schopenhauer) THANKS To my family, for the love and support in all my choices. For teaching me to believe in my potential, to have faith and perseverance. For being my eternal safe harbor. To my advisors, for the opportunity, confidence, patience and support in the years of work. Thank you for providing such an expressive personal and professional development, you are my examples of successful professionals. To the professors of the Graduate Program in Agronomy (Genetics and Plant Breeding), other Unesp/FCAV programs, and my English teacher, for their willingness to help with whatever was possible. For all the knowledge, advice and criticism. To all Unesp/FCAV employees, for allowing the university to function properly and to execute my project. To the friends of the Laboratory of Biochemistry and Molecular Biology and the Department of Technology, for the joy in daily living, the spirit at coffee time and the outburst and consolation in difficult times. To all the colleagues at Unesp/FCAV that I met, for teaching me with their experiences, for making my days happier and for encouraging me to continue fighting for my dreams. To the Unesp University Prayer Group, for filling me with the faith and hope I needed. To the Rotaract Club of Jaboticabal, for the opportunity to contribute to humanitarian projects and complete me personally. To the friends I met in the city of Jaboticabal and became true brothers. Thank you for so many good moments. To all who contributed directly or indirectly to the execution of this work. My most sincere Thank you. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 i SUMMARY ABSTRACT....................................………............................…...................................iii RESUMO...............................……….....................................................................…...iv LIST OF ABBREVIATIONS..........….....................................................................…...v LIST OF TABLES.....................….....................................................................….....vi LIST OF FIGURES...................……..........................................................................vii APPENDIX..............................…….............................................................................vii 1. INTRODUCTION…...……………………………………………………………………..1 2. LITERATURE REVIEW………………………………………………………..…………2 2.2. Membrane Transporter Proteins in Plants..............................................………5 2.1. The Citriculture and the Citrus Canker disease………………………………..…5 2.2.1 The Multi-Antimicrobial Extrusion Protein - MATE transporter family. .6 2.2.2 The ATP-Binding Cassette Transporters - ABC transporter family......7 2.2.3 The Major Facilitator Superfamily - MFS.............................................8 3. MATERIAL AND METHODS...................................................................................10 3.1 Identification of MATE, ABC, and MFS genes in the C. sinensis genome.......10 3.2 Transcriptome-wide identification of MATE, ABC, and MFS transcripts in Citrus species....................................................................................................................12 3.3 Phylogenetic analyses of MATE, ABC, and MFS genomic and transcriptomic sequences...............................................................................................................13 3.4 MATE, ABC, and MFS gene expression analysis based on CitrusKB Knowledge Base.....................................................................................................14 4. RESULTS................................................................................................................14 4.1 Identification of MATE, ABC, and MFS genes in the C. sinensis genome.......14 4.2 Transcriptome-wide identification of MATE, ABC, and MFS transcripts in Citrus species....................................................................................................................16 4.3 Phylogenetic analyses of MATE, ABC, and MFS genomic and transcriptomic sequences...............................................................................................................17 4.4 Comparison between MATE, ABC, and MFS genomic and transcriptomic data .................................................................................................................................19 4.5 MATE, ABC, and MFS gene expression analysis based on CitrusKB Knowledge Base.....................................................................................................20 5. DISCUSSION..........................................................................................................25 ii 5.1 Identification of MATE, ABC, and MFS genes in the C. sinensis genome.......25 5.2 Transcriptome-wide identification of MATE, ABC, and MFS transcripts in Citrus species....................................................................................................................26 5.3 Phylogenetic based classification and gene expression analyses...................27 5.3.1 Phylogenetics and gene expression analyses of MATE sequences.............28 5.3.2 Phylogenetics and gene expression analyses of ABC sequences...........30 5.3.3 Phylogenetics and gene expression analyses of MFS sequences..........34 6. CONCLUSIONS......................................................................................................37 7. REFERENCES........................................................................................................37 iii GENOMIC IDENTIFICATION OF MATE, ABC, AND MFS TRANSPORTERS IN Citrus sinensis AND EXPRESSION ANALYSIS OF CITRUS SPECIES INTERACTING WITH Xanthomonas citri subsp. citri ABSTRACT Plants as sessile organisms require the synthesis and accumulation of a large array of molecules involved in growth, development, and defense-related processes. The Multi-Antimicrobial Extrusion Protein (MATE), ATP-Binding Cassette (ABC) and Major Facilitator Superfamily (MFS) transporters are the largest families of membrane transporters in plants, playing a central role in the defense-related processes in plant- pathogen interactions. For instance, protecting Citrus species cells under the infection of Xanthomonas citri subsp. citri (Xac), the etiologic agent of the Citrus Canker type A, one of the most devastating Citrus diseases involved with serious economic and environmental impacts. Herein, we identified genes and transcripts from MATE, ABC, and MFS families using the available Citrus sinensis genome (v2.0 HZAU) and the re-annotated Citrus Reference Transcriptome (CRT) from CitrusKB Knowledge Base (http://bioinfo.deinfo.uepg.br). We identified 67 MATE, 91 MFS, and 143 ABC genes in the C. sinensis genome and 82 MATE, 139 MFS, and 226 ABC transcripts in the CRT. The transcripts were mapped in the C. sinensis genome revealing a high rate of paralogs genes and probably alternative splicing (AS) events, whose expression profiles and potential roles in the Citrus-Xac interaction were proposed. The tandem and dispersed copies along with genes that underwent AS events represents sources of transporters’ genes diversity and complexity. Moreover, we also highlighted potential biotechnological targets, which seemed to contribute with the defense responses in the Citrus plants. The seventeen genes belong to MATE I, ABC C and G, and STP subfamilies, potentially involved in the transport of secondary metabolites and xenobiotics, may acts as negative regulators of the disease and can limit the release of sugar from plant cells to apoplast. Overall, this work provides the first MATE, ABC, and MFS transporters’ genomic data in C. sinensis and their transcriptome-wide characterization in Citrus species infected by Xac, providing fundamental information for studies concerning plant membrane transporters and their role in plant-pathogen interactions. iv KEYWORDS: Comparative genomics, membrane transporters, differentially expressed genes, plant-pathogen interactions. IDENTIFICAÇÃO GENÔMICA DE TRANSPORTADORES MATE, ABC E MFS EM Citrus sinensis E ANÁLISE DE EXPRESSÃO EM ESPÉCIES DE CITROS EM INTERAÇÃO COM Xanthomonas citri subsp. citri RESUMO As plantas como organismos sésseis requerem a síntese e o acúmulo de uma ampla variedade de moléculas envolvidas no crescimento, desenvolvimento e processos relacionados à defesa. Os transportadores Proteínas de Extrusão Multi- Antimicrobianas (MATE), Cassette de Ligação de ATP (ABC) e Superfamília dos Facilitadores Maioritários (MFS) são as principais famílias de transportadores de membrana em plantas, desempenhando um papel central nos processos relacionados à defesa nas interações planta-patógenos. Por exemplo, protegem as células das espécies de Citros sob a infecção de Xanthomonas citri subsp. citri (Xac), o agente etiológico do Cancro Cítrico tipo A, uma das doenças de Citros mais devastadoras envolvidas em sérios impactos econômicos e ambientais. Aqui, identificamos genes e transcritos das famílias MATE, ABC e MFS usando o genoma disponível de Citrus sinensis (v2.0 HZAU) e o Transcriptoma Referência de Citros (CRT) re-anotado da base de dados CitrusKB (http://bioinfo.deinfo.uepg.br). Foram identificados 67 genes MATE, 91 MFS e 143 ABC no genoma de C. sinensis e 82 transcritos MATE, 139 MFS e 226 ABC no CRT. Os transcritos foram mapeados no genoma de C. sinensis, revelando uma alta taxa de genes parálogos e putativos eventos de splicing alternativo (AS), cujos perfis de expressão gênica e potenciais papéis na interação Citros-Xac foram propostos. As cópias de genes em tandem e cópias dispersas juntamente com genes que possivelmente sofreram eventos de AS representam fontes de diversidade e complexidade dos genes transportadores. Além disso, nós destacamos potenciais alvos biotecnológicos que parecem contribuir com as respostas de defesa das plantas cítricas. Os dezessete genes pertencem às subfamílias MATE I, ABC C e G e STP, potencialmente involvidas no transporte de metabólitos secundários e xenobióticos, podem atuar como reguladores negativos da doença e limitar liberação de açúcar das células das plantas para o apoplasto. No geral, este trabalho fornece os primeiros dados genômicos de transportadores v MATE, ABC e MFS em C. sinensis e sua caracterização no transcriptoma de espécies de Citros infectadas por Xac, fornecendo informações fundamentais para estudos sobre transportadores de membrana em plantas e seu papel nas interações planta-patógeno. PALAVRAS-CHAVE: Genômica comparativa, Transportadores de Membrana, Genes Diferencialmente Expressos, Interações Planta-Patógeno. vi LIST OF ABBREVIATIONS ABC ATP-Binding Cassette AIC Akaike Information Criteria AS Alternative Splicing CRT Citrus Reference Transcriptome CC Citrus Canker type A CitrusKB A Knowledge Base for Transcriptome of Citrus species and Xanthomonas citri subsp. citri Interactome Chr Chromosome CsMATE MATE genomic sequences from the Citrus sinensis genome CsABC ABC genomic sequences from the Citrus sinensis genome CsMFS MFS genomic sequences from the Citrus sinensis genome CstMATE potential MATE sequences expressed by Citrus species CstABC potential ABC sequences expressed by Citrus species CstMFS potential MFS sequences expressed by Citrus species DE Differentially Expressed DTX Detoxification Proteins FBT Folate-Biopterin Transporter MATE Multi-Antimicrobial Extrusion Protein MFS Major Facilitator Superfamily MW Molecular Weight pI Isoelectric point PHT Phosphate Transporter STP Sugar Transporter Protein WGD Whole-genome/segmental duplication Xac Xanthomonas citri subsp. citri vii LIST OF TABLES Table 1. Susceptibility level of major Citrus commercially important cultivars and Fortunella species to Xanthomonas citri subsp. citri……………………….……….…...4 Table 2. Genomic data on Citrus species until 2020…………………………………….4 Table 3. MATE, ABC, and MFS-related Domains……………………………………….10 Table 4. The Citrus Reference Transcriptome species and its respective abbreviation used in the Figures of this work…………………………………………………………...12 Table 5. Promising candidates for further exploitation based on their potential role in the Citrus-Xac interaction………………………………………………………………….36 viii LIST OF FIGURES Figure 1. Genome distribution and gene duplication events of MATE, ABC, and MFS genes from Citrus sinensis. The size of a chromosome is indicated by its relative length given in Mb. Chromosome numbers (Chr) are indicated at the top of each chromosome. Gene duplication events are indicated with symbols. Genes with transcriptomic evidence from the Citrus Reference Transcriptome under Xac infection were shaded using yellow color and bold letters. The C. sinensis unplaced chromosome (chrUn) was not considered in the genome comparative analyses…..15 Figure 2. Duplication events of MATE, ABC, and MFS genes in the Citrus sinensis genome………………………………….………………………………………………..…16 Figure 3. Maximum Likelihood tree of 67 MATE amino acid sequences from Citrus sinensis genome. Numbers above the branches represent bootstrap values. The black circles represent genes that have an associated transcript sequence in the CRT. AK812_OLP99436 was used as outgroup (Symbiodinium microadriaticum str. CCMP2467, Gene: slc47a1, Multidrug and toxin extrusion protein 1)...……...……...17 Figure 4. Maximum Likelihood tree of 143 ABC amino acid sequences from Citrus sinensis genome. Numbers above the branches represent bootstrap values. The black circles represent genes that have an associated transcript sequence in the CRT. AK812_OLP95568 was used as outgroup (Symbiodinium microadriaticum str. CCMP2467, Gene ABCF3, ATP-binding cassette subfamily F member 3)…...……..18 Figure 5. Maximum Likelihood tree of 91 MFS amino acid sequences from Citrus sinensis genome. Numbers above the branches represent bootstrap values. The black circles represent genes that have an associated transcript sequence in the CRT. DB43_AL00090 was used as outgroup (Parachlamydia acanthamoebae, Gene ywtG, putative metabolite transport protein YwtG).………………………………….….19 Figure 6. Heatmap of expression profiles of MATE transcripts differentially expressed on at least one HAI in a cultivar. K: ‘Kumquat’, PK: ‘Ponkan’, S: ‘Satsuma’, PR: ‘Pera Rio’, H: ‘Hamlin’, BA: ‘Bahia’, V: ‘Valencia’, LG: Lima Ácida ‘Galego’, HAI: Hours After bacterial Inoculation. The subfamily annotation of each transcript precedes its respective identification number…….………………………………………………….…21 Figure 7. Heatmap of expression profiles of ABC transcripts differentially expressed on at least one HAI in a cultivar. K: ‘Kumquat’, PK: ‘Ponkan’, S: ‘Satsuma’, PR: ‘Pera Rio’, H: ‘Hamlin’, BA: ‘Bahia’, V: ‘Valencia’, LG: Lima Ácida ‘Galego’, HAI: Hours After ix bacterial Inoculation. The subfamily annotation of each transcript precedes its respective identification number…….………………………………………………….…22 Figure 8. Heatmap of expression profiles of MFS transcripts differentially expressed on at least one HAI in a cultivar. K: ‘Kumquat’, PK: ‘Ponkan’, S: ‘Satsuma’, PR: ‘Pera Rio’, H: ‘Hamlin’, BA: ‘Bahia’, V: ‘Valencia’, LG: Lima Ácida ‘Galego’, HAI: Hours After bacterial Inoculation. The subfamily annotation of each transcript precedes its respective identification number…….………………………………………………….…23 Figure 9. Bubble chart of MATE, ABC, and MFS transcripts differentially expressed in response to Xac infection in 24, 48, and 72 hours after bacterial inoculation. K: ‘Kumquat’, LG: Lima Ácida ‘Galego’. The color of markers represents the -log10(p- value) values and the size is proportional to the log2FC values. The subfamily annotation of each transcript precedes its respective identification number..……..…24 x APPENDIX Fig A1. Maximum Likelihood tree of MATE amino acid sequences expressed by Citrus spp. identified in the Citrus Reference Transcriptome……....….………………47 Fig A2. Maximum Likelihood tree of ABC amino acid sequences expressed by Citrus spp. identified in the Citrus Reference Transcriptome.…………………………….…...48 Fig A3. Maximum Likelihood tree of MFS amino acid sequences expressed by Citrus spp. identified in the Citrus Reference Transcriptome………………...………….…….49 Table A1. MATE, ABC, and MFS transcripts expressed by Citrus spp., Molecular Weigh, Isoelectric Point, Sequence Length, Subcellular Localization, and Putative Gene Name from Citrus sinensis……………………………………………….………...50 Table A2. MATE, ABC, and MFS expressed genes by Citrus spp., including gene duplication status, number of putative isoforms produced and the annotation……...60 Table A3. MATE, ABC, and MFS differentially expressed, Log2FC values according to the time points after bacterial inoculation (HAI) and cultivars, p-value, and annotation………………………………………………………..…………………….……65 1 1. INTRODUCTION Plant-pathogen interactions result in macro and microscopic changes in the host plant, involving a wide range of morphological, biochemical, genetic, and molecular processes (Schenk et al., 2000; Melotto et al., 2006; Uchida and Tasaka, 2010; Cheval and Faulkner, 2018). The defense-related processes triggered by plants during the interaction are fast and targeted to counter-attack the pathogen to maintain the cellular homeostasis (Jones and Dangl, 2006). One of the most studied and devastating plant diseases affecting all commercial citrus varieties in production areas around the world is the Citrus Canker type A (CC), caused by the Gram-negative bacterium Xanthomonas citri subsp. citri (Xac) (Behlau et al., 2010). The Xac infects the citrus tissues through the penetration in stomatal pores or wounds made by thorns and insects. The symptoms of infection start like high injuries soaked with water and evolve until it forms the cankers, reaching plant defoliation and premature fall of fruits (Gottwald et al., 2002). Moreover, distinct susceptibility levels to Citrus Canker across Citrus species (de Carvalho et al., 2015) were observed, reflecting in a complex array of plant-pathogen interaction and defense-response mechanisms. Among the mechanisms conducted during the defense responses, plants developed and expanded transport mechanisms to excrete or sequester a broad range of synthesized molecules and xenobiotics to provide an efficient immune response (Tegos et al., 2002; Wang et al., 2016b). A large number of primary and secondary active transporter genes found in plants improve the plant competition and adaptation to stress conditions (Hwang et al., 2016), such as under the Citrus Canker disease. The major transporters families Multi-Antimicrobial Extrusion Protein (MATE), ATP-Binding Cassette transporters (ABC), and Major Facilitator Superfamily (MFS) play an essential role in the plants’ membrane trafficking network (Shoji, 2014), are ubiquitously present in prokaryotic and eukaryotes organisms, and present distinct protein structures and source of energy used to execute the transport of molecules (Fath and Kolter, 1993; Takanashi et al., 2014a). Identifying and understanding the features and roles of membrane transporter proteins in plant species, as the MATE, ABC, and MFS transporters in Citrus species has only been possible due to the growing number of genomic and transcriptomic data available in the public databases. Despite that, information concerning membrane transporters in Citrus species is still patchy. Thus, the importance of citriculture along with 2 the constant threating to citrus cultivation and the posing substantial economic impacts of the citrus canker, and also the possibility of adding scientific advance to the knowledge on membrane transport proteins prompted us to characterize and investigate the role and impact of these important gene families into the Citrus-Xac interaction. As part of our efforts to understand the Citrus-Xac interaction, we recently build a knowledge base for transcriptome of Citrus and Xac interactome (CitrusKB, http://bioinfo.deinfo.uepg.br/citrus), providing data from Citrus species of divergent Citrus Canker susceptibility levels (e.g. from the less susceptible cultivars: ‘Kumquat’ Fortunella spp., Tangerine mandarin ‘Satsuma’ C. unshiu, and Tangerine mandarin ‘Ponkan’ C. reticulata, to the intermediate susceptible as Sweet oranges ‘Pera Rio’ and ‘Valencia’ C. sinensis, and highly susceptible as Sweet oranges ‘Hamlin’ and ‘Bahia’ C. sinensis, and Mexican lime ‘Galego’ C. aurantifolia) (Ferrasa et al., 2020). Using the CitrusKB database along with publicly available Citrus sinensis genome (v2.0 HZAU), we identified, classified, and compared the MATE, ABC, and MFS families in the C. sinensis genome and in the Citrus Reference Transcriptome (CRT). We identified the genomic context in which the membrane transporters genes exist to understand how duplicate genes have contributed to their expansion and function and highlighted promising candidates for further exploitation from subfamilies MATE I, ABC C, ABC G, and STP based on their potential role in the Citrus-Xac interaction. Taken together, our results are not only providing novel insights about the main membrane transporters families in Citrus defense-related processes but also revealing a complex layer of the history of these gene families expansions and the transcriptional regulation under a plant-pathogen interaction. 36 6. CONCLUSIONS MATE, ABC, and MFS transporters are involved beyond development and survival processes in plants, are essential proteins under plant-pathogen interactions due to their role in the excretion or uptake of macronutrients, defense-related compounds, xenobiotics, and metabolic products. Five MATE, eight ABC, and fourteen MFS subfamilies were identified in Citrus sinensis, of which their putative roles and impact during the Citrus- Xac interaction revealed potential targets for functional studies and a common transport of secondary metabolites and xenobiotics. Moreover, the subfamilies MATE I and ABC G seem to be key players in the management of the compounds produced by plants during the defense responses. Altogether, the transcriptional evidence of both membrane transporter family members based on CRT data supports the proposal for a highly complex pattern of gene expression regulation during the Citrus-Xac interaction, which reflects the 37 intricate defense-related processes in CC susceptibility levels between Citrus cultivars. 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