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Mauro Antonio Alves Castrohttp://lattes.cnpq.br/6484877487662355José Miguel OrtegaGlória Regina FrancoRodrigo Juliani Siqueira DalmolinDaniela Fiori GradiaFábio Fernandes da Rocha Vicentehttp://lattes.cnpq.br/5103650321212050Sheyla Trefflich2023-04-05T15:15:11Z2023-04-05T15:15:11Z2021-10-06http://hdl.handle.net/1843/51619A investigação funcional de genes, RNAs e proteı́nas em larga escala demanda novas estratégias computacionais para extração de informação relevante. Em procariotos, genes relacionados a um mesmo efeito biológico estão usualmente localizados em operons. Em eucariotos não existe a mesma organização, sendo em geral o processo de transcrição independente para cada gene. Apesar disso, nestes organismos existem unidades funcionais controladas por fatores de transcrição, denominadas regulons. As relações regulatórias de um regulon podem surgir ao longo do desenvolvimento de um organismo, em determinado tecido, ou no curso do processo evolutivo. Descrever a formação de regulons pode contribuir com o entendimento de como eles atuam em organismos atuais, tais como o controle transcricional em câncer. Neste estudo investigamos o padrão de origem evolutiva de unidades regulatórias de eucariotos para responder a seguinte pergunta: quem surgiu primeiro, reguladores ou regulados? Testamos 3 hipóteses concorrentes para explicar a formação de regulons: i) fatores de transcrição e seus alvos surgiram de maneira independente; ii) fatores de transcrição surgiram previamente aos seus alvos; iii) fatores de transcrição surgiram posteriormente ao surgimento de seus alvos. Inferimos regulons em câncer de mama e desenvolvemos um método para estimar a distância evolutiva entre reguladores e regulados, inferindo o enraizamento evolutivo em uma dada árvore de espécies. Foram avaliadas 307 regulons, das quais 76 (24,7%) tinham reguladores enraizados junto com seus alvos, 137 (44,3%) tinham reguladores enraizados antes de seus alvos e 94 (30,6%) tinham reguladores enraizados depois de seus alvos. Esses resultados sugerem cenários evolutivos que são consistentes com as três hipóteses apresentadas neste estudo. Em seguida, avaliamos a significância dessas observações e descobrimos que a distribuição geral das raı́zes evolutivas inferidas dos reguladores precede as raı́zes evolutivas dos alvos (p-valor = 1e-6, teste de Wilcoxon-Mann-Whitney). Estes resultados sugerem que regulons não somente são organizados ao redor dos reguladores, como foram formados à partir dos reguladores. Além disso, a identificação de diferentes histórias evolutivas oferece a oportunidade de explicarmos aspectos funcionais tais como o padrão de enraizamento evolutivo em uma rede regulatória. Observamos 4 padrões marcantes: (i) em geral, regulons enraizados em pontos evolutivos próximos se agrupam; (ii) a maioria dos regulons tem enraizamento evolutivo em (LCA) de organismos unicelulares; (iii) regulons associados ao desenvolvimento do câncer de mama são mais recentes; (iv) a maioria dos regulons relacionados a tumores estrogênio positivo e estrogênio negativo estão enraizados em LCA de metazoários. Estes resultados são consistentes com um dos principais aspectos do câncer, em que só é possı́vel observar desorganização tecidual em organismos que possuem um processo de diferenciação celular capaz de formar tecidos.High-throughput functional analysis of genes, RNAs and proteins demands new computational strategies in order to extract relevant regulatory information. In prokaryotes, genes related to the same biological functions are usually located in operons. In eukaryotes, however, the transcriptional process is organized in a different way, as each gene is independently transcribed. Despite these differences, functional units controlled by transcription factors are present in eukaryotes, which are called regulons, and consist of a set of genes whose activation or repression are under the control of the same transcription factor. The regulatory relations of a regulon can emerge along the development of an organism, in a certain tissue, or even during the evolution process. Describing the formation of regulons may contribute to the understanding of how they act in the extant organisms, such as transcriptional control in cancer. In this research we investigated the evolutionary patterns of eukaryotic regulatory units in order to address the following question: who came first, regulators or regulated targets? Three hypotheses were tested: i) transcription factors and its targets appeared independently; ii) transcription factors came prior to their targets; iii) transcription factors came after their targets. We reconstructed regulons from gene expression data and developed a method to estimate the evolutionary distance between regulators and targets, inferring the point of emergence in a given species tree. A total of 307 regulatory units were evaluated, of which 76 (24.7%) had regulators rooted along with their targets, 137 (44.3%) had regulators rooted before their targets, and 94 (30.6%) had regulators rooted after their targets. These results suggest evolutionary scenarios that are consistent with the three hypotheses stated in this study. We then assessed the significance of these observations and found that the overall distribution of the inferred evolutionary roots of the regulators precedes the evolutionary roots of the targets (p-value = 1e-6, Wilcoxon-Mann-Whitney test). In addition, the identification of different evolutionary scenarios offers the opportunity to explain functional aspects found in the inferred regulons for breast cancer. Using a metric that estimates the functional similarity between regulons, regulatory units were clustered according to a regulatory network, and onto this regulatory network we mapped the evolutionary roots. Four important patterns were observed: (I) in general, regulons rooted at near evolutionary distances cluster to each other in the regulatory network; (ii) most of the regulons are rooted at the LCA of unicellular organisms; (iii) regulons associated with the development of breast cancer are more recent; (iv) most of the regulons related with positive/negative estrogen tumors are rooted at the LCA of metazoans. These results are consistent with one of the main aspects of cancer, in which tissue disarrangement is only possible in organisms able to form tissues.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em BioinformaticaUFMGBrasilBioinformáticaRegulonEucariotosAtivação TranscricionalBioinformáticaRegulonEucariotos.Ativação TranscricionalOrigem evolutiva de unidades regulatórias de eucariotos: quem surgiu primeiro, reguladores ou regulados?info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALTESE_versao_final_depositada.pdfTESE_versao_final_depositada.pdfapplication/pdf43649709https://repositorio.ufmg.br/bitstream/1843/51619/1/TESE_versao_final_depositada.pdf3ca8d51eda2ff83e6dad9965a32129f4MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/51619/2/license.txtcda590c95a0b51b4d15f60c9642ca272MD521843/516192023-04-05 12:15:11.728oai:repositorio.ufmg.br:1843/51619TElDRU7Dh0EgREUgRElTVFJJQlVJw4fDg08gTsODTy1FWENMVVNJVkEgRE8gUkVQT1NJVMOTUklPIElOU1RJVFVDSU9OQUwgREEgVUZNRwoKQ29tIGEgYXByZXNlbnRhw6fDo28gZGVzdGEgbGljZW7Dp2EsIHZvY8OqIChvIGF1dG9yIChlcykgb3UgbyB0aXR1bGFyIGRvcyBkaXJlaXRvcyBkZSBhdXRvcikgY29uY2VkZSBhbyBSZXBvc2l0w7NyaW8gSW5zdGl0dWNpb25hbCBkYSBVRk1HIChSSS1VRk1HKSBvIGRpcmVpdG8gbsOjbyBleGNsdXNpdm8gZSBpcnJldm9nw6F2ZWwgZGUgcmVwcm9kdXppciBlL291IGRpc3RyaWJ1aXIgYSBzdWEgcHVibGljYcOnw6NvIChpbmNsdWluZG8gbyByZXN1bW8pIHBvciB0b2RvIG8gbXVuZG8gbm8gZm9ybWF0byBpbXByZXNzbyBlIGVsZXRyw7RuaWNvIGUgZW0gcXVhbHF1ZXIgbWVpbywgaW5jbHVpbmRvIG9zIGZvcm1hdG9zIMOhdWRpbyBvdSB2w61kZW8uCgpWb2PDqiBkZWNsYXJhIHF1ZSBjb25oZWNlIGEgcG9sw610aWNhIGRlIGNvcHlyaWdodCBkYSBlZGl0b3JhIGRvIHNldSBkb2N1bWVudG8gZSBxdWUgY29uaGVjZSBlIGFjZWl0YSBhcyBEaXJldHJpemVzIGRvIFJJLVVGTUcuCgpWb2PDqiBjb25jb3JkYSBxdWUgbyBSZXBvc2l0w7NyaW8gSW5zdGl0dWNpb25hbCBkYSBVRk1HIHBvZGUsIHNlbSBhbHRlcmFyIG8gY29udGXDumRvLCB0cmFuc3BvciBhIHN1YSBwdWJsaWNhw6fDo28gcGFyYSBxdWFscXVlciBtZWlvIG91IGZvcm1hdG8gcGFyYSBmaW5zIGRlIHByZXNlcnZhw6fDo28uCgpWb2PDqiB0YW1iw6ltIGNvbmNvcmRhIHF1ZSBvIFJlcG9zaXTDs3JpbyBJbnN0aXR1Y2lvbmFsIGRhIFVGTUcgcG9kZSBtYW50ZXIgbWFpcyBkZSB1bWEgY8OzcGlhIGRlIHN1YSBwdWJsaWNhw6fDo28gcGFyYSBmaW5zIGRlIHNlZ3VyYW7Dp2EsIGJhY2stdXAgZSBwcmVzZXJ2YcOnw6NvLgoKVm9jw6ogZGVjbGFyYSBxdWUgYSBzdWEgcHVibGljYcOnw6NvIMOpIG9yaWdpbmFsIGUgcXVlIHZvY8OqIHRlbSBvIHBvZGVyIGRlIGNvbmNlZGVyIG9zIGRpcmVpdG9zIGNvbnRpZG9zIG5lc3RhIGxpY2Vuw6dhLiBWb2PDqiB0YW1iw6ltIGRlY2xhcmEgcXVlIG8gZGVww7NzaXRvIGRlIHN1YSBwdWJsaWNhw6fDo28gbsOjbywgcXVlIHNlamEgZGUgc2V1IGNvbmhlY2ltZW50bywgaW5mcmluZ2UgZGlyZWl0b3MgYXV0b3JhaXMgZGUgbmluZ3XDqW0uCgpDYXNvIGEgc3VhIHB1YmxpY2HDp8OjbyBjb250ZW5oYSBtYXRlcmlhbCBxdWUgdm9jw6ogbsOjbyBwb3NzdWkgYSB0aXR1bGFyaWRhZGUgZG9zIGRpcmVpdG9zIGF1dG9yYWlzLCB2b2PDqiBkZWNsYXJhIHF1ZSBvYnRldmUgYSBwZXJtaXNzw6NvIGlycmVzdHJpdGEgZG8gZGV0ZW50b3IgZG9zIGRpcmVpdG9zIGF1dG9yYWlzIHBhcmEgY29uY2VkZXIgYW8gUmVwb3NpdMOzcmlvIEluc3RpdHVjaW9uYWwgZGEgVUZNRyBvcyBkaXJlaXRvcyBhcHJlc2VudGFkb3MgbmVzdGEgbGljZW7Dp2EsIGUgcXVlIGVzc2UgbWF0ZXJpYWwgZGUgcHJvcHJpZWRhZGUgZGUgdGVyY2Vpcm9zIGVzdMOhIGNsYXJhbWVudGUgaWRlbnRpZmljYWRvIGUgcmVjb25oZWNpZG8gbm8gdGV4dG8gb3Ugbm8gY29udGXDumRvIGRhIHB1YmxpY2HDp8OjbyBvcmEgZGVwb3NpdGFkYS4KCkNBU08gQSBQVUJMSUNBw4fDg08gT1JBIERFUE9TSVRBREEgVEVOSEEgU0lETyBSRVNVTFRBRE8gREUgVU0gUEFUUk9Dw41OSU8gT1UgQVBPSU8gREUgVU1BIEFHw4pOQ0lBIERFIEZPTUVOVE8gT1UgT1VUUk8gT1JHQU5JU01PLCBWT0PDiiBERUNMQVJBIFFVRSBSRVNQRUlUT1UgVE9ET1MgRSBRVUFJU1FVRVIgRElSRUlUT1MgREUgUkVWSVPDg08gQ09NTyBUQU1Cw4lNIEFTIERFTUFJUyBPQlJJR0HDh8OVRVMgRVhJR0lEQVMgUE9SIENPTlRSQVRPIE9VIEFDT1JETy4KCk8gUmVwb3NpdMOzcmlvIEluc3RpdHVjaW9uYWwgZGEgVUZNRyBzZSBjb21wcm9tZXRlIGEgaWRlbnRpZmljYXIgY2xhcmFtZW50ZSBvIHNldSBub21lKHMpIG91IG8ocykgbm9tZXMocykgZG8ocykgZGV0ZW50b3IoZXMpIGRvcyBkaXJlaXRvcyBhdXRvcmFpcyBkYSBwdWJsaWNhw6fDo28sIGUgbsOjbyBmYXLDoSBxdWFscXVlciBhbHRlcmHDp8OjbywgYWzDqW0gZGFxdWVsYXMgY29uY2VkaWRhcyBwb3IgZXN0YSBsaWNlbsOnYS4KRepositório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-04-05T15:15:11Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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