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DECIPHERING FOXO1-MEDIATED GENE REGULATION THROUGH MULTI-OMICS INTEGRATION
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A regulação da expressão génica é um processo complexo e rigorosamente regulado, que permite às nossas células manter a homeostase e respondera estímulos extracelulares. OFOXO1éumfatorde transcrição crucial envolvido na regulação da expressão génica, mas os seus exatos mecanismos de ação, particularmente na repressão, permanecem pouco explorados. Neste estudo, investigámos a regulação diferencial de genes após a sobre-expressão do FOXO1 em células endoteliais da veia do cordão umbilical humano e em células endoteliais dos vasos linfáticos, com ênfase na distinção entre genes alvo diretos e indiretos do FOXO1, através de uma abordagem de multi-ómicas. A nossa análise revelou que uma proporção significativa de genes reprimidos não eram alvos diretos do FOXO1,sendo provavelmente regulados por outros fatores de transcrição (FTs), com 41% dos locais de ligação de FOXO1 a serem indiretos. No entanto, tanto a ligação direta como a indireta ocorreram próximo do local de início da transcrição, tanto em genes ativados como reprimidos. Também observámos padrões distintos na distribuição das marcas das histonas H3K4me3 e H3K27ac, com genes reprimidos a exibirem algum enriquecimento próximo dos locais de fim da transcrição. Os nossos resultados sugerem umarederegulatóriacomplexa,naqualidentificámosqueoFOXO1colaboracomFTscomo ETS,JUN/FOS,SP/KLFeMYC,sendoesteúltimoumintervenientechavenarepressão.A nossa comparação entre duas linhas de células endoteliais permitiu-nos concluir que estes mecanismos eram, em geral, partilhados entre as células. Fomos capazes de determinar mecanismos diferenciadores entre ativação e repressão, e também de identificar FTs que potencialmente associados ao FOXO1 e aos seus mecanismos de ação.
Gene expression regulation is a complex, tightly regulated process that allows our cells to maintain homeostasis and respond to extracellular stimuli. FOXO1 is a critical transcription factor involved in the regulation of gene expression, yet its precise mecha nisms of action, particularly in repressing gene expression, remain underexplored. In this study, we investigated the differential regulation of genes upon FOXO1 overexpression in human umbilical vein and lymphatic endothelial cells integrating multi-omics profiles. Ouranalysis revealed that a significant proportion of down-regulated genes are not direct targets of FOXO1 but are likely regulated through other transcription factors (TFs), with 41% of FOXO1binding sites being indirect. Nonetheless, both direct and indirect binding occurred near the transcription start site both in up- and down-regulated genes. We also observed distinct patterns of histone marks H3K4me3 and H3K27ac distribution, with down-regulated genes exhibiting some enrichment around transcription end sites. Our findings suggested a complex regulatory network where we identified that FOXO1 collaborates with TFs such as ETS, JUN/FOS, SP/KLF, andMYC, thelatterofwhichplays a pivotal role in gene repression. Furthermore, our comparison between two different endothelial cell lines allowed us to understand that these mechanisms are overall shared between these cells. We were able to identify distinguishing features between up- and down-regulated genes, as well as to uncover TFs potentially associated with FOXO1’s different regulation mechanisms.
Gene expression regulation is a complex, tightly regulated process that allows our cells to maintain homeostasis and respond to extracellular stimuli. FOXO1 is a critical transcription factor involved in the regulation of gene expression, yet its precise mecha nisms of action, particularly in repressing gene expression, remain underexplored. In this study, we investigated the differential regulation of genes upon FOXO1 overexpression in human umbilical vein and lymphatic endothelial cells integrating multi-omics profiles. Ouranalysis revealed that a significant proportion of down-regulated genes are not direct targets of FOXO1 but are likely regulated through other transcription factors (TFs), with 41% of FOXO1binding sites being indirect. Nonetheless, both direct and indirect binding occurred near the transcription start site both in up- and down-regulated genes. We also observed distinct patterns of histone marks H3K4me3 and H3K27ac distribution, with down-regulated genes exhibiting some enrichment around transcription end sites. Our findings suggested a complex regulatory network where we identified that FOXO1 collaborates with TFs such as ETS, JUN/FOS, SP/KLF, andMYC, thelatterofwhichplays a pivotal role in gene repression. Furthermore, our comparison between two different endothelial cell lines allowed us to understand that these mechanisms are overall shared between these cells. We were able to identify distinguishing features between up- and down-regulated genes, as well as to uncover TFs potentially associated with FOXO1’s different regulation mechanisms.
Descrição
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FOXO1 Gene expression regulation Transcription Factors Multi-Omics En dothelial Cells