Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nº 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies’ in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucía (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuró for design support.Ye

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population. © 2021, The Author(s)

Unlocking the effective alliance of β-lapachone and hydroxytyrosol against triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is characterised by its aggressiveness and resistance to chemotherapy, demanding the development of effective strategies against its unique characteristics. Derived from lapacho tree bark, β-lapachone (β-LP) selectively targets cancer cells with elevated levels of the detoxifying enzyme NQO1. Hydroxytyrosol (HT) is a phenolic compound derived from olive trees with important anticancer properties that include the inhibition of cancer stem cells (CSCs) and metastatic features in TNBC, as well as relevant antioxidant activities by mechanisms such as the induction of NQO1. We aimed to study whether these compounds could have synergistic anticancer activity in TNBC cells and the possible role of NQO1. For this pourpose, we assessed the impact of β-LP (0.5 or 1.5 μM) and HT (50 and 100 μM) on five TNBC cell lines. We demonstrated that the combination of β-LP and HT exhibits anti-proliferative, pro-apoptotic, and cell cycle arrest effects in several TNBC cells, including docetaxel-resistant TNBC cells. Additionally, it effectively inhibits the self-renewal and clonogenicity of CSCs, modifying their aggressive phenotype. However, the notable impact of the β-LP-HT combination does not appear to be solely associated with the levels of the NQO1 protein and ROS. RNA-Seq analysis revealed that the combination's anticancer activity is linked to a strong induction of endoplasmic reticulum stress and apoptosis through the unfolded protein response. In conclusion, in this study, we demonstrated how the combination of β-LP and HT could offer an affordable, safe, and effective approach against TNBC.</p

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support.Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7/2007-2013) 115,565EFPIA companiesJunta de Andalucia PI/0017/2016Innovative Medicines Initiative 2 Joint Undertaking 806975 European Union's Horizon 2020 research and innovation programmeEFPIAPostdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness FJCI_2014_2065

Integrative epigenomics in Sjögren's syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune populati

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

International audienceAbstract Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population