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1.
Curr Diab Rep ; 21(1): 1, 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387073

RESUMO

PURPOSE OF REVIEW: Type 1 diabetes (T1D) develops as a consequence of a combination of genetic predisposition and environmental factors. Combined, these events trigger an autoimmune disease that results in progressive loss of pancreatic ß cells, leading to insulin deficiency. This article reviews the current knowledge on the genetics of T1D with a specific focus on genetic variation in pancreatic islet regulatory networks and its implication to T1D risk and disease development. RECENT FINDINGS: Accumulating evidence suggest an active role of ß cells in T1D pathogenesis. Based on such observation several studies aimed in mapping T1D risk variants acting at the ß cell level. Such studies unravel T1D risk loci shared with type 2 diabetes (T2D) and T1D risk variants potentially interfering with ß-cell responses to external stimuli. The characterization of regulatory genomics maps of disease-relevant states and cell types can be used to elucidate the mechanistic role of ß cells in the pathogenesis of T1D.

2.
Nat Commun ; 11(1): 2584, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444635

RESUMO

Interferon-α (IFNα), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFNα by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFNα induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFNα effects on human beta cells.


Assuntos
Processamento Alternativo , Células Secretoras de Insulina/fisiologia , Interferon-alfa/metabolismo , Interferon-alfa/farmacologia , Processamento Alternativo/efeitos dos fármacos , Células Cultivadas , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Mineração de Dados , Diabetes Mellitus Tipo 1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Mapas de Interação de Proteínas , Proteômica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição
3.
Nat Rev Endocrinol ; 16(7): 349-362, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32398822

RESUMO

Loss of functional ß-cell mass is the key mechanism leading to the two main forms of diabetes mellitus - type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind ß-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early ß-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on ß-cells in human disease. These advances include studies of islet morphology and human ß-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the ß-cell level and the endoplasmic reticulum stress signalling that contributes to ß-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK-eIF2α dependent). Here, we review these new findings, focusing on studies performed on human ß-cells or on samples obtained from patients with diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Insuficiência Pancreática Exócrina/etiologia , Células Secretoras de Insulina/fisiologia , Animais , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Insuficiência Pancreática Exócrina/fisiopatologia , Humanos , Células Secretoras de Insulina/patologia , Transdução de Sinais/fisiologia
4.
Sci Rep ; 10(1): 3637, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32108138

RESUMO

Cutaneous Squamous Cell Carcinoma (cSCC) is the most common and fastest-increasing cancer with metastatic potential. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression. To identify mRNAs, lncRNAs and circRNAs, which can be involved in cSCC, RNA-seq was performed on nine cSCCs and seven healthy skin samples. Representative transcripts were validated by NanoString nCounter assays using an extended cohort, which also included samples from pre-cancerous skin lesions (actinic keratosis). 5,352 protein-coding genes, 908 lncRNAs and 55 circular RNAs were identified to be differentially expressed in cSCC. Targets of 519 transcription factors were enriched among differentially expressed genes, 105 of which displayed altered level in cSCCs, including fundamental regulators of skin development (MYC, RELA, ETS1, TP63). Pathways related to cell cycle, apoptosis, inflammation and epidermal differentiation were enriched. In addition to known oncogenic lncRNAs (PVT1, LUCAT1, CASC9), a set of skin-specific lncRNAs were were identified to be dysregulated. A global downregulation of circRNAs was observed in cSCC, and novel skin-enriched circRNAs, circ_IFFO2 and circ_POF1B, were identified and validated. In conclusion, a reference set of coding and non-coding transcripts were identified in cSCC, which may become potential therapeutic targets or biomarkers.


Assuntos
Carcinoma de Células Escamosas/genética , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas/metabolismo , Estudos de Coortes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/metabolismo , Transcriptoma
5.
Mol Biol Cell ; 31(6): 419-438, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31967936

RESUMO

Chromosome segregation during mitosis is antagonistically regulated by the Aurora-B kinase and RepoMan (recruits PP1 onto mitotic chromatin at anaphase)-associated phosphatases PP1/PP2A. Aurora B is overexpressed in many cancers but, surprisingly, this only rarely causes lethal aneuploidy. Here we show that RepoMan abundance is regulated by the same mechanisms that control Aurora B, including FOXM1-regulated expression and proteasomal degradation following ubiquitination by APC/C-CDH1 or SCFFBXW7. The deregulation of these mechanisms can account for the balanced co-overexpression of Aurora B and RepoMan in many cancers, which limits chromosome segregation errors. In addition, Aurora B and RepoMan independently promote cancer cell proliferation by reducing checkpoint--induced cell-cycle arrest during interphase. The co-up-regulation of RepoMan and Aurora B in tumors is inversely correlated with patient survival, underscoring its potential importance for tumor progression. Finally, we demonstrate that high RepoMan levels sensitize cancer cells to Aurora-B inhibitors. Hence, the co-up-regulation of RepoMan and Aurora B is associated with tumor aggressiveness but also exposes a vulnerable target for therapeutic intervention.

7.
Nat Genet ; 51(11): 1588-1595, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676868

RESUMO

The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic ß cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the ß-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the ß-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the ß-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human ß cells. Our study illustrates how ß cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.


Assuntos
Cromatina/genética , Citocinas/farmacologia , Diabetes Mellitus Tipo 1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Células Secretoras de Insulina/metabolismo , Transcriptoma , Cromatina/química , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Elementos Facilitadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Fatores de Transcrição
8.
Nat Genet ; 51(7): 1137-1148, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31253982

RESUMO

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.


Assuntos
Cromatina/química , Diabetes Mellitus Tipo 2/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Secreção de Insulina/genética , Ilhotas Pancreáticas/metabolismo , Cromatina/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Conformação Molecular , Regiões Promotoras Genéticas
10.
Acta Derm Venereol ; 99(2): 196-205, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30320872

RESUMO

Psoriasis is a common immune-mediated disease resulting from altered cross-talk between keratinocytes and immune cells. Previous transcriptomic studies have identified thousands of deregulated genes in psoriasis skin; however, the transcriptomic changes confined to the epidermal compartment remained poorly characterized. The aim of this study was to characterize the transcriptomic landscape of psoriatic keratinocytes, using sorted CD45neg epidermal cells. Genes with functions in innate immunity, type I interferon response, cell cycle and keratinization were enriched among deregulated genes in psoriatic keratinocytes. Gene set enrichment analysis indicated the dominance of interleukin (IL)-22/IL-17A signatures in the epidermal psoriasis-signature. A set of deregulated genes overlapped with psoriasis-associated genetic regions, suggesting that genetic variations affecting gene expression in keratinocytes contribute to susceptibility to psoriasis. Several psoriasis-susceptibility genes, which were previously believed to be expressed preferentially or exclusively in immune cells, were identified as having altered expression in psoriatic keratinocytes. These results highlight the role of keratinocytes in the pathogenesis of psoriasis, and indicate that both genetic factors and an inflammatory microenvironment contribute to epidermal alterations in psoriasis.


Assuntos
Ciclo Celular/genética , Epiderme/metabolismo , Imunidade Inata/genética , Queratinócitos/metabolismo , Queratinas/metabolismo , Psoríase/genética , Transcriptoma , Adulto , Idoso , Estudos de Casos e Controles , Microambiente Celular , Epiderme/imunologia , Epiderme/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Queratinócitos/imunologia , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Transdução de Sinais , Adulto Jovem
11.
Biomark Res ; 6: 31, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30450210

RESUMO

Background: We aim to characterize the heterogeneous circulating tumour cells (CTCs) in peripheral blood, independently of physical or immunological purification, by using patient-derived xenografts (PDXs) models. CTC studies from blood generally rely on enrichment or purification. Conversely, we devised a method for the inclusive study of human cells from blood of PDX models, without pre-selection or enrichment. Methods: A qRT-PCR assay was developed to detect human and cancer-related transcripts from CTCs in PDXs. We quantified the EPCAM and keratins CTC markers, in a PDX cohort of breast cancer. The murine beta actin gene was used for normalization. Spearman's rho coefficients were calculated for correlation. Results: We demonstrated, for the first time, that we can quantify the content of CTCs and the expression of human CTC markers in PDX blood using human-specific qRT-PCR. Our method holds strong potential for the study of CTC heterogeneity and for the identification of novel CTC markers. Conclusions: The identification and the relative quantification of the diverse spectrum of CTCs in patients, irrespective of EPCAM or other currently used markers, will have a great impact on personalized medicine: unrestricted CTCs characterization will allow the early detection of metastases in cancer patients and the assessment of personalized therapies.

12.
Diabetes ; 67(9): 1807-1815, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30084829

RESUMO

Type 2 diabetes mellitus (T2DM) is characterized by the inability of the insulin-producing ß-cells to overcome insulin resistance. We previously identified an imprinted region on chromosome 14, the DLK1-MEG3 locus, as being downregulated in islets from humans with T2DM. In this study, using targeted epigenetic modifiers, we prove that increased methylation at the promoter of Meg3 in mouse ßTC6 ß-cells results in decreased transcription of the maternal transcripts associated with this locus. As a result, the sensitivity of ß-cells to cytokine-mediated oxidative stress was increased. Additionally, we demonstrate that an evolutionarily conserved intronic region at the MEG3 locus can function as an enhancer in ßTC6 ß-cells. Using circular chromosome conformation capture followed by high-throughput sequencing, we demonstrate that the promoter of MEG3 physically interacts with this novel enhancer and other putative regulatory elements in this imprinted region in human islets. Remarkably, this enhancer is bound in an allele-specific manner by the transcription factors FOXA2, PDX1, and NKX2.2. Overall, these data suggest that the intronic MEG3 enhancer plays an important role in the regulation of allele-specific expression at the imprinted DLK1-MEG3 locus in human ß-cells, which in turn impacts the sensitivity of ß-cells to cytokine-mediated oxidative stress.


Assuntos
Metilação de DNA , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ilhotas Pancreáticas/metabolismo , Proteínas de Membrana/metabolismo , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , Animais , Proteínas de Ligação ao Cálcio , Linhagem Celular , Citocinas/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/química , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Diabetes Mellitus Tipo 2/patologia , Elementos Facilitadores Genéticos , Epigênese Genética , Loci Gênicos , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ilhotas Pancreáticas/patologia , Região de Controle de Locus Gênico , Proteínas de Membrana/genética , Camundongos , Mutação , Estresse Oxidativo/efeitos dos fármacos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Bancos de Tecidos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Methods Mol Biol ; 1766: 197-208, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29605854

RESUMO

The regulatory mechanisms that ensure an accurate control of gene transcription are central to cellular function, development and disease. Such mechanisms rely largely on noncoding regulatory sequences that allow the establishment and maintenance of cell identity and tissue-specific cellular functions.The study of chromatin structure and nucleosome positioning allowed revealing transcription factor accessible genomic sites with regulatory potential, facilitating the comprehension of tissue-specific cis-regulatory networks. Recently a new technique coupled with high-throughput sequencing named Assay for Transposase Accessible Chromatin (ATAC-seq) emerged as an efficient method to chart open chromatin genome wide. The application of such technique to different cell types allowed unmasking tissue-specific regulatory elements and characterizing cis-regulatory networks. Herein we describe the implementation of the ATAC-seq method to human pancreatic islets, a tissue playing a central role in the control of glucose metabolism.


Assuntos
Cromatina/efeitos dos fármacos , Cromatina/genética , Ensaios de Triagem em Larga Escala , Ilhotas Pancreáticas/enzimologia , Transposases/farmacologia , Cromatina/química , Epigenômica , Humanos , Ilhotas Pancreáticas/química , Nucleossomos/química , Nucleossomos/efeitos dos fármacos , Nucleossomos/genética , Controle de Qualidade , Alinhamento de Sequência , Análise de Sequência de DNA , Técnicas de Cultura de Tecidos , Transcrição Genética , Transposases/química
14.
J Invest Dermatol ; 138(4): 882-892, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29104160

RESUMO

Melanoma is one of the deadliest human cancers with limited therapeutic options. MicroRNAs are a class of short noncoding RNAs regulating gene expression at the post-transcriptional level. To identify important miRNAs in melanoma, we compared the miRNome of primary and metastatic melanomas in The Cancer Genome Atlas dataset and found lower miR-203 abundance in metastatic melanoma. Lower level of miR-203 was associated with poor overall survival in metastatic disease. We found that the methylation levels of several CpGs in the MIR203 promoter negatively correlated with miR-203 expression and that treatment with the demethylating agent 5-aza-2-deoxycytidine induced miR-203 expression, which was associated with demethylation of the promoter CpGs, in melanoma cell lines. In vitro, there was a decreased expression of miR-203 in melanoma cell lines in comparison with primary melanocytes. Ectopic overexpression of miR-203 suppressed cell motility, colony formation, and sphere formation as well as the angiogenesis-inducing capacity of melanoma cells. In vivo, miR-203 inhibited xenograft tumor growth and reduced lymph node and lung metastasis. SLUG was shown as a target of miR-203, and knockdown of SLUG recapitulated the effects of miR-203, whereas its restoration was able to reverse the miR-203-mediated suppression of cell motility. These results establish a role for miR-203 as a tumor suppressor in melanoma which suppresses both early and late steps of metastasis. Hence, restoration of miR-203 has therapeutic potential in melanoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , MicroRNAs/genética , RNA Neoplásico/genética , Neoplasias Cutâneas/genética , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Estudo de Associação Genômica Ampla , Humanos , Melanoma/metabolismo , Melanoma/secundário , MicroRNAs/biossíntese , Regiões Promotoras Genéticas , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
15.
Front Genet ; 8: 13, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28261261

RESUMO

The pancreatic islet is a highly specialized tissue embedded in the exocrine pancreas whose primary function is that of controlling glucose homeostasis. Thus, understanding the transcriptional control of islet-cell may help to puzzle out the pathogenesis of glucose metabolism disorders. Integrative computational analyses of transcriptomic and epigenomic data allows predicting genomic coordinates of putative regulatory elements across the genome and, decipher tissue-specific functions of the non-coding genome. We herein present the Islet Regulome Browser, a tool that allows fast access and exploration of pancreatic islet epigenomic and transcriptomic data produced by different labs worldwide. The Islet Regulome Browser is now accessible on the internet or may be installed locally. It allows uploading custom tracks as well as providing interactive access to a wealth of information including Genome-Wide Association Studies (GWAS) variants, different classes of regulatory elements, together with enhancer clusters, stretch-enhancers and transcription factor binding sites in pancreatic progenitors and adult human pancreatic islets. Integration and visualization of such data may allow a deeper understanding of the regulatory networks driving tissue-specific transcription and guide the identification of regulatory variants. We believe that such tool will facilitate the access to pancreatic islet public genomic datasets providing a major boost to functional genomics studies in glucose metabolism related traits including diabetes.

16.
Cell Metab ; 25(2): 400-411, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28041957

RESUMO

Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic ß cells. ß cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in ß cell gene regulation and diabetes, the function of ß cell lncRNAs remains largely unknown. In this study, we investigated the function of ß cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate ß cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key ß cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of ß cell-specific transcription factor networks.


Assuntos
Redes Reguladoras de Genes/genética , Células Secretoras de Insulina/metabolismo , RNA Longo não Codificante/genética , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/metabolismo , Secreção de Insulina , Família Multigênica , Fenótipo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética
17.
Int J Genomics ; 2016: 4503840, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27965971

RESUMO

The recent advantage obtained by next generation sequencing allows a depth investigation of a new "old" kind of noncoding transcript, the circular RNAs. Circular RNAs are nontranslated RNAs, typically nonpolyadenylated, with a resistance to exonucleases that gives them the ability to be more stable than the common linear RNA isoforms. We used a bioinformatic detection tool (CIRCexplorer) to research predictive circRNAs from the next generation sequenced data of five samples of ductal in situ carcinoma (DCIS) and matched adjacent invasive ductal carcinoma (IDC). Furthermore, we also investigated the circular RNAs expressed in MCF7, an invasive breast ductal carcinoma cell line. We described the genomic context of the predicted circular RNAs and we address the hypothetical possible functional roles. This study showed a perspective of a panel of predictive circRNAs identified and the function that circRNAs could exert.

18.
Hum Mol Genet ; 25(10): 2070-2081, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26911676

RESUMO

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.


Assuntos
Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Afro-Americanos/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p18/genética , Diabetes Mellitus Tipo 2/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Canal de Potássio KCNQ1/genética , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Elementos Reguladores de Transcrição/genética , tRNA Metiltransferases/genética
19.
J Mol Endocrinol ; 56(1): R1-R20, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26438568

RESUMO

Most of the genetic variation associated with diabetes, through genome-wide association studies, does not reside in protein-coding regions, making the identification of functional variants and their eventual translation to the clinic challenging. In recent years, high-throughput sequencing-based methods have enabled genome-scale high-resolution epigenomic profiling in a variety of human tissues, allowing the exploration of the human genome outside of the well-studied coding regions. These experiments unmasked tens of thousands of regulatory elements across several cell types, including diabetes-relevant tissues, providing new insights into their mechanisms of gene regulation. Regulatory landscapes are highly dynamic and cell-type specific and, being sensitive to DNA sequence variation, can vary with individual genomes. The scientific community is now in place to exploit the regulatory maps of tissues central to diabetes etiology, such as pancreatic progenitors and adult islets. This giant leap forward in the understanding of pancreatic gene regulation is revolutionizing our capacity to discriminate between functional and non-functional non-coding variants, opening opportunities to uncover regulatory links between sequence variation and diabetes susceptibility. In this review, we focus on the non-coding regulatory landscape of the pancreatic endocrine cells and provide an overview of the recent developments in this field.


Assuntos
DNA Intergênico/genética , Diabetes Mellitus Tipo 2/genética , Animais , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Sequências Reguladoras de Ácido Nucleico
20.
Curr Opin Genet Dev ; 33: 71-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26433090

RESUMO

In recent years, studies of cis-regulatory mechanisms have evolved from a predominant focus on promoter regions to the realization that spatial and temporal gene regulation is frequently driven by long-range enhancer clusters that operate within chromosomal compartments. This increased understanding of genome function, together with the emergence of technologies that enable whole-genome sequencing of patients' DNAs, open the prospect of dissecting the role of cis-regulatory defects in human disease. In this review we discuss how recent epigenomic studies have provided insights into the function of transcriptional enhancers. We then present examples that illustrate how integrative genomics can help uncover enhancer sequence variants underlying Mendelian and common polygenic human disease.


Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Doenças Genéticas Inatas/genética , Transcrição Genética , Epigênese Genética/genética , Doenças Genéticas Inatas/patologia , Humanos
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