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1.
Nat Med ; 25(5): 792-804, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31068711

RESUMO

Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n = 109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8 years (median, 2.8 years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.


Assuntos
Big Data , Diabetes Mellitus Tipo 2/etiologia , Medicina de Precisão/estatística & dados numéricos , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Exoma , Feminino , Microbioma Gastrointestinal , Humanos , Resistência à Insulina , Estudos Longitudinais , Masculino , Metaboloma , Pessoa de Meia-Idade , Modelos Biológicos , Fatores de Risco , Transcriptoma
2.
Nature ; 569(7758): 663-671, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31142858

RESUMO

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.


Assuntos
Biomarcadores/metabolismo , Biologia Computacional , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal , Interações entre Hospedeiro e Microrganismos/genética , Estado Pré-Diabético/microbiologia , Proteoma/metabolismo , Transcriptoma , Adulto , Idoso , Antibacterianos/administração & dosagem , Biomarcadores/análise , Estudos de Coortes , Conjuntos de Dados como Assunto , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Voluntários Saudáveis , Humanos , Inflamação/metabolismo , Vacinas contra Influenza/imunologia , Insulina/metabolismo , Resistência à Insulina , Estudos Longitudinais , Masculino , Microbiota/fisiologia , Pessoa de Meia-Idade , Estado Pré-Diabético/genética , Estado Pré-Diabético/metabolismo , Infecções Respiratórias/genética , Infecções Respiratórias/metabolismo , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Estresse Fisiológico , Vacinação/estatística & dados numéricos
3.
Science ; 364(6436)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30975860

RESUMO

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.


Assuntos
Adaptação Fisiológica , Astronautas , Voo Espacial , Imunidade Adaptativa , Peso Corporal , Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Dano ao DNA , Metilação de DNA , Microbioma Gastrointestinal , Instabilidade Genômica , Humanos , Masculino , Homeostase do Telômero , Fatores de Tempo , Estados Unidos , United States National Aeronautics and Space Administration
4.
Leuk Lymphoma ; : 1-11, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29616851

RESUMO

To provide biologic insights into mechanisms underlying myelodysplastic syndromes (MDS) we evaluated the CD34+ marrow cells transcriptome using high-throughput RNA sequencing (RNA-Seq). We demonstrated significant differential gene expression profiles (GEPs) between MDS and normal and identified 41 disease classifier genes. Additionally, two main clusters of GEPs distinguished patients based on their major clinical features, particularly between those whose disease remained stable versus patients who transformed into acute myeloid leukemia within 12 months. The genes whose expression was associated with disease outcome were involved in functional pathways and biologic processes highly relevant for MDS. Combined with exomic analysis we identified differential isoform usage of genes in MDS mutational subgroups, with consequent dysregulation of distinct biologic functions. This combination of clinical, transcriptomic and exomic findings provides valuable understanding of mechanisms underlying MDS and its progression to a more aggressive stage and also facilitates prognostic characterization of MDS patients.

5.
Cell Syst ; 6(2): 157-170.e8, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29361466

RESUMO

Advances in omics technologies now allow an unprecedented level of phenotyping for human diseases, including obesity, in which individual responses to excess weight are heterogeneous and unpredictable. To aid the development of better understanding of these phenotypes, we performed a controlled longitudinal weight perturbation study combining multiple omics strategies (genomics, transcriptomics, multiple proteomics assays, metabolomics, and microbiomics) during periods of weight gain and loss in humans. Results demonstrated that: (1) weight gain is associated with the activation of strong inflammatory and hypertrophic cardiomyopathy signatures in blood; (2) although weight loss reverses some changes, a number of signatures persist, indicative of long-term physiologic changes; (3) we observed omics signatures associated with insulin resistance that may serve as novel diagnostics; (4) specific biomolecules were highly individualized and stable in response to perturbations, potentially representing stable personalized markers. Most data are available open access and serve as a valuable resource for the community.

6.
Nucleic Acids Res ; 44(D1): D925-31, 2016 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-26590403

RESUMO

Extensive research into hematopoiesis (the development of blood cells) over several decades has generated large sets of expression and epigenetic profiles in multiple human and mouse blood cell types. However, there is no single location to analyze how gene regulatory processes lead to different mature blood cells. We have developed a new database framework called hematopoietic Systems Biology Repository (SBR-Blood), available online at http://sbrblood.nhgri.nih.gov, which allows user-initiated analyses for cell type correlations or gene-specific behavior during differentiation using publicly available datasets for array- and sequencing-based platforms from mouse hematopoietic cells. SBR-Blood organizes information by both cell identity and by hematopoietic lineage. The validity and usability of SBR-Blood has been established through the reproduction of workflows relevant to expression data, DNA methylation, histone modifications and transcription factor occupancy profiles.


Assuntos
Bases de Dados Genéticas , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Animais , Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica , Humanos , Camundongos , Biologia de Sistemas
7.
Genom Data ; 4: 1-7, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25729644

RESUMO

During the maturation phase of mammalian erythroid differentiation, highly proliferative cells committed to the erythroid lineage undergo dramatic changes in morphology and function to produce circulating, enucleated erythrocytes. These changes are caused by equally dramatic alterations in gene expression, which in turn are driven by changes in the abundance and binding patterns of transcription factors such as GATA1. We have studied the dynamics of GATA1 binding by ChIP-seq and the global expression responses by RNA-seq in a GATA1-dependent mouse cell line model for erythroid maturation, in both cases examining seven progressive stages during differentiation. Analyses of these data should provide insights both into mechanisms of regulation (early versus late targets) and the consequences in cell physiology (e.g. distinctive categories of genes regulated at progressive stages of differentiation). The data are deposited in the Gene Expression Omnibus, series GSE36029, GSE40522, GSE49847, and GSE51338.

8.
Genome Res ; 24(12): 1945-62, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25319994

RESUMO

We used mouse ENCODE data along with complementary data from other laboratories to study the dynamics of occupancy and the role in gene regulation of the transcription factor TAL1, a critical regulator of hematopoiesis, at multiple stages of hematopoietic differentiation. We combined ChIP-seq and RNA-seq data in six mouse cell types representing a progression from multilineage precursors to differentiated erythroblasts and megakaryocytes. We found that sites of occupancy shift dramatically during commitment to the erythroid lineage, vary further during terminal maturation, and are strongly associated with changes in gene expression. In multilineage progenitors, the likely target genes are enriched for hematopoietic growth and functions associated with the mature cells of specific daughter lineages (such as megakaryocytes). In contrast, target genes in erythroblasts are specifically enriched for red cell functions. Furthermore, shifts in TAL1 occupancy during erythroid differentiation are associated with gene repression (dissociation) and induction (co-occupancy with GATA1). Based on both enrichment for transcription factor binding site motifs and co-occupancy determined by ChIP-seq, recruitment by GATA transcription factors appears to be a stronger determinant of TAL1 binding to chromatin than the canonical E-box binding site motif. Studies of additional proteins lead to the model that TAL1 regulates expression after being directed to a distinct subset of genomic binding sites in each cell type via its association with different complexes containing master regulators such as GATA2, ERG, and RUNX1 in multilineage cells and the lineage-specific master regulator GATA1 in erythroblasts.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição GATA/metabolismo , Regulação da Expressão Gênica , Hematopoese , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sítios de Ligação , Diferenciação Celular/genética , Cromatina/genética , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Análise por Conglomerados , Biologia Computacional , Conjuntos de Dados como Assunto , Células Eritroides/citologia , Células Eritroides/metabolismo , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/metabolismo , Camundongos , Modelos Biológicos , Anotação de Sequência Molecular , Motivos de Nucleotídeos , Matrizes de Pontuação de Posição Específica , Ligação Proteica , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Transcriptoma
9.
Genome Res ; 24(12): 1932-44, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25319996

RESUMO

Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors.


Assuntos
Diferenciação Celular , Linhagem da Célula , Eritropoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Trombopoese/fisiologia , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação , Cromatina/genética , Cromatina/metabolismo , Análise por Conglomerados , Fator de Transcrição GATA1/metabolismo , Fator de Transcrição GATA2/metabolismo , Perfilação da Expressão Gênica , Inativação Gênica , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Camundongos , Modelos Biológicos , Motivos de Nucleotídeos , Ligação Proteica , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Fatores de Transcrição/genética , Transcrição Genética
10.
Cell Rep ; 8(2): 514-27, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25043190

RESUMO

Tumor suppressor p53 regulates transcription of stress-response genes. Many p53 targets remain undiscovered because of uncertainty as to where p53 binds in the genome and the fact that few genes reside near p53-bound recognition elements (REs). Using chromatin immunoprecipitation followed by exonuclease treatment (ChIP-exo), we associated p53 with 2,183 unsplit REs. REs were positionally constrained with other REs and other regulatory elements, which may reflect structurally organized p53 interactions. Surprisingly, stress resulted in increased occupancy of transcription factor IIB (TFIIB) and RNA polymerase (Pol) II near REs, which was reduced when p53 was present. A subset associated with antisense RNA near stress-response genes. The combination of high-confidence locations for p53/REs, TFIIB/Pol II, and their changes in response to stress allowed us to identify 151 high-confidence p53-regulated genes, substantially increasing the number of p53 targets. These genes composed a large portion of a predefined DNA-damage stress-response network. Thus, p53 plays a comprehensive role in regulating the stress-response network, including regulating noncoding transcription.


Assuntos
Genoma Humano , Elementos de Resposta , Estresse Fisiológico , Proteína Supressora de Tumor p53/genética , Células HCT116 , Humanos , Ligação Proteica , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Fator de Transcrição TFIIB/genética , Fator de Transcrição TFIIB/metabolismo , Proteína Supressora de Tumor p53/metabolismo
11.
Blood ; 123(12): 1927-37, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24497530

RESUMO

Mammals express thousands of long noncoding (lnc) RNAs, a few of which are known to function in tissue development. However, the entire repertoire of lncRNAs in most tissues and species is not defined. Indeed, most lncRNAs are not conserved, raising questions about function. We used RNA sequencing to identify 1109 polyadenylated lncRNAs expressed in erythroblasts, megakaryocytes, and megakaryocyte-erythroid precursors of mice, and 594 in erythroblasts of humans. More than half of these lncRNAs were unannotated, emphasizing the opportunity for new discovery through studies of specialized cell types. Analysis of the mouse erythro-megakaryocytic polyadenylated lncRNA transcriptome indicates that ~75% arise from promoters and 25% from enhancers, many of which are regulated by key transcription factors including GATA1 and TAL1. Erythroid lncRNA expression is largely conserved among 8 different mouse strains, yet only 15% of mouse lncRNAs are expressed in humans and vice versa, reflecting dramatic species-specificity. RNA interference assays of 21 abundant erythroid-specific murine lncRNAs in primary mouse erythroid precursors identified 7 whose knockdown inhibited terminal erythroid maturation. At least 6 of these 7 functional lncRNAs have no detectable expression in human erythroblasts, suggesting that lack of conservation between mammalian species does not predict lack of function.


Assuntos
Eritropoese/genética , RNA Longo não Codificante/genética , Trombopoese/genética , Animais , Linhagem da Célula/genética , Sequência Conservada , Elementos Facilitadores Genéticos , Eritroblastos/metabolismo , Humanos , Células Progenitoras de Megacariócitos e Eritrócitos/metabolismo , Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Interferência de RNA , RNA Longo não Codificante/metabolismo , Especificidade da Espécie , Fatores de Transcrição/metabolismo
12.
J Biol Chem ; 288(12): 8433-44, 2013 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-23341446

RESUMO

Identification of cell type-specific enhancers is important for understanding the regulation of programs controlling cellular development and differentiation. Enhancers are typically marked by the co-transcriptional activator protein p300 or by groups of cell-expressed transcription factors. We hypothesized that a unique set of enhancers regulates gene expression in human erythroid cells, a highly specialized cell type evolved to provide adequate amounts of oxygen throughout the body. Using chromatin immunoprecipitation followed by massively parallel sequencing, genome-wide maps of candidate enhancers were constructed for p300 and four transcription factors, GATA1, NF-E2, KLF1, and SCL, using primary human erythroid cells. These data were combined with gene expression analyses, and candidate enhancers were identified. Consistent with their predicted function as candidate enhancers, there was statistically significant enrichment of p300 and combinations of co-localizing erythroid transcription factors within 1-50 kb of the transcriptional start site (TSS) of genes highly expressed in erythroid cells. Candidate enhancers were also enriched near genes with known erythroid cell function or phenotype. Candidate enhancers exhibited moderate conservation with mouse and minimal conservation with nonplacental vertebrates. Candidate enhancers were mapped to a set of erythroid-associated, biologically relevant, SNPs from the genome-wide association studies (GWAS) catalogue of NHGRI, National Institutes of Health. Fourteen candidate enhancers, representing 10 genetic loci, mapped to sites associated with biologically relevant erythroid traits. Fragments from these loci directed statistically significant expression in reporter gene assays. Identification of enhancers in human erythroid cells will allow a better understanding of erythroid cell development, differentiation, structure, and function and provide insights into inherited and acquired hematologic disease.


Assuntos
Elementos Facilitadores Genéticos , Células Eritroides/metabolismo , Regulação da Expressão Gênica , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Sequência Conservada , Proteína p300 Associada a E1A/metabolismo , Fator de Transcrição GATA1/metabolismo , Fator de Transcrição GATA1/fisiologia , Genes Reporter , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/fisiologia , Luciferases de Vaga-Lume/biossíntese , Luciferases de Vaga-Lume/genética , Anotação de Sequência Molecular , Subunidade p45 do Fator de Transcrição NF-E2/metabolismo , Subunidade p45 do Fator de Transcrição NF-E2/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de DNA , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Transcriptoma
14.
Genome Res ; 21(10): 1659-71, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21795386

RESUMO

Interplays among lineage-specific nuclear proteins, chromatin modifying enzymes, and the basal transcription machinery govern cellular differentiation, but their dynamics of action and coordination with transcriptional control are not fully understood. Alterations in chromatin structure appear to establish a permissive state for gene activation at some loci, but they play an integral role in activation at other loci. To determine the predominant roles of chromatin states and factor occupancy in directing gene regulation during differentiation, we mapped chromatin accessibility, histone modifications, and nuclear factor occupancy genome-wide during mouse erythroid differentiation dependent on the master regulatory transcription factor GATA1. Notably, despite extensive changes in gene expression, the chromatin state profiles (proportions of a gene in a chromatin state dominated by activating or repressive histone modifications) and accessibility remain largely unchanged during GATA1-induced erythroid differentiation. In contrast, gene induction and repression are strongly associated with changes in patterns of transcription factor occupancy. Our results indicate that during erythroid differentiation, the broad features of chromatin states are established at the stage of lineage commitment, largely independently of GATA1. These determine permissiveness for expression, with subsequent induction or repression mediated by distinctive combinations of transcription factors.


Assuntos
Diferenciação Celular/genética , Epigênese Genética , Eritropoese/genética , Fator de Transcrição GATA1/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina , Estradiol/farmacologia , Estradiol/fisiologia , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA2/metabolismo , Perfilação da Expressão Gênica , Inativação Gênica , Camundongos , Análise Multivariada , Peptídeo Hidrolases/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Receptores Estrogênicos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sequências Reguladoras de Ácido Nucleico , Proteína 1 de Leucemia Linfocítica Aguda de Células T
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