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1.
Genome Res ; 27(12): 2096-2107, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29141961

RESUMO

Chromatin accessibility, a crucial component of genome regulation, has primarily been studied in homogeneous and simple systems, such as isolated cell populations or early-development models. Whether chromatin accessibility can be assessed in complex, dynamic systems in vivo with high sensitivity remains largely unexplored. In this study, we use ATAC-seq to identify chromatin accessibility changes in a whole animal, the model organism Caenorhabditis elegans, from embryogenesis to adulthood. Chromatin accessibility changes between developmental stages are highly reproducible, recapitulate histone modification changes, and reveal key regulatory aspects of the epigenomic landscape throughout organismal development. We find that over 5000 distal noncoding regions exhibit dynamic changes in chromatin accessibility between developmental stages and could thereby represent putative enhancers. When tested in vivo, several of these putative enhancers indeed drive novel cell-type- and temporal-specific patterns of expression. Finally, by integrating transcription factor binding motifs in a machine learning framework, we identify EOR-1 as a unique transcription factor that may regulate chromatin dynamics during development. Our study provides a unique resource for C. elegans, a system in which the prevalence and importance of enhancers remains poorly characterized, and demonstrates the power of using whole organism chromatin accessibility to identify novel regulatory regions in complex systems.


Assuntos
Caenorhabditis elegans/genética , Cromatina , Elementos Facilitadores Genéticos , Motivos de Aminoácidos , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/metabolismo , Cromatina/química , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA de Helmintos , Epigênese Genética , Proteínas Nucleares/metabolismo
2.
J Am Med Inform Assoc ; 24(3): 565-576, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27940607

RESUMO

OBJECTIVE: Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding. METHOD: We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis. RESULTS: From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence. CONCLUSIONS: This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Registros Eletrônicos de Saúde , Expressão Gênica , Adulto , Idoso , Neoplasias da Mama/genética , Quimioterapia Combinada , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade
4.
Cell ; 158(3): 673-88, 2014 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-25083876

RESUMO

Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to mark the transcription start sites of active genes. Here, we show that H3K4me3 domains that spread more broadly over genes in a given cell type preferentially mark genes that are essential for the identity and function of that cell type. Using the broadest H3K4me3 domains as a discovery tool in neural progenitor cells, we identify novel regulators of these cells. Machine learning models reveal that the broadest H3K4me3 domains represent a distinct entity, characterized by increased marks of elongation. The broadest H3K4me3 domains also have more paused polymerase at their promoters, suggesting a unique transcriptional output. Indeed, genes marked by the broadest H3K4me3 domains exhibit enhanced transcriptional consistency and [corrected] increased transcriptional levels, and perturbation of H3K4me3 breadth leads to changes in transcriptional consistency. Thus, H3K4me3 breadth contains information that could ensure transcriptional precision at key cell identity/function genes.


Assuntos
Células/metabolismo , Código das Histonas , Histonas/metabolismo , Transcrição Gênica , Animais , Inteligência Artificial , Genômica , Humanos , Lisina/metabolismo , Metilação , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , RNA Polimerase II/metabolismo
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