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Institute for Systems Biology

NonprofitSeattle, Washington, United States
About: Institute for Systems Biology is a nonprofit organization based out in Seattle, Washington, United States. It is known for research contribution in the topics: Population & Proteomics. The organization has 1277 authors who have published 2777 publications receiving 353165 citations.


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Journal ArticleDOI
TL;DR: By quantifying the cell population structure during a critical state transition, key regulators of lineages commitment are identified and the percentage of desired cell types for several protocol variations are predicted 2 wk in advance, affording a tool to forecast cell fate outcomes and can be used to optimize differentiation protocols to obtain desired cell populations.
Abstract: Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent progenitor cells commit to the desired cell fate. Cell fate commitment represents a critical state transition or "tipping point" at which complex systems undergo a sudden qualitative shift. To characterize such transitions during iPSC to cardiomyocyte differentiation, we analyzed the gene expression patterns of 96 developmental genes at single-cell resolution. We identified a bifurcation event early in the trajectory when a primitive streak-like cell population segregated into the mesodermal and endodermal lineages. Before this branching point, we could detect the signature of an imminent critical transition: increase in cell heterogeneity and coordination of gene expression. Correlation analysis of gene expression profiles at the tipping point indicates transcription factors that drive the state transition toward each alternative cell fate and their relationships with specific phenotypic readouts. The latter helps us to facilitate small molecule screening for differentiation efficiency. To this end, we set up an analysis of cell population structure at the tipping point after systematic variation of the protocol to bias the differentiation toward mesodermal or endodermal cell lineage. We were able to predict the proportion of cardiomyocytes many days before cells manifest the differentiated phenotype. The analysis of cell populations undergoing a critical state transition thus affords a tool to forecast cell fate outcomes and can be used to optimize differentiation protocols to obtain desired cell populations.

78 citations

Journal ArticleDOI
TL;DR: The authors generate DNA methylomes from the three most frequent types of brain metastases, identify epigenetic signatures specific to each type of metastasis and construct a DNA methylation-based classifier (BrainMETH) to advance brain metastasis diagnosis.
Abstract: Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes. BrainMETH predictions are supported by routine histopathologic evaluation. We further characterize and validate the most predictive genomic regions in a large cohort of brain tumors (n = 165) using quantitative-methylation-specific PCR. Our study highlights the importance of brain tumor-defining epigenetic alterations, which can be utilized to further develop DNA methylation profiling as a critical tool in the histomolecular stratification of patients with brain metastases.

78 citations

Journal ArticleDOI
TL;DR: The synthesis of superparamagnetic silica particles with hydrazide groups on the surface and their use as the solid support for SPEG are described and demonstrated, demonstrating the potential of thesesuperparamagnetic colloidal particles for high-throughput analysis of glycoproteins.
Abstract: Solid-phase extraction of glycopeptides (SPEG) coupled with quantitative proteomic analysis using mass spectrometry has shown great potential for investigating glycoproteins in an effort to discover new diagnostic biomarkers or therapeutic targets. As a solid-phase approach, SPEG can be performed with a microtiter plate to provide a high-throughput platform for large-scale screening of clinical samples. Here we describe the synthesis of superparamagnetic silica particles with hydrazide groups on the surface and further evaluate their use as the solid support for SPEG. We produced nonspherical silica particles containing superparamagnetic iron oxide cores using a modified Stober method and then derivatized their surface with hydrazide-terminated silane. Such composite particles displayed a strong response to the external magnetic field, and this feature enabled us to capture and release the particles easily for automated, high-throughput sample preparation of glycopeptides. When measured with standard glycoproteins, the adsorption capacity of these particles was >36 mg of glycoproteins per g of nanoparticles. The nanoparticles were used in a microtiter plate format for glycopeptide capture using a liquid handler. The captured glycopeptides were then analyzed by LC-MS and LC-MS/MS to determine the specificity and reproducibility of glycopeptide isolation. Our results demonstrate the potential of these superparamagnetic colloidal particles for high-throughput analysis of glycoproteins.

78 citations

Journal ArticleDOI
TL;DR: This strategy of assessing all pathway enzymes kinetically under the same conditions may be necessary to avoid inadvertent differences between in vivo and in vitro biochemistry and serve to reveal otherwise unnoticed pleiotropic regulation, such as that demonstrated in the present study by K+ and phosphate.
Abstract: Does the understanding of the dynamics of biochemical networks in vivo, in terms of the properties of their components determined in vitro, require the latter to be determined all under the same conditions? An in vivo-like assay medium for enzyme activity determination was designed based on the concentrations of the major ionic constituents of the Escherichia coli cytosol: K(+) , Na(+) , Mg(2+) , phosphate, glutamate, sulfate and Cl(-) . The maximum capacities (V(max) ) of the extracted enzymes of two pathways were determined using both this in vivo-like assay medium and the assay medium specific for each enzyme. The enzyme activities differed between the two assay conditions. Most of the differences could be attributed to unsuspected, pleiotropic effects of K(+) and phosphate. K(+) activated some enzymes (aldolase, enolase and glutamate dehydrogenase) and inhibited others (phosphoglucose isomerase, phosphofructokinase, triosephosphate isomerase, glyceraldehyde 3-phosphate dehydrogenase, phosphoglycerate kinase, phosphoglycerate mutase), whereas phosphate inhibited all glycolytic enzymes and glutamine synthetase but only activated glutamine 2-oxoglutarate amidotransferase. Neither a high glutamate concentration, nor macromolecular crowding affected the glycolytic or nitrogen assimilation enzymes, other than through the product inhibition of glutamate dehydrogenase by glutamate. This strategy of assessing all pathway enzymes kinetically under the same conditions may be necessary to avoid inadvertent differences between in vivo and in vitro biochemistry. It may also serve to reveal otherwise unnoticed pleiotropic regulation, such as that demonstrated in the present study by K(+) and phosphate.

78 citations

Journal ArticleDOI
TL;DR: It is shown that both activation and repression target genes can be bound by Bcl11b in vivo, and that B cl11b effects overlap with E2A-dependent effects, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.
Abstract: T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

78 citations


Authors

Showing all 1292 results

NameH-indexPapersCitations
Younan Xia216943175757
Ruedi Aebersold182879141881
David Haussler172488224960
Steven P. Gygi172704129173
Nahum Sonenberg167647104053
Leroy Hood158853128452
Mark H. Ellisman11763755289
Wei Zhang112118993641
John Ralph10944239238
Eric H. Davidson10645447058
James R. Heath10342558548
Alan Aderem9924646682
Anne-Claude Gingras9733640714
Trey Ideker9730672276
Michael H. Gelb9450634714
Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
20233
202260
2021216
2020204
2019188
2018168