| 1. |
- Adoue, Veronique, et al.
(författare)
-
Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs
- 2014
-
Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292 .- 1744-4292. ; 10:10, s. 754-
-
Tidskriftsartikel (refereegranskat)abstract
- Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.
|
|
| 2. |
- Ali, Muhammad, et al.
(författare)
-
High-throughput discovery of functional disordered regions
- 2018
-
Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292 .- 1744-4292. ; 14:5
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Partially or fully intrinsically disordered proteins are widespread in eukaryotic proteomes and play important biological functions. With the recognition that well defined protein structure is not a fundamental requirement for function come novel challenges, such as assigning function to disordered regions. In their recent work, Babu and colleagues (Ravarani etal,) took on this challenge by developing IDR-Screen, a robust high-throughput approach for identifying functions of disordered regions.
|
|
| 3. |
|
|
| 4. |
- Azimi, Alireza, et al.
(författare)
-
Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
- 2018
-
Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 14:3
-
Tidskriftsartikel (refereegranskat)abstract
- Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression.
|
|
| 5. |
- Bachmann, Julie, et al.
(författare)
-
Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range
- 2011
-
Ingår i: Molecular Systems Biology. - : Nature Publishing Group / European Molecular Biology Organization. - 1744-4292 .- 1744-4292. ; 7:516
-
Tidskriftsartikel (refereegranskat)abstract
- Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. The specific contributions of individual feedback regulators, however, remain unclear. Based on extensive time-resolved data sets in primary erythroid progenitor cells, we established a dynamic pathway model to dissect the roles of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK2/STAT5 signaling. Facilitated by the model, we calculated the STAT5 response for experimentally unobservable Epo concentrations and provide a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. Model predictions show that the two feedbacks CIS and SOCS3 are most effective at different ligand concentration ranges due to their distinct inhibitory mechanisms. This divided function of dual feedback regulation enables control of STAT5 responses for Epo concentrations that can vary 1000-fold in vivo. Our modeling approach reveals dose-dependent feedback control as key property to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.
|
|
| 6. |
- Bader, J. M., et al.
(författare)
-
Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease
- 2020
-
Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 16:6
-
Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higherCSFlevels of tau, but we lack knowledge of systems-wide changes ofCSFprotein levels that accompanyAD. Here, we present a highly reproducible mass spectrometry (MS)-based proteomics workflow for the in-depth analysis ofCSFfrom minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins byADstatus (> 1,000 proteins,CV < 20%). Proteins with previous links to neurodegeneration such as tau,SOD1, andPARK7 differed most strongly byADstatus, providing strong positive controls for our approach.CSFproteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature.
|
|
| 7. |
- Beck, Martin, et al.
(författare)
-
The quantitative proteome of a human cell line
- 2011
-
Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- The generation of mathematical models of biological processes, the simulation of these processes under different conditions, and the comparison and integration of multiple data sets are explicit goals of systems biology that require the knowledge of the absolute quantity of the system's components. To date, systematic estimates of cellular protein concentrations have been exceptionally scarce. Here, we provide a quantitative description of the proteome of a commonly used human cell line in two functional states, interphase and mitosis. We show that these human cultured cells express at least similar to 10 000 proteins and that the quantified proteins span a concentration range of seven orders of magnitude up to 20 000 000 copies per cell. We discuss how protein abundance is linked to function and evolution. Molecular Systems Biology 7: 549; published online 8 November 2011; doi:10.1038/msb.2011.82
|
|
| 8. |
- Benz, Caroline, et al.
(författare)
-
Proteome-scale mapping of binding sites in the unstructured regions of the human proteome
- 2022
-
Ingår i: Molecular Systems Biology. - : EMBO Press. - 1744-4292 .- 1744-4292. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- Specific protein-protein interactions are central to all processes that underlie cell physiology. Numerous studies have together identified hundreds of thousands of human protein-protein interactions. However, many interactions remain to be discovered, and low affinity, conditional, and cell type-specific interactions are likely to be disproportionately underrepresented. Here, we describe an optimized proteomic peptide-phage display library that tiles all disordered regions of the human proteome and allows the screening of similar to 1,000,000 overlapping peptides in a single binding assay. We define guidelines for processing, filtering, and ranking the results and provide PepTools, a toolkit to annotate the identified hits. We uncovered >2,000 interaction pairs for 35 known short linear motif (SLiM)-binding domains and confirmed the quality of the produced data by complementary biophysical or cell-based assays. Finally, we show how the amino acid resolution-binding site information can be used to pinpoint functionally important disease mutations and phosphorylation events in intrinsically disordered regions of the proteome. The optimized human disorderome library paired with PepTools represents a powerful pipeline for unbiased proteomewide discovery of SLiM-based interactions.
|
|
| 9. |
- Buchser, William J., et al.
(författare)
-
Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology
- 2010
-
Ingår i: Molecular Systems Biology. - : Nature Publishing Group. - 1744-4292 .- 1744-4292. ; 6, s. 391-
-
Tidskriftsartikel (refereegranskat)abstract
- Development and regeneration of the nervous system requires the precise formation of axons and dendrites. Kinases and phosphatases are pervasive regulators of cellular function and have been implicated in controlling axodendritic development and regeneration. We undertook a gain-of-function analysis to determine the functions of kinases and phosphatases in the regulation of neuron morphology. Over 300 kinases and 124 esterases and phosphatases were studied by high-content analysis of rat hippocampal neurons. Proteins previously implicated in neurite growth, such as ERK1, GSK3, EphA8, FGFR, PI3K, PKC, p38, and PP1a, were confirmed to have effects in our functional assays. We also identified novel positive and negative neurite growth regulators. These include neuronal-developmentally regulated kinases such as the activin receptor, interferon regulatory factor 6 (IRF6) and neural leucine-rich repeat 1 (LRRN1). The protein kinase N2 (PKN2) and choline kinase alpha (CHKA) kinases, and the phosphatases PPEF2 and SMPD1, have little or no established functions in neuronal function, but were sufficient to promote neurite growth. In addition, pathway analysis revealed that members of signaling pathways involved in cancer progression and axis formation enhanced neurite outgrowth, whereas cytokine-related pathways significantly inhibited neurite formation.
|
|
| 10. |
|
|
