Mapping transcription factor interactome networks using HaloTag protein arrays.
PNAS 113(29):E4238 (2016)
Protein microarrays enable investigation of diverse biochemical properties for thousands of proteins in a single experiment, an unparalleled capacity. Using a high-density system called HaloTag nucleic acid programmable protein array (HaloTag-NAPPA), we created high-density protein arrays compri...
The transcription factor ERG recruits CCR4-NOT to control mRNA decay and mitotic progression.
Nature Structural & Molecular Biology 23(7):663 (2016)
Control of mRNA levels, a fundamental aspect in the regulation of gene expression, is achieved through a balance between mRNA synthesis and decay. E26-related gene (Erg) proteins are canonical transcription factors whose previously described functions are confined to the control of mRNA synthesi...
An extended set of yeast-based functional assays accurately identifies human disease mutations.
Genome Research 26(5):670 (2016)
We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a s...
Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
Molecular Systems Biology 12(4):863 (2016)
High-throughput binary protein interaction mapping is continuing to extend our understanding of cellular function and disease mechanisms. However, we remain one or two orders of magnitude away from a complete interaction map for humans and other major model organisms. Completion will require scr...
An inter-species protein-protein interaction network across vast evolutionary distance.
Molecular Systems Biology 12(4):865 (2016)
In cellular systems, biophysical interactions between macromolecules underlie a complex web of functional interactions. How biophysical and functional networks are coordinated, whether all biophysical interactions correspond to functional interactions, and how such biophysical-versus-functional ...
Survey of variation in human transcription factors reveals prevalent DNA binding changes.
Science 351(6280):1450 (2016)
Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their...
A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States.
Neuron 89(4):842 (2016)
Neuromodulation of arousal states ensures that an animal appropriately responds to its environment and engages in behaviors necessary for survival. However, the molecular and circuit properties underlying neuromodulation of arousal states such as sleep and wakefulness remain unclear. To tackle t...
Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
Cell 164(4):805 (2016)
While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alte...
MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy.
Cancer Discovery 6(1):45 (2016)
An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers...
Network-based in silico drug efficacy screening.
Nature Communications 7:10331 (2016)
The increasing cost of drug development together with a significant drop in the number of new drug approvals raises the need for innovative approaches for target identification and efficacy prediction. Here, we take advantage of our increasing understanding of the network-based origins of diseas...
How much of the human protein interactome remains to be mapped?
Science Signaling 9(427):eg7 (2016)
Using systematic approaches, a high-quality reference map of the human protein-protein interactome is within reach. Such a reference will help researchers connect genomic data to cellular phenotypes and enable full exploitation of the output of the genomic revolution for biomedical applications....
Global Edgetic Rewiring in Cancer Networks.
Cell Systems 1(4):251 (2015)
Two recent papers in Cell interpret lists of cancer genomic alterations in terms of how mutations rewire interactome networks.
Copyright © 2015 Elsevier Inc. All rights reserved.
A disease module in the interactome explains disease heterogeneity, drug response and captures novel pathways and genes in asthma.
Human Molecular Genetics 24(11):3005 (2015)
Recent advances in genetics have spurred rapid progress towards the systematic identification of genes involved in complex diseases. Still, the detailed understanding of the molecular and physiological mechanisms through which these genes affect disease phenotypes remains a major challenge. Here...
Widespread macromolecular interaction perturbations in human genetic disorders.
Cell 161(3):647 (2015)
How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile sever...
Human gene-centered transcription factor networks for enhancers and disease variants.
Cell 161(3):661 (2015)
Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping m...
Protein domain-level landscape of cancer-type-specific somatic mutations.
PLoS computational biology 11(3):e1004147 (2015)
Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we syst...
Disease networks. Uncovering disease-disease relationships through the incomplete interactome.
Science 347(6224):1257601 (2015)
According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of diseas...
Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases.
Neuron 85(4):742 (2015)
The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. H...
Selecting causal genes from genome-wide association studies via functionally coherent subnetworks.
Nature Methods 12(2):154 (2015)
Genome-wide association (GWA) studies have linked thousands of loci to human diseases, but the causal genes and variants at these loci generally remain unknown. Although investigators typically focus on genes closest to the associated polymorphisms, the causal gene is often more distal. Reliance...
The yeast two-hybrid assay: still finding connections after 25 years.
Nature Methods 11(12):1203 (2014)