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Recent Publications

Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate.

Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate.

Cell Stem Cell. 2018 Apr 05;22(4):471-473

Authors: Sharma E, Blencowe BJ

Abstract
The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production.

PMID: 29625061 [PubMed - in process]



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An incoherent feedforward loop facilitates adaptive tuning of gene expression.

An incoherent feedforward loop facilitates adaptive tuning of gene expression.

Elife. 2018 Apr 05;7:

Authors: Hong J, Brandt N, Abdual-Rahman F, Yang AWH, Hughes TR, Gresham D

Abstract
We studied adaptive evolution of gene expression using long-term experimental evolution of Saccharomyces cerevisiae in ammonium-limited chemostats. We found repeated selection for non-synonymous variation in the DNA binding domain of the transcriptional activator, GAT1, which functions with the repressor, DAL80 in an incoherent type-1 feedforward loop (I1-FFL) to control expression of the high affinity ammonium transporter gene, MEP2. Missense mutations in the DNA binding domain of GAT1 reduce its binding to the GATAA consensus sequence. However, we show experimentally, and using mathematical modeling, that decreases in GAT1 binding result in increased expression of MEP2 as a consequence of properties of I1-FFLs. Our results show that I1-FFLs, one of the most commonly occurring network motifs in transcriptional networks, can facilitate adaptive tuning of gene expression through modulation of transcription factor binding affinities. Our findings highlight the importance of gene regulatory architectures in the evolution of gene expression.

PMID: 29620523 [PubMed - as supplied by publisher]



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Integrating images from multiple microscopy screens reveals diverse patterns of protein subcellular localization change.

Integrating images from multiple microscopy screens reveals diverse patterns of protein subcellular localization change.

Elife. 2018 Apr 05;7:

Authors: Lu AX, Chong YT, Hsu IS, Strome B, Handfield LF, Kraus O, Andrews BJ, Moses AM

Abstract
Evaluating protein localization changes on a systematic level is a powerful tool for understanding how cells respond to environmental, chemical, or genetic perturbations. To date, work in understanding these proteomic responses through high-throughput imaging has catalogued localization changes independently for each perturbation. To distinguish changes that are targeted responses to the specific perturbation and more generalized programs, we developed a scalable approach to visualize the localization behavior of proteins across multiple experiments as a quantitative pattern. By applying this approach to 24 experimental screens consisting of nearly 400,000 images, we differentiate specific responses from more generalized ones, discover nuance in the localization behavior of stress-responsive proteins, and form hypotheses by clustering proteins with similar patterns. While previous approaches aim to capture all localization changes for a single screen as accurately as possible, our work aims to integrate large amounts of imaging data to find unexpected new cell biology.

PMID: 29620521 [PubMed - as supplied by publisher]



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Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer.

Related Articles

Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer.

Cell Rep. 2018 Apr 03;23(1):112-126

Authors: Liu JC, Granieri L, Shrestha M, Wang DY, Vorobieva I, Rubie EA, Jones R, Ju Y, Pellecchia G, Jiang Z, Palmerini CA, Ben-David Y, Egan SE, Woodgett JR, Bader GD, Datti A, Zacksenhaus E

Abstract
CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition. Minimal cooperation was observed in vitro between CDC25 antagonists and CDK1, CDK2, or CDK4/6 inhibitors, but strong synergy with WEE1 inhibition was apparent. In accordance with increased PI3K signaling following long-term CDC25 inhibition, CDC25 and PI3K inhibitors effectively synergized to suppress TNBC growth both in vitro and in xenotransplantation models. These results provide a rationale for the development of CDC25-based therapies for diverse RB1/PTEN/TP53-deficient and -proficient TNBCs.

PMID: 29617654 [PubMed - in process]



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Automated Computational Inference of Multi-protein Assemblies from Biochemical Co-purification Data.

Automated Computational Inference of Multi-protein Assemblies from Biochemical Co-purification Data.

Methods Mol Biol. 2018;1764:391-399

Authors: Goebels F, Hu L, Bader G, Emili A

Abstract
Biology has amassed a wealth of information about the function of a multitude of protein-coding genes across species. The challenge now is to understand how all these proteins work together to form a living organism, and a crucial step for gaining this knowledge is a complete description of the molecular "wiring circuits" that underlie cellular processes. In this chapter, we describe a general computational framework for predicting multi-protein assemblies from biochemical co-fractionation data.

PMID: 29605929 [PubMed - in process]



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Global Characterization of Protein Complexes by Biochemical Purification-Mass Spectrometry (BP/MS).

Global Characterization of Protein Complexes by Biochemical Purification-Mass Spectrometry (BP/MS).

Methods Mol Biol. 2018;1764:185-191

Authors: Pourhaghighi R, Emili A

Abstract
A proteomic platform for global analysis of protein complexes and protein-protein interactions (PPIs) is described. Briefly, after comprehensive physiochemical separation of soluble protein extracts using non-denaturing ion exchange chromatography (IEX), each fraction is subjected to quantitative tandem mass spectrometry analysis.

PMID: 29605916 [PubMed - in process]



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Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging.

Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging.

Eur Heart J Cardiovasc Imaging. 2018 Mar 27;:

Authors: Badano LP, Kolias TJ, Muraru D, Abraham TP, Aurigemma G, Edvardsen T, D'Hooge J, Donal E, Fraser AG, Marwick T, Mertens L, Popescu BA, Sengupta PP, Lancellotti P, Thomas JD, Voigt JU, EACVI Scientific Documents Committee

Abstract
The EACVI/ASE/Industry Task Force to standardize deformation imaging prepared this consensus document to standardize definitions and techniques for using two-dimensional (2D) speckle tracking echocardiography (STE) to assess left atrial, right ventricular, and right atrial myocardial deformation. This document is intended for both the technical engineering community and the clinical community at large to provide guidance on selecting the functional parameters to measure and how to measure them using 2D STE.This document aims to represent a significant step forward in the collaboration between the scientific societies and the industry since technical specifications of the software packages designed to post-process echocardiographic datasets have been agreed and shared before their actual development. Hopefully, this will lead to more clinically oriented software packages which will be better tailored to clinical needs and will allow industry to save time and resources in their development.

PMID: 29596561 [PubMed - as supplied by publisher]



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Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2017.

Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2017.

J Integr Bioinform. 2018 Mar 29;:

Authors: Schreiber F, Bader GD, Gleeson P, Golebiewski M, Hucka M, Keating SM, Novère NL, Myers C, Nickerson D, Sommer B, Waltemath D

Abstract
Standards are essential to the advancement of Systems and Synthetic Biology. COMBINE provides a formal body and a centralised platform to help develop and disseminate relevant standards and related resources. The regular special issue of the Journal of Integrative Bioinformatics aims to support the exchange, distribution and archiving of these standards by providing unified, easily citable access. This paper provides an overview of existing COMBINE standards and presents developments of the last year.

PMID: 29596055 [PubMed - as supplied by publisher]



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QAPA: a new method for the systematic analysis of alternative polyadenylation from RNA-seq data.

Related Articles

QAPA: a new method for the systematic analysis of alternative polyadenylation from RNA-seq data.

Genome Biol. 2018 Mar 28;19(1):45

Authors: Ha KCH, Blencowe BJ, Morris Q

Abstract
Alternative polyadenylation (APA) affects most mammalian genes. The genome-wide investigation of APA has been hampered by an inability to reliably profile it using conventional RNA-seq. We describe 'Quantification of APA' (QAPA), a method that infers APA from conventional RNA-seq data. QAPA is faster and more sensitive than other methods. Application of QAPA reveals discrete, temporally coordinated APA programs during neurogenesis and that there is little overlap between genes regulated by alternative splicing and those by APA. Modeling of these data uncovers an APA sequence code. QAPA thus enables the discovery and characterization of programs of regulated APA using conventional RNA-seq.

PMID: 29592814 [PubMed - in process]



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Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA.

Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA.

J Biol Chem. 2018 Mar 22;:

Authors: Liu K, Xu C, Lei M, Yang A, Loppnau P, Hughes TR, Min J

Abstract
Cytosine methylation is a well characterized epigenetic mark and occurs at both CG and non-CG sites in DNA. Both methylated CG (mCG)- and mCH (H = A, C, or T)-containing DNAs, especially mCAC-containing DNAs, are recognized by methyl-CpG-binding protein 2 (MeCP2) to regulate gene expression in neuron development. However, the molecular mechanism involved in the binding of methyl-CpG-binding domain (MBD) of MeCP2 to these different DNA motifs is unclear. Here, we systematically characterized the DNA-binding selectivity of the MBDs in MeCP2 and MBD1-4 with isothermal titration calorimetry-based binding assays, mutagenesis studies, and X-ray crystallography. We found that the MBD domains of MeCP2 and MBD1-4<br />bind mCG-containing DNAs independently of the sequence outside the mCG dinucleotide. Moreover, some 1 MBDs bound to both methylated and unmethylated CA dinucleotide-<br />containing DNAs, with a preference for the CAC sequence motif. We also found that MBD domains bind to mCA or nonmethylated CA DNA by recognizing the complementary TG dinucleotide, which is consistent with an overlooked ligand of MeCP2, i.e., the matrix/scaffold attachment regions (MARs/SARs) with a consensus sequence of 5'-GGTGT-3', which was<br />identified in early 1990s. Our results also explain why MeCP2 exhibits similar binding affinity to both mCAand hmCA-containing dsDNAs. In summary, our results suggest that in addition to mCG sites, unmethylated CA or TG sites also serve as DNA-binding sites for MeCP2 and other MBDcontaining proteins. This discovery expands the genome-wide activity of MBD-containing proteins in gene regulation.

PMID: 29567833 [PubMed - as supplied by publisher]



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