COLLEGE OF MEDICINE AND HEALTH
Medicine, Nursing and Allied Health Professions

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Dr Benjamin Housden

Dr Benjamin Housden

Research Fellow (LSI)

 01392 72 7475

 Living Systems Institute T04.13

 

Living Systems Institute, University of Exeter, Stocker Road, Exeter, EX4 4QD

Overview

My research is focussed on using interdisciplinary methods to study cell function and how genetic mutations lead to disease. This involves a combination of new technology development and high-throughput synthetic lethal screening to analyse gene functions in specific contexts as well as to identify and characterise candidate drugs to treat genetic diseases.

I began my research career in the laboratory of Prof. Sarah Bray at the University of Cambridge. There, I studied the direct transcriptional outputs of Notch signaling and crosstalk with the EGFR pathway using Drosophila as a model system. From this work, I gained valuable experience working with transcriptomics datasets and developed an appreciation of the network-like organization of signaling pathways. In addition, I realized the advantages of using model organisms such as Drosophila to tease apart the mechanisms of complex systems relevant to mammalian models and humans.

For my postdoctoral work, I joined Prof. Norbert Perrimon’s laboratory at Harvard Medical School. Here, my interest in signaling networks led me to develop combinatorial screening methods to identify synthetic lethal interactions in a high-throughput manner. A synthetic lethal interaction is a relationship between two genes where simultaneous disruption of both is lethal but disruption of either gene alone is not. Knowledge of synthetic lethal interactions has many applications, including mapping of signaling networks, determining the functions of individual network components and identifying drug targets for human disease. However, while synthetic lethal interaction maps have been generated for single celled organisms such as yeast, methods that allow robust and systematic mapping of synthetic lethal interactions in multicellular models are currently lacking. I therefore focused on developing improved methods to identify synthetic lethal interactions using Drosophila as a model organism.

Qualifications

  • BA
  • MA
  • PhD

Research

Research interests

Project 1: Accelerating drug discovery by developing improved technologies for synthetic lethal screens

The overall aim of this project is to improve the process of identifying new drug targets for the treatment of human diseases. We are using an interdisciplinary approach to improve all aspects of the high-throughput screens that are often used for drug target discovery. For example, we developed a new assay for cell viability called Variable Dose Analysis (VDA), which improves the sensitivity of screens and enables better detection of candidate targets amongst essential genes. In addition, we are working with industry partners to develop miniaturised and automated methods for VDA screening. Finally, we are developing machine-learning methods to improve the analysis of screen data. Together, these improvements will facilitate rapid identification of the most promising candidate drug targets for further development.

 

Project 2: Identification and characterisation of novel drug targets for Tuberous Sclerosis Complex (TSC)

Tuberous Sclerosis Complex (TSC) is a tumourigenic disease caused by mutations in the TSC1 or TSC2 genes and is currently treated with rapamycin. However, this drug is insufficient because it prevents tumour growth but does not kill tumour cells. Therefore, tumours regrow rapidly when treatment is stopped. The aim of this project is to use the VDA screening method to identify single drugs and combinations of drugs that specifically kill TSC mutant cells. Such drugs represent promising new candidates for the treatment of TSC. This project is being performed by Chris Baxter (Graduate research assistant and Msc student) and Katarzyna Seirzputowska (PhD student)

 

Project 3: An integrated analysis of the protein-protein interaction network of the conserved mitotic kinase, Polo

Katarzyna Seirzputowska (Kasia) is a PhD student in the lab, co-supervised with James Wakefield, who is studying the roles of the kinase Polo during cell division. Kasia is applying the VDA screening method to search for genetic interactions with Polo and will then further characterise these interactors to gain a deeper understanding of both the regulation and downstream mechanisms of Polo function.

Research grants

  • 2018 MRC
    Development of a high-throughput multiplex screening platform for drug discovery
  • 2018 ISSF Wellcome Trust Seed Corn Fund
    Developing a multiplex RNAi screening method for drug target discovery
  • 2016 DoD/TSCRP
    DoD/TSCRP: A unique opportunity for TSC: Repurposing FDA approved drugs using a unique combinatorial screening strategy. July 2016 - July 2018.

Publications

Key publications | Publications by category | Publications by year

Publications by category


Journal articles

Mohr SE, Hu Y, Ewen-Campen B, Housden BE, Viswanatha R, Perrimon N (In Press). CRISPR guide RNA design for research applications. FEBS J, 283(17), 3232-3238. Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Cas9-Mediated Genome Engineering in Drosophila melanogaster. Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Comparing CRISPR and RNAi-based screening technologies. Nat Biotechnol, 34(6), 621-623. Author URL.
Chavez A, Tuttle M, Pruitt BW, Ewen-Campen B, Chari R, Ter-Ovanesyan D, Haque SJ, Cecchi RJ, Kowal EJK, Buchthal J, et al (In Press). Comparison of Cas9 activators in multiple species. Nat Methods, 13(7), 563-567. Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Design and Generation of Donor Constructs for Genome Engineering in Drosophila. Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Housden BE, Hu Y, Perrimon N (In Press). Design and Generation of Drosophila Single Guide RNA Expression Constructs. Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Detection of Indel Mutations in Drosophila by High-Resolution Melt Analysis (HRMA). Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Ammeux N, Housden BE, Georgiadis A, Hu Y, Perrimon N (In Press). Mapping signaling pathway cross-talk in Drosophila cells. Proc Natl Acad Sci U S A, 113(35), 9940-9945. Abstract.  Author URL.
Mohr SE, Rudd K, Hu Y, Song WR, Gilly Q, Buckner M, Housden BE, Kelley C, Zirin J, Tao R, et al (In Press). Zinc Detoxification: a Functional Genomics and Transcriptomics Analysis in Drosophila melanogaster Cultured Cells. G3 (Bethesda), 8(2), 631-641. Abstract.  Author URL.
Lee P-T, Zirin J, Kanca O, Lin W-W, Schulze KL, Li-Kroeger D, Tao R, Devereaux C, Hu Y, Chung V, et al (2018). A gene-specific T2A-GAL4 library for Drosophila. Elife, 7 Abstract.  Author URL.
Rajan A, Housden BE, Wirtz-Peitz F, Holderbaum L, Perrimon N (2017). A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion. Developmental Cell, 43(1), 83-98.e6.
Housden BE, Li Z, Kelley C, Wang Y, Hu Y, Valvezan AJ, Manning BD, Perrimon N (2017). Improved detection of synthetic lethal interactions in Drosophila cells using Variable Dose Analysis (VDA). Proceedings of the National Academy of Sciences Full text.
Housden BE, Muhar M, Gemberling M, Gersbach CA, Stainier DYR, Seydoux G, Mohr SE, Zuber J, Perrimon N (2017). Loss-of-function genetic tools for animal models: cross-species and cross-platform differences. Nat Rev Genet, 18(1), 24-40. Abstract.
Housden B, Nicholson H, Perrimon N (2017). Synthetic Lethality Screens Using RNAi in Combination with CRISPR-based Knockout in Drosophila Cells. BIO-PROTOCOL, 7(3).
Valvezan AJ, Turner M, Belaid A, Lam HC, Miller SK, McNamara MC, Baglini C, Housden BE, Perrimon N, Kwiatkowski DJ, et al (2017). mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability. Cancer Cell, 32(5), 624-638.e5.
Zacharioudaki E, Housden BE, Garinis G, Stojnic R, Delidakis C, Bray SJ (2016). Genes implicated in stem cell identity and temporal programme are directly targeted by Notch in neuroblast tumours. Development, 143(2), 219-231. Abstract.  Author URL.
Wang H, Becuwe M, Housden BE, Chitraju C, Porras AJ, Graham MM, Liu XN, Thiam AR, Savage DB, Agarwal AK, et al (2016). Seipin is required for converting nascent to mature lipid droplets. Elife, 5 Abstract.  Author URL.
Chavez A, Scheiman J, Vora S, Pruitt BW, Tuttle M, P R Iyer E, Lin S, Kiani S, Guzman CD, Wiegand DJ, et al (2015). Highly efficient Cas9-mediated transcriptional programming. Nat Methods, 12(4), 326-328. Abstract.  Author URL.
Housden BE, Valvezan AJ, Kelley C, Sopko R, Hu Y, Roesel C, Lin S, Buckner M, Tao R, Yilmazel B, et al (2015). Identification of potential drug targets for tuberous sclerosis complex by synthetic screens combining CRISPR-based knockouts with RNAi. Sci Signal, 8(393). Abstract.  Author URL.
Lin S, Ewen-Campen B, Ni X, Housden BE, Perrimon N (2015). In Vivo Transcriptional Activation Using CRISPR/Cas9 in Drosophila. Genetics, 201(2), 433-442. Abstract.  Author URL.
Housden BE, Lin S, Perrimon N (2014). Cas9-based genome editing in Drosophila. Methods Enzymol, 546, 415-439. Abstract.  Author URL.
Housden BE, Terriente-Felix A, Bray SJ (2014). Context-dependent enhancer selection confers alternate modes of notch regulation on argos. Mol Cell Biol, 34(4), 664-672. Abstract.  Author URL.
Simón R, Aparicio R, Housden BE, Bray S, Busturia A (2014). Drosophila p53 controls Notch expression and balances apoptosis and proliferation. Apoptosis, 19(10), 1430-1443. Abstract.  Author URL.
Li J, Housden BE, Bray SJ (2014). Notch signaling assays in Drosophila cultured cell lines. Methods Mol Biol, 1187, 131-141. Abstract.  Author URL.
Mohr SE, Hu Y, Kim K, Housden BE, Perrimon N (2014). Resources for functional genomics studies in Drosophila melanogaster. Genetics, 197(1), 1-18. Abstract.  Author URL.
Housden BE, Perrimon N (2014). Spatial and temporal organization of signaling pathways. Trends Biochem Sci, 39(10), 457-464. Abstract.  Author URL.
Housden BE, Li J, Bray SJ (2014). Visualizing Notch signaling in vivo in Drosophila tissues. Methods Mol Biol, 1187, 101-113. Abstract.  Author URL.
Babaoğlan AB, Housden BE, Furriols M, Bray SJ (2013). Deadpan contributes to the robustness of the notch response. PLoS One, 8(9). Abstract.  Author URL.
Ren X, Sun J, Housden BE, Hu Y, Roesel C, Lin S, Liu L-P, Yang Z, Mao D, Sun L, et al (2013). Optimized gene editing technology for Drosophila melanogaster using germ line-specific Cas9. Proc Natl Acad Sci U S A, 110(47), 19012-19017. Abstract.  Author URL.
Housden BE, Fu AQ, Krejci A, Bernard F, Fischer B, Tavaré S, Russell S, Bray SJ (2013). Transcriptional dynamics elicited by a short pulse of notch activation involves feed-forward regulation by E(spl)/Hes genes. PLoS Genet, 9(1). Abstract.  Author URL.
Housden BE, Millen K, Bray SJ (2012). Drosophila Reporter Vectors Compatible with ΦC31 Integrase Transgenesis Techniques and Their Use to Generate New Notch Reporter Fly Lines. G3 (Bethesda), 2(1), 79-82. Abstract.  Author URL.
Bernard F, Krejci A, Housden B, Adryan B, Bray SJ (2010). Specificity of Notch pathway activation: twist controls the transcriptional output in adult muscle progenitors. Development, 137(16), 2633-2642. Abstract.  Author URL.
Pines MK, Housden BE, Bernard F, Bray SJ, Röper K (2010). The cytolinker Pigs is a direct target and a negative regulator of Notch signalling. Development, 137(6), 913-922. Abstract.  Author URL.
Krejcí A, Bernard F, Housden BE, Collins S, Bray SJ (2009). Direct response to Notch activation: signaling crosstalk and incoherent logic. Sci Signal, 2(55). Abstract.  Author URL.

Publications by year


In Press

Mohr SE, Hu Y, Ewen-Campen B, Housden BE, Viswanatha R, Perrimon N (In Press). CRISPR guide RNA design for research applications. FEBS J, 283(17), 3232-3238. Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Cas9-Mediated Genome Engineering in Drosophila melanogaster. Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Comparing CRISPR and RNAi-based screening technologies. Nat Biotechnol, 34(6), 621-623. Author URL.
Chavez A, Tuttle M, Pruitt BW, Ewen-Campen B, Chari R, Ter-Ovanesyan D, Haque SJ, Cecchi RJ, Kowal EJK, Buchthal J, et al (In Press). Comparison of Cas9 activators in multiple species. Nat Methods, 13(7), 563-567. Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Design and Generation of Donor Constructs for Genome Engineering in Drosophila. Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Housden BE, Hu Y, Perrimon N (In Press). Design and Generation of Drosophila Single Guide RNA Expression Constructs. Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Housden BE, Perrimon N (In Press). Detection of Indel Mutations in Drosophila by High-Resolution Melt Analysis (HRMA). Cold Spring Harb Protoc, 2016(9). Abstract.  Author URL.
Ammeux N, Housden BE, Georgiadis A, Hu Y, Perrimon N (In Press). Mapping signaling pathway cross-talk in Drosophila cells. Proc Natl Acad Sci U S A, 113(35), 9940-9945. Abstract.  Author URL.
Mohr SE, Rudd K, Hu Y, Song WR, Gilly Q, Buckner M, Housden BE, Kelley C, Zirin J, Tao R, et al (In Press). Zinc Detoxification: a Functional Genomics and Transcriptomics Analysis in Drosophila melanogaster Cultured Cells. G3 (Bethesda), 8(2), 631-641. Abstract.  Author URL.

2018

Lee P-T, Zirin J, Kanca O, Lin W-W, Schulze KL, Li-Kroeger D, Tao R, Devereaux C, Hu Y, Chung V, et al (2018). A gene-specific T2A-GAL4 library for Drosophila. Elife, 7 Abstract.  Author URL.

2017

Rajan A, Housden BE, Wirtz-Peitz F, Holderbaum L, Perrimon N (2017). A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion. Developmental Cell, 43(1), 83-98.e6.
Housden BE, Li Z, Kelley C, Wang Y, Hu Y, Valvezan AJ, Manning BD, Perrimon N (2017). Improved detection of synthetic lethal interactions in Drosophila cells using Variable Dose Analysis (VDA). Proceedings of the National Academy of Sciences Full text.
Housden BE, Muhar M, Gemberling M, Gersbach CA, Stainier DYR, Seydoux G, Mohr SE, Zuber J, Perrimon N (2017). Loss-of-function genetic tools for animal models: cross-species and cross-platform differences. Nat Rev Genet, 18(1), 24-40. Abstract.
Housden B, Nicholson H, Perrimon N (2017). Synthetic Lethality Screens Using RNAi in Combination with CRISPR-based Knockout in Drosophila Cells. BIO-PROTOCOL, 7(3).
Valvezan AJ, Turner M, Belaid A, Lam HC, Miller SK, McNamara MC, Baglini C, Housden BE, Perrimon N, Kwiatkowski DJ, et al (2017). mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability. Cancer Cell, 32(5), 624-638.e5.

2016

Perrimon N, Housden B, Valvezan A, Manning B (2016). Composition and methods for inhibiting cell proliferation.
Zacharioudaki E, Housden BE, Garinis G, Stojnic R, Delidakis C, Bray SJ (2016). Genes implicated in stem cell identity and temporal programme are directly targeted by Notch in neuroblast tumours. Development, 143(2), 219-231. Abstract.  Author URL.
Wang H, Becuwe M, Housden BE, Chitraju C, Porras AJ, Graham MM, Liu XN, Thiam AR, Savage DB, Agarwal AK, et al (2016). Seipin is required for converting nascent to mature lipid droplets. Elife, 5 Abstract.  Author URL.

2015

Chavez A, Scheiman J, Vora S, Pruitt BW, Tuttle M, P R Iyer E, Lin S, Kiani S, Guzman CD, Wiegand DJ, et al (2015). Highly efficient Cas9-mediated transcriptional programming. Nat Methods, 12(4), 326-328. Abstract.  Author URL.
Housden BE, Valvezan AJ, Kelley C, Sopko R, Hu Y, Roesel C, Lin S, Buckner M, Tao R, Yilmazel B, et al (2015). Identification of potential drug targets for tuberous sclerosis complex by synthetic screens combining CRISPR-based knockouts with RNAi. Sci Signal, 8(393). Abstract.  Author URL.
Lin S, Ewen-Campen B, Ni X, Housden BE, Perrimon N (2015). In Vivo Transcriptional Activation Using CRISPR/Cas9 in Drosophila. Genetics, 201(2), 433-442. Abstract.  Author URL.

2014

Housden BE, Lin S, Perrimon N (2014). Cas9-based genome editing in Drosophila. Methods Enzymol, 546, 415-439. Abstract.  Author URL.
Housden BE, Terriente-Felix A, Bray SJ (2014). Context-dependent enhancer selection confers alternate modes of notch regulation on argos. Mol Cell Biol, 34(4), 664-672. Abstract.  Author URL.
Simón R, Aparicio R, Housden BE, Bray S, Busturia A (2014). Drosophila p53 controls Notch expression and balances apoptosis and proliferation. Apoptosis, 19(10), 1430-1443. Abstract.  Author URL.
Li J, Housden BE, Bray SJ (2014). Notch signaling assays in Drosophila cultured cell lines. Methods Mol Biol, 1187, 131-141. Abstract.  Author URL.
Mohr SE, Hu Y, Kim K, Housden BE, Perrimon N (2014). Resources for functional genomics studies in Drosophila melanogaster. Genetics, 197(1), 1-18. Abstract.  Author URL.
Housden BE, Perrimon N (2014). Spatial and temporal organization of signaling pathways. Trends Biochem Sci, 39(10), 457-464. Abstract.  Author URL.
Housden BE, Li J, Bray SJ (2014). Visualizing Notch signaling in vivo in Drosophila tissues. Methods Mol Biol, 1187, 101-113. Abstract.  Author URL.

2013

Babaoğlan AB, Housden BE, Furriols M, Bray SJ (2013). Deadpan contributes to the robustness of the notch response. PLoS One, 8(9). Abstract.  Author URL.
Ren X, Sun J, Housden BE, Hu Y, Roesel C, Lin S, Liu L-P, Yang Z, Mao D, Sun L, et al (2013). Optimized gene editing technology for Drosophila melanogaster using germ line-specific Cas9. Proc Natl Acad Sci U S A, 110(47), 19012-19017. Abstract.  Author URL.
Housden BE, Fu AQ, Krejci A, Bernard F, Fischer B, Tavaré S, Russell S, Bray SJ (2013). Transcriptional dynamics elicited by a short pulse of notch activation involves feed-forward regulation by E(spl)/Hes genes. PLoS Genet, 9(1). Abstract.  Author URL.

2012

Housden BE, Millen K, Bray SJ (2012). Drosophila Reporter Vectors Compatible with ΦC31 Integrase Transgenesis Techniques and Their Use to Generate New Notch Reporter Fly Lines. G3 (Bethesda), 2(1), 79-82. Abstract.  Author URL.

2010

Bernard F, Krejci A, Housden B, Adryan B, Bray SJ (2010). Specificity of Notch pathway activation: twist controls the transcriptional output in adult muscle progenitors. Development, 137(16), 2633-2642. Abstract.  Author URL.
Pines MK, Housden BE, Bernard F, Bray SJ, Röper K (2010). The cytolinker Pigs is a direct target and a negative regulator of Notch signalling. Development, 137(6), 913-922. Abstract.  Author URL.

2009

Krejcí A, Bernard F, Housden BE, Collins S, Bray SJ (2009). Direct response to Notch activation: signaling crosstalk and incoherent logic. Sci Signal, 2(55). Abstract.  Author URL.

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