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A global genetic interaction network maps a wiring diagram of cellular function.

ABSTRACT: We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing more than 23 million double mutants, identifying about 550,000 negative and about 350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell.

SUBMITTER: Costanzo M

PROVIDER: S-EPMC5661885 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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A global genetic interaction network maps a wiring diagram of cellular function.

Costanzo Michael M VanderSluis Benjamin B Koch Elizabeth N EN Baryshnikova Anastasia A Pons Carles C Tan Guihong G Wang Wen W Usaj Matej M Hanchard Julia J Lee Susan D SD Pelechano Vicent V Styles Erin B EB Billmann Maximilian M van Leeuwen Jolanda J van Dyk Nydia N Lin Zhen-Yuan ZY Kuzmin Elena E Nelson Justin J Piotrowski Jeff S JS Srikumar Tharan T Bahr Sondra S Chen Yiqun Y Deshpande Raamesh R Kurat Christoph F CF Li Sheena C SC Li Zhijian Z Usaj Mojca Mattiazzi MM Okada Hiroki H Pascoe Natasha N San Luis Bryan-Joseph BJ Sharifpoor Sara S Shuteriqi Emira E Simpkins Scott W SW Snider Jamie J Suresh Harsha Garadi HG Tan Yizhao Y Zhu Hongwei H Malod-Dognin Noel N Janjic Vuk V Przulj Natasa N Troyanskaya Olga G OG Stagljar Igor I Xia Tian T Ohya Yoshikazu Y Gingras Anne-Claude AC Raught Brian B Boutros Michael M Steinmetz Lars M LM Moore Claire L CL Rosebrock Adam P AP Caudy Amy A AA Myers Chad L CL Andrews Brenda B Boone Charles C

Science (New York, N.Y.) 20160901 6306

We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing more than 23 million double mutants, identifying about 550,000 negative and about 350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathwa ...[more]

PMID: 27708008

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Project description:Oxytocin (Oxt) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of Oxt neurons and their quantitative relationship with Oxt receptor (Oxtr) expression presents challenges to understanding circuit-specific Oxt functions. Here, we establish a whole-brain distribution and anatomic connectivity map of Oxt neurons, and their relationship with Oxtr expression using high-resolution 3D mapping methods in adult male and female mice. We use a flatmap to describe Oxt neuronal expression in four hypothalamic domains including under-characterized Oxt neurons in the tuberal nucleus (TU). Oxt neurons in the paraventricular hypothalamus (PVH) broadly project to nine functional circuits that control cognition, brain state, and somatic visceral response. In contrast, Oxt neurons in the supraoptic (SO) and accessory (AN) nuclei have limited central projection to a small subset of the nine circuits. Surprisingly, quantitative comparison between Oxt output and Oxtr expression showed no significant correlation across the whole brain, suggesting abundant indirect Oxt signaling in Oxtr-expressing areas. Unlike output, Oxt neurons in both the PVH and SO receive similar monosynaptic inputs from a subset of the nine circuits mainly in the thalamic, hypothalamic, and cerebral nuclei areas. Our results suggest that PVH-Oxt neurons serve as a central modulator to integrate external and internal information via largely reciprocal connection with the nine circuits while the SO-Oxt neurons act mainly as unidirectional Oxt hormonal output. In summary, our Oxt wiring diagram provides anatomic insights about distinct behavioral functions of Oxt signaling in the brain.SIGNIFICANCE STATEMENT Oxytocin (Oxt) neurons regulate diverse physiological functions from prosocial behavior to pain sensation via central projection in the brain. Thus, understanding detailed anatomic connectivity of Oxt neurons can provide insight on circuit-specific roles of Oxt signaling in regulating different physiological functions. Here, we use high-resolution mapping methods to describe the 3D distribution, monosynaptic input and long-range output of Oxt neurons, and their relationship with Oxt receptor (Oxtr) expression across the entire mouse brain. We found Oxt connections with nine functional circuits controlling cognition, brain state, and somatic visceral response. Furthermore, we identified a quantitatively unmatched Oxt-Oxtr relationship, suggesting broad indirect Oxt signaling. Together, our comprehensive Oxt wiring diagram advances our understanding of circuit-specific roles of Oxt neurons.

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A global genetic interaction network maps a wiring diagram of cellular function.

Publications

A global genetic interaction network maps a wiring diagram of cellular function.

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