Differential gene expression plays a critical role in the development of multicellular organisms. At a 'systems level'(e.g. at the level of an organ, tissue or whole organism), this process can be studied using gene regulatory network (GRN) models that capture physical and regulatory interactions between genes and their regulators, e.g. transcription factors (TFs), transcriptional cofactors and microRNAs. In the past years, significant progress has been made toward the characterization of developmental GRNs. However little is known about the organization and function of GRNs that control post-developmental physiology. Differential gene expression likely plays an important and broad role in different aspects of organismal physiology (e.g. homeostasis, response to environmental cues, hereafter referred to as 'systems physiology'). This is because the majority of TFs are expressed throughout the lifetime of an organism, which strongly suggests that they function in post-developmental processes. However, only few TFs involved in systems physiology have been identified and/or characterized. We use the digestive tract of the nematode C. elegans as a model system to study metazoan GRNs. The digestive tract is composed of the pharynx, intestine and rectum, its development has been well documented, and multiple regulators expressed in this system have already been identified. The digestive tract plays many important roles in C. elegans physiology;it is not only important for digestion and metabolism, it is also a major interface between the animal and the environment. For instance, it responds to different environmental stressors and provides the innate immune response upon exposure to pathogens. Thus, the digestive tract is an ideal model to study GRNs that pertain to systems physiology. In the proposed project, we will focus on the following questions: 1) Which regulators of differential gene expression are expressed in the C. elegans digestive tract? 2) How are these regulators regulated? 3) How is the expression of genes involved in physiological functions, such as metabolism, stress response and innate immunity controlled? And 4) What is the relative contribution of different 'genic'regions (e.g. promoters, exons, introns and enhancers) to differential gene expression in the digestive tract? We, and others, have generated many C. elegans resources and tools that uniquely enable us to carry out the proposed project. These include high-quality TF predictions, high-throughput gene-centered yeast one-hybrid (Y1H) assays for the delineation of systems-level GRNs and two complementary full-length TF clone collections that can be used in high-throughput Y1H assays and RNAi experiments, respectively.

Public Health Relevance

Differential gene expression plays a critical role in organism development, homeostasis and response to physiological or environmental cues, as well as in a multitude of diseases such as cancer, obesity and diabetes. At a systems level, differential gene expression can be studied using gene regulatory network (GRN) models that capture physical and regulatory interactions between genes and their regulators. We will continue our studies of digestive tract GRNs in the nematode C. elegans. Importantly, many genes and functions are highly conserved between worms and humans, and thus the C. elegans digestive tract provides a highly suitable model for metazoan GRN analysis. Our studies will provide insights into the functions of GRNs during development and in a wide variety of physiological functions such as stress response, metabolism and fighting pathogenic infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068429-08
Application #
8321041
Study Section
Special Emphasis Panel (ZRG1-GGG-M (91))
Program Officer
Karp, Robert W
Project Start
2004-07-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$576,329
Indirect Cost
$222,755
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Walhout, Albertha J M (2014) Genetic adaptation to diet preserves longevity. Cell Metab 19:177-8
Fuxman Bass, Juan I; Tamburino, Alex M; Mori, Akihiro et al. (2014) Transcription factor binding to Caenorhabditis elegans first introns reveals lack of redundancy with gene promoters. Nucleic Acids Res 42:153-62
Watson, Emma; MacNeil, Lesley T; Arda, H Efsun et al. (2013) Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response. Cell 153:253-66
MacNeil, Lesley T; Watson, Emma; Arda, H Efsun et al. (2013) Diet-induced developmental acceleration independent of TOR and insulin in C. elegans. Cell 153:240-52
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Reece-Hoyes, John S; Walhout, Albertha J M (2012) Gene-centered yeast one-hybrid assays. Methods Mol Biol 812:189-208
Feng, Huiyun; Reece-Hoyes, John S; Walhout, Albertha J M et al. (2012) A regulatory cascade of three transcription factors in a single specific neuron, DVC, in Caenorhabditis elegans. Gene 494:73-84
Reece-Hoyes, John S; Barutcu, A Rasim; McCord, Rachel Patton et al. (2011) Yeast one-hybrid assays for gene-centered human gene regulatory network mapping. Nat Methods 8:1050-2

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