The transcriptional regulation of gene expression is pivotal to all biological processes. Each of our ~20,000 protein-coding genes must be expressed at the right place, time and level, as well as under the right developmental or physiological circumstances. Consequently, inappropriate gene expression is implicated in a myriad of human diseases, including congenital disorders, cancer and obesity. Transcription has been studied intensively for decades, resulting in a detailed picture of the basic biochemical mechanisms of mRNA production. However, we know little about gene regulation at a 'systems level', i.e. how TFs function together in complex gene regulatory networks (GRNs) to faithfully orchestrate the expression of large sets of genes. Our long-term goal is to comprehensively characterize the structure, function and evolution of complex metazoan GRNs to gain insights into global mechanisms of gene regulation. It is becoming increasingly clear that textbook explanations of gene regulation in which a TF binds DNA in the genome and upon doing so regulates the most proximal gene are too simplistic because many physical TF binding events lack an apparent regulatory consequence. There are several explanations for this, ranging from technical (e.g. detection limits, attribution of a bindng event to the wrong gene) to biological (e.g. redundancy between TFs, condition-dependent effects). Conversely, regulatory interactions are not necessarily due to a direct effect. For instance, TFs can function in cascades to propagate functional regulation. A major challenge is to combine physical and regulatory interactions to increase our understanding of the mechanisms of gene regulation in the context of complex multicellular organisms. Many GRN studies focus either solely on physical TF interactions, whereas others focus primarily on regulatory interactions. However, integrated GRNs that combine both are scarce and, when available are relatively small in scale. If we had high-quality, large- scale physical and regulatoy interaction data, as well as spatiotemporal and conditional gene expression data, we could build increasingly precise GRNs. Here, we will continue our studies on the nematode C. elegans to map and integrate physical and regulatory GRNs, which will help us to go beyond mapping to understanding the regulatory mechanisms of gene expression at a systems level in a complex multicellular organism.

Public Health Relevance

The regulation of gene expression is vital for healthy development and homeostasis and many diseases are caused by or associated with severe changes in gene expression. In recent years, tremendous progress has been made in the identification of gene regulatory networks that describe physical interactions between regulators and their targets. This project will generate a large physical network, delineate regulatory interactions and combine the two types of interactions to gain insights into the mechanisms of gene regulation at a systems level.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Sledjeski, Darren D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Weirauch, Matthew T; Yang, Ally; Albu, Mihai et al. (2014) Determination and inference of eukaryotic transcription factor sequence specificity. Cell 158:1431-43
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
Liu, Wan-Ju; Reece-Hoyes, John S; Walhout, Albertha J M et al. (2014) Multiple transcription factors directly regulate Hox gene lin-39 expression in ventral hypodermal cells of the C. elegans embryo and larva, including the hypodermal fate regulators LIN-26 and ELT-6. BMC Dev Biol 14:17
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
Walhout, Albertha J M (2011) What does biologically meaningful mean? A perspective on gene regulatory network validation. Genome Biol 12:109
Brady, Siobhan M; Zhang, Lifang; Megraw, Molly et al. (2011) A stele-enriched gene regulatory network in the Arabidopsis root. Mol Syst Biol 7:459
Walhout, Albertha J M (2011) Gene-centered regulatory network mapping. Methods Cell Biol 106:271-88
Tabuchi, Tomoko M; Deplancke, Bart; Osato, Naoki et al. (2011) Chromosome-biased binding and gene regulation by the Caenorhabditis elegans DRM complex. PLoS Genet 7:e1002074

Showing the most recent 10 out of 15 publications