Systems biology: gene regulatory and metabolic networks
Biological systems are extremely complex, yet remarkably robust. One of the major questions in the field of Systems Biology is how is complexity organized, how does it evolve and how is it maintained? Questions such as these require the use of high-quality large-scale approaches to first map the organization of systems, as well as close collaborations with computational biologists to integrate the data such that the organizing principles and emergent properties of biological systems are unveiled.
The research in the Walhout lab focuses on two major avenues of research:
- 1:The Structure, Function And Evolution Of Biological Networks
- 2:Systems-Level Dietary Response And Metabolic Networks
NEW!!!! Handbook in Systems Biology. Edited by Marian Walhout, Job Dekker and Marc Vidal. Top-level scientists from different disciplines contributed 27 chapters on all aspects of Systems Biology. From defining Systems components and their network interactions to highly quantitative mathematical systems modeling, from yeast to plants and worms, and from cells to organisms to populations."
THE STRUCTURE, FUNCTION AND EVOLUTION OF BIOLOGICAL NETWORKS
Gene regulation and transcription
The regulation of gene expression is pivotal to most biological processes from development, to homeostasis and physiology, and the response to environmental stresses.
The first and most important step in gene regulation occurs at the level of transcription, by regulatory transcription factors (TFs) that directly bind DNA elements in the genome and activate and/or repress the expression of associated target genes.
While the mechanics of transcription have been extensively studied, little is known about how hundreds of TFs that are expressed altogether regulate the expression of thousands of genes.
Gene regulatory networks
Gene regulatory networks capture physical and/or regulatory interactions between regulators and their targets.
Physical interactions include the direct binding of TFs to DNA targets, while regulatory interactions describe the effect of TF perturbation on a downstream target gene (i.e., in the absence of the TF the gene goes down, thus the TF is an activator).
Surprisingly, only a small proportion of physical interactions confer a regulatory consequence. Further, regulatory interactions are not necessarily the result of a direct interaction (for instance, an activator can activate an activator of a gene and removal of either results in a decrease in the mRNA levels of that gene).
In the Walhout lab, we systematically map both physical and regulatory interactions between TFs and their target genes. We primarily focus on the nematode C. elegans, but have also initiated some studies on human regulatory genomic sequences. Further, we collaborate for studies in the plant Arabidopsis thaliana with the lab of Dr. Siobhan Brady at UC Davis.
We study gene regulatory networks by using a combination of experiments and computation. Together with Chad Myers at U Minnesota, we have developed a set of tools that are publicly available (Lab Software).
Biological systems are both highly complex and amazingly robust. A well-known mechanism of acquiring complexity and robustness is by the expansion of gene families due to gene duplications. After a duplication, both paralogs diverge through mutations and neo-functionalization of one (or both) paralogs can lead to functional innovation, and hence and increase in complexity. Gene duplication also provides (partial) redundancy, which is essential to ensure systems robustness. We study the balance between functional innovation and robustness using different gene families, including transcription factor families such as basic helix-loop-helix (bHLH) and nuclear hormone receptors (NHR), microRNAs Victor Ambros at UMASS Worcester and insulins Heidi Tissenbaum at UMASS Worcester.
We are one of few labs that aim to delineate multiparameter networks and study their organization and function.
Genes and proteins do not function in isolation, which is why studying networks is important. They also do not only function in one type of network, and this is why we have started the characterization of multiparameter networks.
For instance, TFs bind DNA, other proteins and are modified by signaling networks. In addition to these direct molecular networks, we further add networks that describe when and where genes are expressed, and, longer term which phenotypes they can convey.Our first systematic study of gene families involved the basic helix-loop-helix (bHLH) family of TFs
Click below to view our YouTube video made in conjunction with our publication in Cell.
Relevant publications – for additional publications please see Publications page (link)
SYSTEMS-LEVEL DIETARY RESPONSE AND METABOLIC NETWORKS
‘You are what you eat’ is a well-known phrase. While of course not literally true, it is well appreciated that our diet plays a fundamental role in our development, physiology and performance, as well as in a variety of inherited and acquired diseases such as diabetes and obesity.
We have started to delineate regulatory networks of metabolic genes and found this network to be enriched for nuclear hormone receptors (Arda et al., MSB 2010). Interestingly, while we humans have only 48 of such NHRs, worms have more than 250! A big question is what are these doing? How do they work? What are their ligands, etc. We areinvestigating how NHRs contribute to the overall function of the animal and how they are wired in different types of regulatory networks.
We collaborate with Heidi Tissenbaum to understand how the family of 40 worm insulins function in the context ofintricate expression networks to facilitate important processes such as development, physiology and reproduction. We recently published a paper describing the complexity in insulin gene expression in living animals and under a variety of stresses (Ritter et al., Genome Research 2013)
Recently, we have started to use C. elegans to study how diet affects major life history traits such as development, reproduction and aging. We have started to use systems approaches to unravel the networks that govern different dietary responses. Two papers describing our recent findings were published recently (MacNeil et al., Cell 2013; Watson et al., Cell 2013 ). This work was featured on the Cell cover, andin the Boston Globe and on this YouTube video