Aviv Regev and her colleagues develop experimental and computational approaches to systematically decipher the mechanisms that underlie the transcriptional regulatory circuits in organisms ranging from yeast to humans.
Regev lab members study how these transcriptional circuits change on a variety of timescales: for example, when cells respond to changing growth conditions (within hours); when cells differentiate (within hours to days); and when species evolve (across millions of years). These studies yield detailed reconstructions and highlight key principles that govern the emergence of novel functions in gene regulation.
Major research areas in the Regev lab include:
I. Reconstructing the regulatory circuitry of mammalian cells
The next frontier in genomics is to systematically assemble the functional components of genomes and cells into the circuits that transform signals into cellular responses. Among cellular circuits, the regulatory circuits controlling gene transcription are the most accessible for systems-scale analysis. The Regev lab harnesses advances in genomic technologies to reconstruct in an unbiased way the dynamic circuits that control gene expression in mammalian cells.
The group uses molecular profiling to comprehensively identify circuit elements. They then use computational approaches to build provisional circuit models of regulatory proteins and non-coding RNAs and their target genes. The researchers test and validate the model by systematically perturbing each regulator and monitoring its effect on the circuit output using novel and affordable multiplexing technologies, and then refine the preliminary circuit into a validated model. Regev and her colleagues have recently applied this approach to reconstruct the regulatory circuit controlling the response of immune dendritic cells to pathogens, and to build a physical and genetic map of interactions between influenza and the human host. They are now deepening and expanding this approach to other forms of molecular interactions and biological regulations in these cells and others.
II. Circuits controlling cell differentiation
Similar approaches can be applied to other biological systems, particularly to cells undergoing differentiation. For example, Regev and her colleagues study gene regulation in the hematopoietic (blood cell) lineages in human and mouse. They apply an algorithm that can detect potential genetic regulators based on changes in the genes’ own expression levels. This analytical framework enables the researchers to probe the general principles and the transcriptional regulatory code that controls hematopoietic development. They then test this program by direct experimental manipulation.
III. The evolution of gene regulation
Differences in gene regulation are likely a major driving force in species evolution, ranging from bacteria to mammals. By combining the power of comparative functional genomics together with biological experiments in multiple species, the Regev lab aims to understand the mechanisms through which genes and gene regulation evolve.
Regev and her colleagues have developed an experimental and computational system to reconstruct the transcriptional profiles and regulatory mechanisms of ancestral species and to identify how gene regulatory systems evolved. They are applying this approach to 15 species of Ascomycota fungi, which span 300 million years of evolution. This approach is applicable to other species, including mammals. The lab also studies the evolution of gene regulation on much shorter time scales, following genetic and epigenetic changes in evolving strains of S. cerevisiae and C. albicans.
Little is known about how specific genetic alterations in cancer-causing genes (oncogenes and tumor suppressor genes, for example) translate into the large-scale transcriptional changes that occur in tumor cells.
The Regev lab has generated a comprehensive “cancer module map” that reveals the regulatory changes in hundreds of gene modules across thousands of tumors and more than 20 tumor types. Analyses of this map suggest that some changes are shared across multiple tumor types and may reflect general processes related to tumor growth, while other changes are unique to specific tumors and may therefore reflect tissue-specific behaviors.
Using a similar approach, Regev and her colleagues recently discovered that aggressive, poorly differentiated tumors exhibit patterns of gene expression similar to those of embryonic stem (ES) cells. Moreover, patients who carry tumors with ES-cell “signatures” generally exhibit a poorer prognosis than patients whose tumors lack such signatures. This work establishes a new link between gene regulatory networks that operate in cancer cells and ES cells.
With the increasing availability of genome-scale profiles of the cancer genome and cancer transcriptome, it should be possible to systematically determine how these regulatory changes are established early in tumorigenesis.