We identify mechanisms that activate and repress genes that specify cell identity. We explore regulatory pathways that orchestrate gene expression programs, and investigate how they enable switches in cell-heritable differentiation programs. We illuminate the contribution of aberrant gene control programs to malignant phenotypes, and use these insights to create therapeutic concepts for the next generation of gene control medicines.
PRECISION GENE CONTROL
The laboratory of
The body of all complex animals consists of hundreds of cell types with unique morphologies and cellular functions. The identities of the cell types are defined by the sets of genes they express, i.e. their gene expression programs. Precise control of gene expression programs is essential for cell identity and differentiation. Many genetic diseases - e.g. cancer - arise due to a malignant alteration of cell specifying gene expression programs.
The Hnisz lab uses experimental and computational technologies to study gene control in development and cancer.
Understanding how transcriptional enhancers control over 20,000 protein-coding genes to maintain cell-type-specific gene expression programs in all human cells is a fundamental challenge. Recent studies suggest that gene regulatory elements and their target genes generally occur within insulated neighborhoods, which are chromosomal loops formed by the interaction of two DNA sites bound by the CTCF protein and occupied by the cohesin complex. Insulated neighborhoods provide for specific enhancer-gene interactions, are essential for both normal gene activation and repression, are largely preserved throughout development, form the mechanistic basis of higher order genome folding (e.g. Topologically Associating Domains) and are perturbed by genetic and epigenetic factors in disease.
We develop novel assays to identify protein components involved in the control of insulated neighborhoods. We develop state-of-the-art genetic and protein perturbation approaches to dissect regulatory pathways of insulated neighborhood function. We ascertain mutations that alter neighborhood anchors in cancer cells, and explore models how such mutations promote oncogenic expression programs.
Mammalian cells contain several hundred large clusters of transcriptional enhancers referred to as super-enhancers or stretch enhancers, which control genes that have especially prominent roles in cell-type-specific processes. Super-enhancers are occupied by an unusually high density of interacting factors, and are exceptionally vulnerable to perturbation of components commonly associated with most enhancers.
Based on the similar features of biomolecular condensates and super-enhancers, we recently proposed a model that a phase-separated multi-molecular assembly underlies the formation and function of super-enhancers. We are conducting experimental tests of this model, and explore the predictions of this model in diverse cellular contexts. We develop approaches to assess the functional importance of phase separation in gene control during differentiation and tumorigenesis.
Phase separation / transcriptional condensates
Compartmentalization of biochemical reactions often occurs in biomolecular condensates, which are membraneless bodies within the cytosol or nucleus. These condensates, e.g. nucleoli, Cajal bodies, nuclear speckles or DNA damage foci are formed as a result of liquid-liquid phase separation. Components are highly concentrated within condensates, and the formation and dissolution of condensates occurs with sharp transitions.