Robert Francis Furchgott Professor Biochemistry and Pediatrics; Simpson Querrey Center for Epigenetics; Chairman, Department of Biochemistry and Molecular Genetics Northwestern University Feinberg School of Medicine
Principles of Epigenetics and Chromatin in Development and Human Disease
Epigenetic regulation of gene expression in metazoans is central for establishing cellular diversity, and the perturbation of this process results in pathological conditions. Although transcription factors are essential for implementing gene expression programs, they do not function in isolation and require the recruitment of various chromatin-modifying and remodeling machineries. A classic example of developmental gene expression through chromatin is the regulation of the balanced activities of the Polycomb group (PcG) proteins within the PRC1 and PRC2 complexes, and the Trithorax group (TrxG) proteins within the COMPASS family. Recent large scale genome sequencing efforts of human cancer have demonstrated that PcG and COMPASS subunits are highly mutated in a large number of human solid tumors and hematological malignancies. I will discuss our laboratory’s latest biochemical and genetic studies defining the molecular properties of COMPASS and PcG families in the regulation of gene expression, during development, the central role they play in cancer pathogenesis, and how we have taken advantage of such basic molecular information to develop targeted therapeutics for the treatment of hematological malignancies, pediatric brain cancer, and other forms of solid tumors.
The regulation of gene transcription by RNA polymerase II is critical for development and differentiation, and its misregulation contributes to the pathogenesis of many cancers, including leukemia. The overall goal of our laboratory is to define the molecular mechanisms underlying leukemogenesis and to identify potential targets for therapy through detailed studies of proteins and protein complexes that regulate chromatin modifications, transcription initiation, and transcription elongation. For example, some of the homeotic (HOX) proteins are transcriptional regulators essential for normal hematopoiesis, and their misregulation is associated with hematological malignancies. Similarly, the mixed lineage leukemia (MLL) protein normally positively regulates multiple HOX genes, and several chromosomal rearrangements and translocations that result in the creation of MLL chimeric proteins cause various forms of leukemia.
Such malignancies presumably arise through changes in the hematopoiesis program, which results from the misregulation of the HOX genes by the MLL fusion proteins. Much of our understanding of the mechanisms—by which MLL, its target genes such as the HOX gene family, and its chimeras function—arises from studies on their close homologs in model organisms, such as yeast and Drosophila. Therefore, our laboratory takes full advantage of the powers of genetic, biochemistry, and cell biology in yeast, mammalian and Drosophila systems to decipher the roles of these factors during development and how their misregulation results in the pathogenesis of hematological malignancies.