Gene Regulation and Genome Maintenance
Weihang (Valerie) Chai, PhD
• Genomic stability, DNA replication and repair
Genome instability is a hallmark of cancer. Faithful DNA replication is important for preventing detrimental replication errors and maintaining genome integrity. DNA replication frequently encounters obstacles arising from both cellular metabolic processes and environmental sources that slow or stall replication forks, which disrupts proper progression of replication and threatens genome stability. To protect genome integrity, cells have evolved a panoply of mechanisms to suppress replication fork stalling and rescue stalled replication. Understanding these mechanisms is important for understanding early events in carcinogenesis. In addition, recent research has revealed that targeting replication in tumor cells may offer a promising cancer therapeutic approach, in particular for treating cancers harboring mutations in DNA repair genes. The Chai Lab integrates next-gen sequencing, molecular biology, cellular imaging methods, as well as in vivo animal models to understand the molecular mechanisms for protecting genome stability under replication stress.
Curriculum Vitae Weihang (Valerie) Chai, PhD
Laboratory website: https://weihangchai.wixsite.com/chailab/about
Manuel Diaz, MD
• MLL and MLL fusion proteins
Dr. Diaz's research activities focus on the mechanisms that lead to leukemia development by mutant proteins that arise from mutations of the MLL gene. This is primarily through the function of the normal MLL protein, and how the mutant MLL-fusion proteins differ from the normal MLL in their function. Since these proteins regulate the expression of a subset of genes that are master regulators of cell proliferation and differentiation during development, studies are directed toward the effect of MLL mutations on the development of blood cells, and especially on the transition from blood stem cells to the lineages of differentiated blood cells. This transition is altered in all leukemias, and understanding how MLL mutants affect it may allow understanding of a crucial initial step for leukemogenesis in general. This may be important not only to find appropriate targets for new and more specific therapies, but also to conceive new ways to reduce the incidence of leukemia by preventive measures.
Andrew Dingwall, PhD
• Chromatin remodeling
In most living cells, chromosomes are formed from highly condensed DNA and basic proteins that function to compact the chromosomes into a structure called chromatin. Dr. Dingwall's research is focused on understanding the multitude of critically important roles chromatin structure and histone modifications play in normal development and disease. The Dingwall lab studies a highly conserved group of proteins that form a histone methyltransferase complex, known as the MLR COMPASS-like complex, whose main function is to regulate gene expression through epigenetic bookmarking and commissioning of transcriptional enhancer chromatin. Research efforts are targeted at understanding how the complex contributes to the various intricate functions in regulating tissue-specific gene expression during organismal development, as well as tumor cells. For example, when individual components of this complex are missing or mutated, certain cells lose the ability to properly control their fates and growth, leading to a variety of developmental disorders and aggressive cancers. In fact, the primary methyltransferase subunits are among the most frequently mutated across all cancer types. The Dingwall lab is focused on understanding the molecular, genetic and epigenetic mechanisms that govern normal animal development, as well as several types of leukemia, lymphoma and aggressive soft-tissue cancers. Investigative approaches utilize a systems biology perspective, incorporating model organism (Drosophila melanogaster) genetics and biochemistry, protein structure determination and modeling, cell biology, fly and mammalian cell culture including therapy-resistant breast cancers, as well gene expression profiling (RNA sequencing) and chromatin and genome-wide binding technologies (ChIP-sequencing) and bioinformatic analyses.
Laboratory website: https://dingwall-lab.weebly.com/
Nancy Zeleznik-Le, PhD
• MLL leukemias
My laboratory is interested in understanding how oncogenic MLL fusion proteins cause aggressive MLL leukemias and how this information could inform novel therapeutic approaches for this devastating cancer. Our focus is on structure-informed functional studies of the chromatin regulators MLL and the MLL fusion partners such as AF9 (MLLT3)and ENL (MLLT1) to understand their gene regulatory mechanisms. The wildtype MLL, AF9 and ENL proteins normally function as master regulators of critical gene expression pathways via chromatin epigenetic reader and writer mechanisms, whereas the oncogenic MLL fusion proteins cause misregulated expression of these same MLL target genes. We utilize a variety of complementary approaches including in vitro and in vivo leukemia models, normal hematopoietic stem and progenitor cell analyses, and advanced molecular and cellular techniques. Our research has implications for improving normal hematopoietic stem cell function and to determine mechanisms that might be amenable to therapeutic targeting of MLL leukemia.