The three-dimensional state of the genome is dynamic and critical in the regulation of gene expression. Recent technological advances have provided an unprecedented view of how the genome is interconnected and how this process changes as cells differentiate or undergo malignant transformation. This session will discuss cutting-edge genomic techniques for understanding the three-dimensional state of the genome and how genome organization and nuclear architecture are important in normal hematopoiesis as well as malignant hematopoietic cells.
Dr. Cigall Kadoch will discuss how recent exome-and genome-wide sequencing studies in human cancers have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes. Her laboratory uses biochemistry, structural biology, systems biology, and genomics-based approaches to define the mechanisms of chromatin and gene regulation carried out by the mSWI/SNF family of chromatin regulators. Specifically, they have studied rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumors and others, all of which involve mSWI/SNF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the diverse mechanisms underlying mSWI/SNF complex targeting and function in a wide array of cancers (including hematologic cancers) and developmental disorders and have provided new foundations for therapeutic development.
Dr. Elisa Oricchio will discuss how genomic lesions modify the chromatin tridimensional organization and their contribution to lymphoma development and progression. Recently, her lab has demonstrated that in non-Hodgkin lymphoma, a significant interplay exists between the compartmentalization of the genome into topologically associating domains (TADs) and the epigenetic and transcriptional changes mediated by mutated EZH2. Indeed, EZH2 mutations drive the aberrant increase of H3K27me3 within specific TADs, resulting in loss of promoter-promoter interactions, synergistic silencing of multiple tumor suppressors and, thus, increased B-cell proliferation and tumor aggressiveness. She will present recent analyses in which her lab combined high-throughput chromatin conformation capture data (Hi-C) in lymphoma cells with whole genome sequencing and transcriptional profiles of primary patient samples to uncover new oncogenic mechanisms that can represent the stepping stone for the design of new therapeutic approaches.
Dr. Erez Lieberman Aiden will discuss his work mapping the three-dimensional architecture of the human genome. Stretched out from end-to-end, the human genome-a sequence of three billion chemical letters inscribed in a molecule called DNA-is over two meters long. Famously, short stretches of DNA fold into a double helix, which wind around histone proteins to form the 10nm fiber. But what about longer pieces? Does the genome's fold influence function? How does the information contained in such an ultra-dense packing even remain accessible? Dr. Aiden will describe his work developing Hi-C and more recently in-situ Hi-C, which use proximity ligation to transform pairs of physically adjacent DNA loci into chimeric DNA sequences. Sequencing a library of such chimeras makes it possible to create genome-wide maps of physical contacts between pairs of loci, thus revealing three-dimensional features of genome folding. Dr. Aiden will also discuss the biophysical mechanisms that underlie chromatin looping.
Erez Lieberman Aiden
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