Lectures and seminars External MBB Seminar: Sandy Klemm "Multi-omic single-cell analysis identifies a conserved epigenetic signature of mixed phenotype acute leukemia that is invariant of its hematopoietic compartment of origin"
Seminar with Sandy Klemm from the Greenleaf laboratory at Stanford University: "Multi-omic single-cell analysis identifies a conserved epigenetic signature of mixed phenotype acute leukemia that is invariant of its hematopoietic compartment of origin"
Sandy did his doctoral work at MIT in the lab of Alexander van Oudenaarden, and then moved to the Greenleaf lab in Stanford as a postdoc. His main research interest is in gene expression noise, cell-to-cell variability, and single-cell technologies.
Abstract
A central challenge of translational single-cell genomics is to establish experimental and analytic methods that reveal the molecular determinants of phenotypic dysregulation in human disease. Yet for epigenetically heterogeneous diseases that arise from multiple cell types, the molecular pathology of the disease state is often intricately convolved with its tissue of origin. Here we resolve this confounding effect by deconvolving the healthy and pathological epigenetic components of a single cell. For this purpose, we have constructed a multi-omic map of hematopoietic development that integrates over 100,000 single-cell immunophenotypic profiles (single-cell antibody-derived tag sequencing, scADT-seq), transcriptomes (single-cell RNA sequencing, scRNA-seq), and chromatin accessibility epigenomes (single-cell chromatin accessibility profiling, scATAC-seq) of healthy peripheral blood and bone marrow mononuclear cells. Using this integrative developmental map of normal hematopoiesis, we have analytically deconvolved a cancer-specific epigenetic signature of mixed phenotype acute leukemia (MPAL), a high-risk and phenotypically heterogeneous acute leukemia arising from developmentally arrested hematopoietic progenitor cells. This computational approach shows that the leukemic program executed by an MPAL cell is invariant of its hematopoietic compartment of origin and it identifies a leukemia-specific epigenetic signature that is conserved across a diverse cohort of patients. Our analysis further identifies a set of transcription factors that dysregulate both leukemia-specific chromatin accessibility and transcription. Collectively this work establishes an experimental and computational framework for deconvolving disease and healthy epigenetic programs within single cells and promises to broaden our understanding of the molecular and physiological basis of human disease.