Hematopoiesis is the process of generating all of the different types of blood cells (erythrocytes, lymphocytes, platelets, etc.) circulating throughout the body. All of these cells are derived from a small population of pluripotent hematopoietic stem cells. As pluripotent hematopoietic stem and progenitor cells multiply and differentiate, their progeny lose the ability to differentiate into some lineages and eventually become committed to one single type of cell that ultimately enters the blood circulation. The Hematopoiesis Section's research focuses on erythropoiesis, the regenerative process in which undifferentiated hematopoietic cells differentiate into red blood cells. Perturbations of this process cause a variety of disorders ranging from hematologic malignancy to anemia.
One of the Hematopoiesis Section's research objectives is to understand the epigenetic changes that accompany erythroid differentiation, including how they differ from the epigenetic profiles of cells from other lineages. To accomplish this goal, the Hematopoiesis Section participates in a consortium known as VISION (Validated Systematic IntegratiON of hematopoietic epigenomes) whose goal is to define the epigenetic changes that occur during erythropoiesis. VISION is designed to extend the ENCyclopedia Of DNA Elements (ENCODE) Project into the study of primary hematopoietic cells. ENCODE was developed to identify all functional elements in the human genome, including epigenetic marks and sites occupied by transcription factors, primarily focusing on cell lines or cultured cells. The hematopoietic system provides a unique opportunity for study because primary hematopoietic cells can be separated into well-defined populations representing distinct lineages and stages of differentiation using flow cytometry, which is not possible in other organs. This allows the determination of the epigenetic state of the genome in freshly isolated, specific cell types. These data can be correlated with transcriptional profiles, chromatin accessibility, DNA methylation and 3D chromatin interactions to determine the regulatory signature that accompanies differentiation into a specific lineage (i.e. red cells).
The goal of these epigenetic studies is to determine how the genome of mouse hematopoietic progenitor cells becomes programed to generate red blood cells. By working with the mouse system, hypotheses derived from observations can be tested directly in the myriad mouse models available to study erythroid differentiation. The Hematopoiesis Section is developing a comprehensive transcriptional profile of single mouse progenitor cells to determine the earliest emergence of the different lineages. The histone code, chromatin accessibility, DNA methylation etc. profiles of these cells will be compared to the profiles we have generated in primary mouse erythroblasts, megakaryocytes (which generate platelets) and earlier bipotential progenitor cells. The collective chromatin signatures emerging from the analysis of these cell populations are compared to find correlations with the RNA expression profiles The long-term goal is to identify the critical regulatory pathways that promote erythroid proliferation and differentiation and to develop small molecules or compounds that could be used to treat anemia.
The Hematopoiesis Section also studies erythropoiesis using the model of a genetically-determined form of anemia that affects humans, called Diamond-Blackfan Anemia syndrome (DBA). DBA is an inherited autosomal dominant disorder associated with failed erythropoiesis, congenital malformations and a predisposition to cancer. Approximately 65 percent of DBA patients have mutations in genes encoding one of 13 ribosomal protein subunits, which result in haploinsufficiency. Because DBA mutations are incompletely penetrant, the lack of a molecular diagnosis in 35 percent of patients prevents the use of sibling donors for hematopoietic stem cell transplantation, the only curative therapy for DBA. The lack of a molecular diagnosis also complicates genotype/phenotype analysis of DBA patients and the possibility of family planning for parents and siblings of affected individuals. A large-scale targeted exome sequence analysis tested the hypothesis that mutations in non-ribosomal protein genes are the cause of DBA in these patients. However, no mutations in non-ribosomal protein genes were identified. The Hematopoiesis Section is currently employing genome sequencing to determine whether small deletions involving ribosomal protein genes or mutations in regulatory sequences are responsible for the "undiagnosed" 35% of DBA patients. The Hematopoiesis Section is also developing reporter cell lines that can be used to screen for drugs that increase the levels of ribosomal proteins, which may offer a new treatment for DBA.
Hematopoiesis Section Members
Nancy E. Seidel, Biologist
Jaya Jagadeesh, Biologist
Jens Lichtenberg, Postdoctoral Fellow
Elisabeth F. Heuston, Ph.D., Postdoctoral Fellow
William Simmons, Post Baccalaureate Student
Last Updated: August 28, 2018