This project of the Hematopoiesis Section is focused on the basic biology of hematopoietic stem cells (HSC) and how they proliferate and differentiate into all of the different cells in the blood. HSC are the rarest population of bone marrow cells and have the unique property of division without differentiation (self-renewal), while the more differentiated progeny of HSC cannot self renew, but have enormous proliferative potential. For patients with a life-threatening hematologic disease, transplantation of HSC from a healthy closely matched donor after ablation of the diseased bone marrow can be a life long cure. However, the main risk in these procedures is the transplantation of inadequate numbers of HSC. Our goal is to understand the processes that promote HSC self-renewal and inhibit HSC differentiation. By manipulating the balance between self-renewal and differentiation we will be able to increase the number of stem cells and consequently increase the effectiveness of bone marrow transplantation to cure acquired or inherited hematopoietic diseases.
Specific Aim 1 : We have initiated a genome-wide ChIP Seq analysis of transcription factor binding in mouse Megakaryocyte/Erythroid progenitor cells, erythroblasts cells and megakaryocytes. We will analyze the binding of GATA1, GATA2, EKLF and NF-E2 in these populations using a whole genome ChIP Seq approach. After sequencing the ChIP enriched DNA fragments, we will use the Eland software to map each sequence tag to the genome and the MACS program to determine where significant enrichment has occurred. We will determine the """"""""signature"""""""" of transcription factor occupancy for each locus and correlate that with mRNA expression, pathway analysis and the histone code using public data bases developed by others.
Specific Aim 2 : CMML is an unusual bone marrow failure syndrome with a clonal out growth of monocyte progenitors (Lin- CD33+ CD34+). This disorder is treated with the DNA methylation inhibitor 5-aza cytidine and histone deacetylase inhibitors. However, whether the effects of these drugs are specifically due to the described actions of these drugs is not known. We will perform methylation pull down and ChIPSeq on tri methylated histones on chromatin extracted from CMML monocyte progenitors before and after treatment with these drugs. We will analyze the genome wide results to determine whether the drugs cause minimal, local or global epigenetic alterations. In addition, we hope to correlate the response with a specific change, allowing a more detailed understanding of the disease process.
|Park, Sunmi; Han, Cho Rong; Park, Jeong Won et al. (2017) Defective erythropoiesis caused by mutations of the thyroid hormone receptor ? gene. PLoS Genet 13:e1006991|
|Bodine, David M (2017) Introduction to the review series on transcription factors in hematopoiesis and hematologic disease. Blood 129:2039|
|Lichtenberg, Jens; Elnitski, Laura; Bodine, David M (2017) SigSeeker: a peak-calling ensemble approach for constructing epigenetic signatures. Bioinformatics 33:2615-2621|
|Lichtenberg, Jens; Heuston, Elisabeth F; Mishra, Tejaswini et al. (2016) SBR-Blood: systems biology repository for hematopoietic cells. Nucleic Acids Res 44:D925-31|
|Psaila, Bethan; Barkas, Nikolaos; Iskander, Deena et al. (2016) Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways. Genome Biol 17:83|
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|Glait-Santar, Chen; Desmond, Ronan; Feng, Xingmin et al. (2015) Functional Niche Competition Between Normal Hematopoietic Stem and Progenitor Cells and Myeloid Leukemia Cells. Stem Cells 33:3635-42|
|Meir, Michal; Galanty, Yaron; Kashani, Lior et al. (2015) The COP9 signalosome is vital for timely repair of DNA double-strand breaks. Nucleic Acids Res 43:4517-30|
|Blobel, Gerd A; Bodine, David; Brand, Marjorie et al. (2015) An international effort to cure a global health problem: A report on the 19th Hemoglobin Switching Conference. Exp Hematol 43:821-37|
|Lee, Minnkyong; Dworkin, Amy M; Lichtenberg, Jens et al. (2014) Metastasis-associated protein ribosomal RNA processing 1 homolog B (RRP1B) modulates metastasis through regulation of histone methylation. Mol Cancer Res 12:1818-28|
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