Abstract
BackgroundAdenosine triphosphate (ATP)-dependent chromatin remodeling SWI/SNF-like BAF and PBAF complexes have been implicated in the regulation of stem cell function and cancers. Several subunits of BAF or PBAF, including BRG1, BAF53a, BAF45a, BAF180, and BAF250a, are known to be involved in hematopoiesis. Baf200, a subunit of PBAF complex, plays a pivotal role in heart morphogenesis and coronary artery angiogenesis. However, little is known on the importance of Baf200 in normal and malignant hematopoiesis.MethodsUtilizing Tie2-Cre-, Vav-iCre-, and Mx1-Cre-mediated Baf200 gene deletion combined with fetal liver/bone marrow transplantation, we investigated the function of Baf200 in fetal and adult hematopoiesis. In addition, a mouse model of MLL-AF9-driven leukemogenesis was used to study the role of Baf200 in malignant hematopoiesis. We also explored the potential mechanism by using RNA-seq, RT-qPCR, cell cycle, and apoptosis assays.ResultsTie2-Cre-mediated loss of Baf200 causes perinatal death due to defective erythropoiesis and impaired hematopoietic stem cell expansion in the fetal liver. Vav-iCre-mediated loss of Baf200 causes only mild anemia and enhanced extramedullary hematopoiesis. Fetal liver hematopoietic stem cells from Tie2-Cre+, Baf200f/f or Vav-iCre+, Baf200f/f embryos and bone marrow hematopoietic stem cells from Vav-iCre+, Baf200f/f mice exhibited impaired long-term reconstitution potential in vivo. A cell-autonomous requirement of Baf200 for hematopoietic stem cell function was confirmed utilizing the interferon-inducible Mx1-Cre mouse strain. Transcriptomes analysis revealed that expression of several erythropoiesis- and hematopoiesis-associated genes were regulated by Baf200. In addition, loss of Baf200 in a mouse model of MLL-AF9-driven leukemogenesis accelerates the tumor burden and shortens the host survival.ConclusionOur current studies uncover critical roles of Baf200 in both normal and malignant hematopoiesis and provide a potential therapeutic target for suppressing the progression of leukemia without interfering with normal hematopoiesis.
Highlights
Adenosine triphosphate (ATP)-dependent chromatin remodeling SWI/SNF-like BRG1-associated factor (BAF) and polybromo BRG1-associated factor (PBAF) complexes have been implicated in the regulation of stem cell function and cancers
Baf200 is widely expressed in all hematopoietic lineages and in fetal liver (FL) LSK (Lin −Sca1+c-Kit+), FL hematopoietic progenitor cell (HPC) (Lin−Sca1−c-Kit+), FL S2 (Ter119lowCD71+), FL S3 (Ter119highCD71+), adult bone marrow (BM) short-term (ST)-Hematopoietic stem cell (HSC) (Lin −Sca1+c-Kit+CD34+Flt3low), multipotent progenitor (MPP) (Lin−Sca1+c-Kit+CD34+Flt3+), megakaryocyte–erythroid progenitor (MEP) (Lin−Sca1−c-Kit+CD34−CD16/32low), and granulocyte-macrophage progenitor (GMP) (Lin−Sca1 −c-Kit+CD34+CD16/32high) lineages (Additional file 1: Figure S1)
Examination of the genotypes in the litters from timed mating intercross found that Tie2-Cre+, Baf200f/f embryos were alive and were recovered at the expected Mendelian ratio at embryonic day (E) 17.5, but that the majority died by E18.5 (Fig. 1a and Additional file 1: Figure S2a)
Summary
Adenosine triphosphate (ATP)-dependent chromatin remodeling SWI/SNF-like BAF and PBAF complexes have been implicated in the regulation of stem cell function and cancers. Hematopoiesis is a continuous process with a rare population of hematopoietic stem cells (HSCs) giving rise to all blood cell types. It is finely orchestrated by both cellintrinsic factors and microenvironmental clues [1]. Hematopoiesis continues with balanced proliferation, differentiation, quiescence, and apoptosis of HSCs. Various transcription factors, signaling pathways, and epigenetic regulators are involved in the regulation of these processes, and abnormalities occurring in these processes cause hematopoietic disorders including anemia or malignant transformation [2,3,4,5,6,7,8,9,10,11]. Defining factors involved in the regulation of hematopoiesis is an important issue in HSC biology
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