The RNA binding protein Ars2 supports hematopoiesis at multiple levels

Autor: G. Aaron Holling, Rachel L. Kandefer, Scott H. Olejniczak, Michael J. Nemeth, Seerat Elahi, Shawn M. Egan
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Clonal Deletion
Apoptosis
Mice
Inbred Strains
RNA-binding protein
Thymus Gland
Biology
Cell fate determination
Real-Time Polymerase Chain Reaction
Article
Colony-Forming Units Assay
Mice
03 medical and health sciences
0302 clinical medicine
Bone Marrow
Gene expression
Genetics
medicine
Animals
Cell Self Renewal
Molecular Biology
Mice
Knockout
Regulation of gene expression
Thymic involution
Thymocytes
Asymmetric Cell Division
Nuclear Proteins
Cell Biology
Hematology
Hematopoietic Stem Cells
Recombinant Proteins
Hematopoiesis
Cell biology
DNA-Binding Proteins
Haematopoiesis
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
Organ Specificity
Radiation Chimera
030220 oncology & carcinogenesis
Bone marrow
Stromal Cells
Stem cell
Transcription Factors
Zdroj: Experimental Hematology. 64:45-58.e9
ISSN: 0301-472X
DOI: 10.1016/j.exphem.2018.05.001
Popis: Recent biochemical characterization of Arsenic resistance protein 2 (Ars2) has established it as central to determining the fate of nascent RNA polymerase II (RNAPII) transcripts. Through interactions with the nuclear 5′-7-methylguanosine (7mG) cap binding complex (CBC), Ars2 promotes co-transcriptional processing coupled with nuclear export or degradation of several classes of RNAPII transcripts, allowing for gene expression programs that facilitate rapid and sustained proliferation of immortalized cells in culture. However, rapidly dividing cells in culture do not represent the physiological condition of the vast majority of cells in an adult mammal. To examine functions of Ars2 in a physiological setting we generated inducible Ars2 knockout mice and found that deletion of Ars2 from adult mice resulted in defective hematopoiesis in bone marrow and thymus. Importantly, only some of this defect could be explained by the requirement of Ars2 for rapid proliferation, which we found to be cell-type specific in vivo. Rather Ars2 was required for survival of developing thymocytes and for limiting differentiation of bone marrow resident long-term hematopoietic stem cells (LT-HSCs). As a result, Ars2 knockout led to rapid thymic involution and loss of the ability of mice to regenerate peripheral blood following myeloablation. These in vivo data demonstrate that Ars2 expression is important at several steps of hematopoiesis, likely because Ars2 acts on gene expression programs underlying essential cell fate decisions such as the decision to die, to proliferate, or to differentiate.
Databáze: OpenAIRE
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