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DNMT3b's Role in Hematopoietic Stem Cells

Boyer, Matthew Jacob (2010) DNMT3b's Role in Hematopoietic Stem Cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Hematopoiesis proceeds from a bone marrow resident population of stem cells responsible for generation of all lineages within the blood. Distinct molecular programs within hematopoietic stem cells regulate maintenance of this population under homeostatic conditions, however the coordination of these programs remains largely undefined. DNA methylation is an epigenetic means of gene regulation in a mammals carried out by a family of DNA methyltransferases. Of these, the de novo methyltransferase is highly expressed in hematopoietic stem cells as compared to other members of this family and somatic mutations in DNMT3b lead to a syndrone characterized by immunodeficiency. Therefore we hypothesized that DNMT3b regulates hematopoietic stem cells via its ability to methylate DNA. By knock-down of DNMT3b with a retrovirally delivered shRNA or Cre mediated recombination of floxed DNMT3b alleles work presented in this thesis demonstrates a critical role for DNMT3b in hematopoiesis in mice. Loss of DNMT3b leads to limited reconstitution of hematopoiesis in irradiated recipients associated with a proliferative defect in vitro and a failure of hematopoietic stem cell self-renewal in vivo. Targeted deletion of DNMT3b in hematopoietic stem cells leads to decreased engraftment following transplantation and decreased proliferation in vitro. DNMT3b's function in hematopoietic cells requires the methyltransferase activity of the enzyme and the defects in hematopoiesis are associated with loss of DNA methylation and decreased expression of MLL. Therefore DNMT3b is necessary for maintenance of the proliferative ability and engraftment capacity of hematopoietic cells and hematopoiesis is dependent upon appropriate DNA methylation.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Boyer, Matthew Jacobmjb36@pitt.eduMJB36
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairChaillet, Richardchaillet@pitt.eduCHAILLET
Committee MemberLagasse,
Committee MemberOrwig, Kylekorwig@pdc.magee.eduKEO6
Committee MemberNiedernhofer,
Committee MemberCheng,
Date: 14 December 2010
Date Type: Completion
Defense Date: 1 December 2010
Approval Date: 14 December 2010
Submission Date: 3 December 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: DNA Methylation; Hematopoiesis; MLL
Other ID:, etd-12032010-144803
Date Deposited: 10 Nov 2011 20:07
Last Modified: 19 Dec 2016 14:37


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