Details

Autor(en) / Beteiligte

• Challen, Grant A.
• Sun, Deqiang
• Mayle, Allison
• Jeong, Mira
• Luo, Min
• Rodriguez, Benjamin
• Mallaney, Cates
• Celik, Hamza
• Yang, Liubin
• Xia, Zheng
• Cullen, Sean
• Berg, Jonathan
• Zheng, Yayun
• Darlington, Gretchen J.
• Li, Wei
• Goodell, Margaret A.

Titel

Dnmt3a and Dnmt3b Have Overlapping and Distinct Functions in Hematopoietic Stem Cells

Ist Teil von

• Cell stem cell, 2014-09, Vol.15 (3), p.350-364

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Epigenetic regulation of hematopoietic stem cells (HSCs) ensures lifelong production of blood and bone marrow. Recently, we reported that loss of de novo DNA methyltransferase Dnmt3a results in HSC expansion and impaired differentiation. Here, we report conditional inactivation of Dnmt3b in HSCs either alone or combined with Dnmt3a deletion. Combined loss of Dnmt3a and Dnmt3b was synergistic, resulting in enhanced HSC self-renewal and a more severe block in differentiation than in Dnmt3a-null cells, whereas loss of Dnmt3b resulted in a mild phenotype. Although the predominant Dnmt3b isoform in adult HSCs is catalytically inactive, its residual activity in Dnmt3a-null HSCs can drive some differentiation and generates paradoxical hypermethylation of CpG islands. Dnmt3a/Dnmt3b-null HSCs displayed activated β-catenin signaling, partly accounting for the differentiation block. These data demonstrate distinct roles for Dnmt3b in HSC differentiation and provide insights into complementary de novo methylation patterns governing regulation of HSC fate decisions. [Display omitted] •De novo DNA methyltransferase enzymes synergize to enable HSC differentiation•β-catenin is partly responsible for Dnmt3a/Dnmt3b-null HSC differentiation arrest•Abnormal Dnmt3b function in the absence of Dnmt3a leads to DNA hypermethylation•The predominant Dnmt3b isoforms expressed in HSCs are catalytically inactive Challen et al. reveal that combined loss of de novo DNA methyltransferases Dnmt3a and Dnmt3b blocks HSC differentiation through hypomethylation, augments β-catenin signaling, and increases constitutive expression of stem cell genes.