Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Abstract

Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of <i>TET2</i> occur in myeloid malignancies, and hematopoietic-specific loss of <i>Tet2</i> induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating <i>TET2</i> as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of <i>AID</i> loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that <i>Aid</i> loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of <i>Cebpa</i> and <i>Gata1</i>, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of <i>AID</i> in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to <i>Tet2</i> loss, <i>Aid</i> loss does not contribute to enhanced HSC self-renewal or cooperate with <i>Flt3-ITD</i> to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of <i>Aid</i> as a key epigenetic regulator. These results indicate that <i>AID</i> and <i>TET2</i> share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation.