Adult Hematopoiesis is Regulated by TIF1γ, a Repressor of TAL1 and PU.1 Transcriptional Activity

SummaryCrosstalk between transcription factors and cytokines precisely regulates tissue homeostasis. Transcriptional intermediary factor 1γ (TIF1γ) regulates vertebrate hematopoietic development, can control transcription elongation, and is a component of the TGF-β signaling pathway. Here we show that deletion of TIF1γ in adult hematopoiesis is compatible with life and long-term maintenance of essential blood cell lineages. However, loss of TIF1γ results in deficient long-term hematopoietic stem cell (LT-HSC) transplantation activity, deficient short-term HSC (ST-HSC) bone marrow retention, and priming ST-HSCs to myelomonocytic lineage. These defects are hematopoietic cell-autonomous, and priming of TIF1γ-deficient ST-HSCs can be partially rescued by wild-type hematopoietic cells. TIF1γ can form complexes with TAL1 or PU.1—two essential DNA-binding proteins in hematopoiesis—occupy specific subsets of their DNA binding sites in vivo, and repress their transcriptional activity. These results suggest a regulation of adult hematopoiesis through TIF1γ-mediated transcriptional repression of TAL1 and PU.1 target genes.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (227 K)Download as PowerPoint slideHighlights► Loss of TIF1γ is compatible with long-term maintenance of blood cell lineages ► TIF1γ contributes to optimal function of HSCs in transplantation assays ► TIF1γ is necessary for restricting the number of GMPs ► TIF1γ can interact with TAL1 and PU.1 and repress their transcriptional activity