Tal1 regulates osteoclast differentiation through suppression of the master regulator of cell fusion DC-STAMP.

The balance between bone-forming osteoblasts and bone-resorbing osteoclasts is crucial to bone homeostasis, an equilibrium that is disturbed in many bone diseases. The transcription factor Tal1 is involved in the establishment of hematopoietic stem cells in the embryo and is a master regulator of hematopoietic gene expression in the adult. Here, we show that Tal1 is expressed in osteoclasts and that loss of Tal1 in osteoclast progenitors leads to altered expression of >1200 genes. We found that DC-STAMP, a key regulator of osteoclast cell fusion, is a direct target gene of Tal1 and show that Tal1 represses DC-STAMP expression by counteracting the activating function of the transcription factors PU.1 and MITF. The identification of Tal1 as a factor involved in cell fusion contributes to the understanding of osteoclast-associated diseases, including osteoporosis.