Abstract
During erythropoiesis, haematopoietic stem cells (HSCs) differentiate in successive steps of commitment and specification to mature erythrocytes. This differentiation process is controlled by transcription factors that establish stage- and cell type-specific gene expression. In this study, we demonstrate that FUSE binding protein 1 (FUBP1), a transcriptional regulator important for HSC self-renewal and survival, is regulated by T-cell acute lymphocytic leukaemia 1 (TAL1) in erythroid progenitor cells. TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation. The binding of TAL1 to the FUBP1 promoter is highly dependent on an intact GATA sequence in a combined E-box/GATA motif. We found that FUBP1 expression is required for efficient erythropoiesis, as FUBP1-deficient progenitor cells were limited in their potential of erythroid differentiation. Thus, the finding of an interconnection between GATA1/TAL1 and FUBP1 reveals a molecular mechanism that is part of the switch from progenitor- to erythrocyte-specific gene expression. In summary, we identified a TAL1/FUBP1 transcriptional relationship, whose physiological function in haematopoiesis is connected to proper erythropoiesis.
Highlights
Every second about two million mature red blood cells are produced in the bone marrow of a human adult and released into the blood stream to allow the continuous supply with oxygen of all tissues [1]
We discovered an important role for FUSE binding protein 1 (FUBP1) in haematopoiesis, namely for the self-renewal of LT-haematopoietic stem cells (HSCs) and during erythroid differentiation of murine embryonic stem cells [11, 12]
We analysed in silico the human FUBP1 promoter region for DNA binding motifs recognized by transcription factors and found, amongst others, an E-box followed by a GATA-box (Fig 1A)
Summary
Every second about two million mature red blood cells (erythrocytes) are produced in the bone marrow of a human adult and released into the blood stream to allow the continuous supply with oxygen of all tissues [1]. Along their route to becoming an erythrocyte, haematopoietic stem cells (HSCs) undergo successive steps of specification, commitment and differentiation to produce mature red blood cells. While a gradual loss of differentiation potential during this pathway is observed in vitro, recent in vivo and in silico analysis revealed that both MPPs and CMPs can already be destined to become an erythrocyte, challenging the classic hierarchical model [4, 5]. Differentiation stages downstream of MEPs are characterized by distinct cell morphology and surface markers [6]
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