Alternative Runx1 promoter usage in mouse developmental hematopoiesis.
ABSTRACT The interest in stem cell based therapies has emphasized the importance of understanding the cellular and molecular mechanisms by which stem cells are generated in ontogeny and maintained throughout adult life. Hematopoietic stem cells (HSCs) are first found in clusters of hematopoietic cells budding from the luminal wall of the major arteries in the developing mammalian embryo. The transcription factor Runx1 is critical for their generation and is specifically expressed at sites of HSC generation, prior to their formation. To understand better the transcriptional hierarchies that converge on Runx1 during HSC emergence, we have initiated studies into its transcriptional regulation. Here we systematically analyzed Runx1 P1 and P2 alternative promoter usage in hematopoietic sites and in sorted cell populations during mouse hematopoietic development. Our results indicate that Runx1 expression in primitive erythrocytes is largely P2-derived, whilst in definitive hematopoietic stem and/or progenitor cells from the yolk sac or AGM and vitelline and umbilical arteries both the distal P1 and proximal P2 promoters are active. After cells have migrated to the fetal liver, the P1 gradually becomes the main hematopoietic promoter and remains this into adulthood. In addition, we identified a novel P2-derived Runx1 isoform.
Article: Transcription factor RUNX1.[show abstract] [hide abstract]
ABSTRACT: Transcription factor RUNX1 is one of the key regulatory proteins in vertebrates. RUNX1 controls hematopoiesis and angiogenesis and is indispensable for the emergence of sites of definitive hematopoiesis during embryogenesis and for blood stem cells differentiation in adult bone marrow. The RUNX1 gene is a frequent target of chromosomal translocations causing acute leukemias. Many human leukemias are some-how associated with RUNX1 mutations. Nevertheless, the precise mechanism guiding the tissue-specific manner of RUNX1 expression remains unknown. The review summarizes the experimental data accumulated over the past twenty years, beginning from the date of the first annotation of the RUNX1 cDNA sequence. The structure, isoforms, covalent modifications, and role in various regulatory cascades are considered for the RUNX1 transcription factor, as well as the RUNX1 expression regulation, mutations, and the involvement in chromosomal translocations.Molecular Biology 11/2012; 46(6):755-767. · 0.66 Impact Factor
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ABSTRACT: The control of differential gene expression is central to all metazoan biology. Haematopoiesis represents one of the best understood developmental systems where multipotent blood stem cells give rise to a range of phenotypically distinct mature cell types, all characterised by their own distinctive gene expression profiles. Small combinations of lineage-determining transcription factors drive the development of specific mature lineages from multipotent precursors. Given their powerful regulatory nature, it is imperative that the expression of these lineage-determining transcription factors is under tight control, a fact underlined by the observation that their misexpression commonly leads to the development of leukaemia. Here we review recent studies on the transcriptional control of key haematopoietic transcription factors, which demonstrate that gene loci contain multiple modular regulatory regions within which specific regulatory codes can be identified, that some modular elements cooperate to mediate appropriate tissue-specific expression, and that long-range approaches will be necessary to capture all relevant regulatory elements. We also explore how changes in technology will impact on this area of research in the future.Stem Cell Research & Therapy 02/2011; 2(1):6. · 3.21 Impact Factor