Transcription Factors and Hematopoietic Development (1995)

INTRODUCTIONHematopoiesis is the process by which mature blood cells of distinct lineages (e.g. red, white, and lymphoid cells) are produced from pluripotent hematopoietic stem cells (HSCs). ( 1The abbreviations used are: HSChematopoietic stem cellLCRlocus control regionESembryonic stembHLHbasic helix-loop-helix.) To sustain hematopoiesis through an individual's lifetime, HSCs must be capable of (i) maintenance in a non-cycling state, (ii) self-renewal to generate additional HSCs, and (iii) production of progenitor cells with more limited developmental potential. Progenitors commit to subsets of lineages and ultimately to single pathways with concomitant expression of the end-stage markers representative of each cell type. Hematopoiesis is dynamic both with respect to lineage decisions and location during development. Within the mammalian embryo the site of hematopoiesis changes from its initial position in the yolk sac blood islands (primitive hematopoiesis) to the fetal liver and then to the bone marrow (definitive hematopoiesis). Although it has been considered axiomatic that HSCs which populate the adult arise within the yolk sac and migrate to the fetal liver, recent evidence suggests an intraembryonic origin(1Godin I.E. Garcia-Porrero J.A. Coutinho A. Dieterlen-Lievre F. Marcos M.A.R. Nature. 1993; 364: 67-70Crossref PubMed Scopus (312) Google Scholar, 2Medvinsky A.L. Samoylina N.L. Muller A.M. Dzierzak E.A. Nature. 1993; 364: 64-66Crossref PubMed Scopus (412) Google Scholar).Hematopoiesis is controlled by the combined effects of growth factors that permit cellular proliferation and nuclear regulators (transcription factors) that activate lineage-specific genes. As the phenotypes of differentiated lineages reflect the sets of genes expressed therein, study of cell-restricted transcription factors has been a fruitful approach to hematopoietic development. Critical regulators have been identified both through the study of nuclear factors binding cis-regulatory elements involved in lineage-specific gene expression and by pursuit of genes aberrantly activated in leukemia. Implicit in the target gene-based approach is the premise that some transcription factors controlling genes expressed late in a lineage may also be used at earlier steps in the developmental pathway. Indeed, this is often the case. In the leukemia-based approach it is presumed that the oncoprotein either inappropriately activates a program of growth or interferes with terminal differentiation.This review summarizes the involvement of selected transcription factors in hematopoietic development and focuses on how study of such regulators addresses questions of lineage selection and commitment. As this review is brief, it is not meant to be exhaustive but rather illustrative of general aspects and gaps in current understanding.Cis-regulatory Motifs and Transcription FactorsDiverse transcription factors serve important regulatory functions in hematopoietic lineages (see Table 1). These have been identified through efforts to delineate the molecular basis of cell-specific gene expression and leukemias. The mapping and functional assessment of cis-elements required for cell-specific gene expression in erythroid, myeloid, and lymphoid lineages have been widely pursued. For each cell lineage a small array of DNA-binding motifs in promoters or enhancers has been identified as critical for cell-specific transcription. In studies of globin gene control in erythroid cells, cis-element analysis has also defined distant regulatory sequences, designated the locus control regions (LCRs), that act over large distances (>50 kilobases) within the globin loci. These elements, which are marked by DNase I hypersensitivity in chromatin, ensure integration site-independent, copy number-dependent erythroid expression of linked genes in transgenic mice(3Grosveld F. van Assendelft G.B. Greaves D.R. Kollias B. Cell. 1987; 51: 975-985Abstract Full Text PDF PubMed Scopus (1430) Google Scholar, 4Crossley M. Orkin S.H. Curr. Opin. Genet. Dev. 1993; 3: 232-237Crossref PubMed Scopus (79) Google Scholar). Remarkably, three motifs recur in the core regions of LCRs and erythroid-expressed gene promoters. These include GATA motifs, AP-1-like sequences, and GT or CACC-like sequences(4Crossley M. Orkin S.H. Curr. Opin. Genet. Dev. 1993; 3: 232-237Crossref PubMed Scopus (79) Google Scholar). Among lymphoid-expressed genes, promoter (or enhancer) motifs recognized by Ikaros(5Georgopoulos K. Moore D.D. Defler B. Science. 1992; 258: 808-812Crossref PubMed Scopus (375) Google Scholar), NF-κB proteins, Oct-1 and Oct-2(6Clerc R.G. Corcoran L.M. LeBowitz J.H. Baltimore D. Sharp P.A. Genes & Dev. 1988; 2: 1570-1581Crossref PubMed Scopus (274) Google Scholar, 7Sturm R.A. Das G. Herr W. Genes & Dev. 1988; 2: 1582-1599Crossref PubMed Scopus (475) Google Scholar), E2A(8Murre C. McCaw P.S. Baltimore D. Cell. 1989; 56: 777-783Abstract Full Text PDF PubMed Scopus (1837) Google Scholar), and the high mobility group (HMG) factors LEF-1 and TCF-1 (9Oosterwegel M. van de Wetering M. Dooijes D. Klomp L. Winoto A. Georgopoulos K. Meijlink F. Clevers H. J. Exp. Med. 1991; 173: 1133-1142Crossref PubMed Scopus (117) Google Scholar, 10Travis A. Amsterdam A. Belanger C. Grosschedl R. Genes & Dev. 1991; 5: 880-894Crossref PubMed Scopus (492) Google Scholar) have been identified. In myeloid-expressed genes, binding motifs recognized by PU.1(11Klemsz M.J. McKercher S.R. Celada A. Van Beveren C. Maki R.A. Cell. 1990; 61: 113-124Abstract Full Text PDF PubMed Scopus (756) Google Scholar), AML1 (or runt)(12Miyoshi H. Shimizu K. Kozu T. Maseki N. Kaneko Y. Ohki M. Proc. Natl. Acad. Sci. A. 1991; PubMed Scopus Google Scholar), and Muller C. K. A. J. 1993; PubMed Scopus Google Scholar) have been I in a For each of binding in nuclear have been identified. For in erythroid cells, the factors and as the and Orkin S.H. Nature. 1989; PubMed Scopus Google Scholar, H. Orkin S.H. Nature. 1993; PubMed Scopus Google Scholar). In lymphoid cells, elements are recognized by and its as as of the NF-κB A. Georgopoulos K. Cell. PubMed Scopus Google are by and by As is from Table the cell-specific transcription factors identified not within a single that is factors of and are the of regulatory factors controlling cell-specific gene expression in a cell be it is not single cis-element to cell-specific gene For erythroid of in the of at motifs of the F. J. 1993; PubMed Scopus Google Scholar). suggests that factors are in distinct of gene expression (see of the lineage-specific factors to a single cell type. For which to with cis-elements of erythroid-expressed genes, is also expressed in cells, G. Orkin S.H. Nature. 1990; PubMed Scopus Google Scholar, M. W. G. G. Nature. 1990; PubMed Scopus Google Scholar, Y. K. E.A. A. Orkin S.H. 1993; PubMed Google Scholar), and not to a single A. M. M. G. L. C. Orkin S.H. C. Proc. Natl. Acad. Sci. A. 1992; PubMed Scopus Google Scholar). factors may (e.g. are also expressed at selected the hematopoietic such as cells of the K. H. H. Y. M. Google Scholar) and the of the K. Moore D.D. Defler B. Science. 1992; 258: 808-812Crossref PubMed Scopus (375) Google Scholar). is a and a of cellular the of transcription factors at binding or target genes is the of with (or binding often in a single cell type. in LCRs are recognized by the erythroid H. Orkin S.H. Nature. 1993; PubMed Scopus Google Scholar), but also by as as Proc. Natl. Acad. Sci. A. 1993; PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar, K. A. Proc. Natl. Acad. Sci. A. PubMed Scopus Google Scholar). a important in the and promoter is by both an erythroid and the Cell. 1993; PubMed Scopus Google Scholar). the in binding of to an the in or is an and it regulatory in pathways or is a of are and in of Transcription in of a lineage-specific transcription and binding in genes expressed in a cell-specific is a for the as a Although of in cells on the of a transcription to a in of binding a for a to which gene in stem cells and of J. Full Text PDF PubMed Google Scholar) has 1). is that in the of a transcription to a of the hematopoietic lineage in the As are with the that factors a in lineage as to genes to the critical In the of the high that it be a critical in erythroid cells, as GATA motifs are in regulatory elements of erythroid-expressed genes and the is the GATA in In of and erythroid the for cells are by with the M.J. G. Orkin S.H. Genes & Dev. PubMed Scopus Google Scholar). the lymphoid or cells, and K. M. A. A. Cell. Full Text PDF PubMed Scopus Google Scholar) and cells of hematopoietic and lymphoid J. H. Science. PubMed Scopus Google Scholar). a gene with in hematopoietic lineages and aberrantly activated gene in is for erythroid development also for some aspects of R. Orkin S.H. Nature. PubMed Scopus Google of some expressed factors in For of the gene at an but not with development of in which it is expressed G. D. A.M. van M. van M. A. C. Cell. Full Text PDF PubMed Scopus Google Scholar, Y. H. Cell. Full Text PDF PubMed Scopus Google Scholar). of the in of at the yolk sac of that of or M.J. Cell. Full Text PDF PubMed Scopus Google at the of the or be to hematopoiesis progenitor at the fetal is of K. S.H. Cell. 1991; Full Text PDF PubMed Scopus Google Scholar). Although erythroid and lymphoid cells are are as the of an are of a of a required in (or as cells a hematopoietic to that cellular G. M.J. M. F. Orkin S.H. Nature. PubMed Scopus Google some cell-restricted transcription factors to be required lineage commitment. of of on globin expression in are ( in evidence that of the gene in cells globin Y. Proc. Natl. Acad. Sci. A. PubMed Scopus Google Scholar). this hematopoietic of is for of to ( in the is expressed of its a of transcription of the adult gene A. and H. in the of in a target is by a to of to be of lineage selection or at an the study of developmental is gene or may this H. H. K. Science. PubMed Scopus Google Scholar). analysis and in of cells be to hematopoietic development in the is to the G. M.J. M. F. Orkin S.H. Nature. PubMed Scopus Google Scholar). functional may a in to a marked in a lineage in which the is expressed be used as evidence in The lineage for selected factors in hematopoiesis are in Transcription and a cell a single of is a in of suggests that growth factors for and proliferation of and that lineage decisions are through of in the of and and the of lymphoid in are with the not that lineage the in which of a in progenitor cells the additional evidence for the of such factors in controlling commitment. it is to that of a single transcription a cell to its an or lymphoid of lineages of a HSCs or is in is that functional of hematopoietic transcription factors must be considered in the of a cellular of in the cell expression of evidence for an on lineage A. J. 1992; PubMed Scopus Google Scholar). lineage by expression of or and by of cells to J. 1993; PubMed Google Scholar). In this the of H. Cell. Full Text PDF PubMed Scopus Google Scholar). The an as in the of L. Orkin S.H. F. Scholar). The of and in of cells that GATA factors are with respect to this and may a basis for in in this aspects of the cell-restricted factors are cell-specific and to activate an developmental how are lineages to are cell-restricted factors with cell-specific as is that lineage is by a of evidence in of this is of transcription factors is of some genes in cells both and T. T. A. Genes & Dev. 1993; PubMed Scopus Google Scholar). evidence suggests that of its and may of a critical for gene G. A. Genes & Dev. PubMed Scopus Google Scholar). The for a of factors is by transcription In some this such as that of with P.A. H. Orkin S.H. Proc. Natl. Acad. Sci. A. 1993; PubMed Scopus Google Scholar) or with L. W. R. Cell. PubMed Scopus Google Scholar), with H. A. J. R. Proc. Natl. Acad. Sci. A. PubMed Scopus Google Scholar), and with M.J. McKercher S.R. Maki R.A. Cell. 1992; PubMed Scopus Google Scholar). of functional may also cell-restricted such as and or a cell-restricted and such as and ( and H. Cell. in the of and the of a cell-restricted factors be the to are cell-specific factors with cell-specific recent a In the of erythroid to the to with which is by to control M.J. G. Orkin S.H. Genes & Dev. PubMed Scopus Google Scholar). in the cell is by or J. 1993; PubMed Google Scholar). developmental of cells of or the GATA Orkin S.H. Cell. PubMed Google Scholar). These for erythroid or by GATA the required for of cells to the DNA-binding of or M. J. Orkin S.H. Cell. PubMed Google Scholar). As that of may be of for in or the DNA-binding functions binding a with recent evidence through this The of the DNA-binding C. Orkin S.H. Proc. Natl. Acad. Sci. A. 1991; PubMed Scopus Google Scholar) is with the of the of GATA factors in expression of lineage-specific may reflect expression rather functional in the and is to selection a evidence that of is also by of of cells by the of gene is by of A. J. 1992; PubMed Scopus Google Scholar). of expression of is in the erythroid lineage and in A. M. M. G. L. C. Orkin S.H. C. Proc. Natl. Acad. Sci. A. 1992; PubMed Scopus Google Scholar). has been to for of it lymphoid K. M. A. A. Cell. Full Text PDF PubMed Scopus Google Scholar). that in cells the factors for lineages each the expression of the genes be as of a are Although the by which regulatory are to be of of target genes of and of factors are to the decisions of hematopoietic it a to in the of cell Full Text PDF PubMed Scopus Google Scholar, Genes & Dev. PubMed Scopus Google Scholar) may additional in which to the functions of hematopoietic transcription INTRODUCTIONHematopoiesis is the process by which mature blood cells of distinct lineages (e.g. red, white, and lymphoid cells) are produced from pluripotent hematopoietic stem cells (HSCs). ( 1The abbreviations used are: HSChematopoietic stem cellLCRlocus control regionESembryonic stembHLHbasic helix-loop-helix.) To sustain hematopoiesis through an individual's lifetime, HSCs must be capable of (i) maintenance in a non-cycling state, (ii) self-renewal to generate additional HSCs, and (iii) production of progenitor cells with more limited developmental potential. Progenitors commit to subsets of lineages and ultimately to single pathways with concomitant expression of the end-stage markers representative of each cell type. Hematopoiesis is dynamic both with respect to lineage decisions and location during development. Within the mammalian embryo the site of hematopoiesis changes from its initial position in the yolk sac blood islands (primitive hematopoiesis) to the fetal liver and then to the bone marrow (definitive hematopoiesis). Although it has been considered axiomatic that HSCs which populate the adult arise within the yolk sac and migrate to the fetal liver, recent evidence suggests an intraembryonic origin(1Godin I.E. Garcia-Porrero J.A. Coutinho A. Dieterlen-Lievre F. Marcos M.A.R. Nature. 1993; 364: 67-70Crossref PubMed Scopus (312) Google Scholar, 2Medvinsky A.L. Samoylina N.L. Muller A.M. Dzierzak E.A. Nature. 1993; 364: 64-66Crossref PubMed Scopus (412) Google Scholar).Hematopoiesis is controlled by the combined effects of growth factors that permit cellular proliferation and nuclear regulators (transcription factors) that activate lineage-specific genes. As the phenotypes of differentiated lineages reflect the sets of genes expressed therein, study of cell-restricted transcription factors has been a fruitful approach to hematopoietic development. Critical regulators have been identified both through the study of nuclear factors binding cis-regulatory elements involved in lineage-specific gene expression and by pursuit of genes aberrantly activated in leukemia. Implicit in the target gene-based approach is the premise that some transcription factors controlling genes expressed late in a lineage may also be used at earlier steps in the developmental pathway. Indeed, this is often the case. In the leukemia-based approach it is presumed that the oncoprotein either inappropriately activates a program of growth or interferes with terminal differentiation.This review summarizes the involvement of selected transcription factors in hematopoietic development and focuses on how study of such regulators addresses questions of lineage selection and commitment. As this review is brief, it is not meant to be exhaustive but rather illustrative of general aspects and gaps in current understanding.Cis-regulatory Motifs and Transcription FactorsDiverse transcription factors serve important regulatory functions in hematopoietic lineages (see Table 1). These have been identified through efforts to delineate the molecular basis of cell-specific gene expression and leukemias. The mapping and functional assessment of cis-elements required for cell-specific gene expression in erythroid, myeloid, and lymphoid lineages have been widely pursued. For each cell lineage a small array of DNA-binding motifs in promoters or enhancers has been identified as critical for cell-specific transcription. In studies of globin gene control in erythroid cells, cis-element analysis has also defined distant regulatory sequences, designated the locus control regions (LCRs), that act over large distances (>50 kilobases) within the globin loci. These elements, which are marked by DNase I hypersensitivity in chromatin, ensure integration site-independent, copy number-dependent erythroid expression of linked genes in transgenic mice(3Grosveld F. van Assendelft G.B. Greaves D.R. Kollias B. Cell. 1987; 51: 975-985Abstract Full Text PDF PubMed Scopus (1430) Google Scholar, 4Crossley M. Orkin S.H. Curr. Opin. Genet. Dev. 1993; 3: 232-237Crossref PubMed Scopus (79) Google Scholar). Remarkably, three motifs recur in the core regions of LCRs and erythroid-expressed gene promoters. These include GATA motifs, AP-1-like sequences, and GT or CACC-like sequences(4Crossley M. Orkin S.H. Curr. Opin. Genet. Dev. 1993; 3: 232-237Crossref PubMed Scopus (79) Google Scholar). Among lymphoid-expressed genes, promoter (or enhancer) motifs recognized by Ikaros(5Georgopoulos K. Moore D.D. Defler B. Science. 1992; 258: 808-812Crossref PubMed Scopus (375) Google Scholar), NF-κB proteins, Oct-1 and Oct-2(6Clerc R.G. Corcoran L.M. LeBowitz J.H. Baltimore D. Sharp P.A. Genes & Dev. 1988; 2: 1570-1581Crossref PubMed Scopus (274) Google Scholar, 7Sturm R.A. Das G. Herr W. Genes & Dev. 1988; 2: 1582-1599Crossref PubMed Scopus (475) Google Scholar), E2A(8Murre C. McCaw P.S. Baltimore D. Cell. 1989; 56: 777-783Abstract Full Text PDF PubMed Scopus (1837) Google Scholar), and the high mobility group (HMG) factors LEF-1 and TCF-1 (9Oosterwegel M. van de Wetering M. Dooijes D. Klomp L. Winoto A. Georgopoulos K. Meijlink F. Clevers H. J. Exp. Med. 1991; 173: 1133-1142Crossref PubMed Scopus (117) Google Scholar, 10Travis A. Amsterdam A. Belanger C. Grosschedl R. Genes & Dev. 1991; 5: 880-894Crossref PubMed Scopus (492) Google Scholar) have been identified. In myeloid-expressed genes, binding motifs recognized by PU.1(11Klemsz M.J. McKercher S.R. Celada A. Van Beveren C. Maki R.A. Cell. 1990; 61: 113-124Abstract Full Text PDF PubMed Scopus (756) Google Scholar), AML1 (or runt)(12Miyoshi H. Shimizu K. Kozu T. Maseki N. Kaneko Y. Ohki M. Proc. Natl. Acad. Sci. A. 1991; PubMed Scopus Google Scholar), and Muller C. K. A. J. 1993; PubMed Scopus Google Scholar) have been I in a For each of binding in nuclear have been identified. For in erythroid cells, the factors and as the and Orkin S.H. Nature. 1989; PubMed Scopus Google Scholar, H. Orkin S.H. Nature. 1993; PubMed Scopus Google Scholar). In lymphoid cells, elements are recognized by and its as as of the NF-κB A. Georgopoulos K. Cell. PubMed Scopus Google are by and by As is from Table the cell-specific transcription factors identified not within a single that is factors of and are the of regulatory factors controlling cell-specific gene expression in a cell be it is not single cis-element to cell-specific gene For erythroid of in the of at motifs of the F. J. 1993; PubMed Scopus Google Scholar). suggests that factors are in distinct of gene expression (see of the lineage-specific factors to a single cell type. For which to with cis-elements of erythroid-expressed genes, is also expressed in cells, G. Orkin S.H. Nature. 1990; PubMed Scopus Google Scholar, M. W. G. G. Nature. 1990; PubMed Scopus Google Scholar, Y. K. E.A. A. Orkin S.H. 1993; PubMed Google Scholar), and not to a single A. M. M. G. L. C. Orkin S.H. C. Proc. Natl. Acad. Sci. A. 1992; PubMed Scopus Google Scholar). factors may (e.g. are also expressed at selected the hematopoietic such as cells of the K. H. H. Y. M. Google Scholar) and the of the K. Moore D.D. Defler B. Science. 1992; 258: 808-812Crossref PubMed Scopus (375) Google Scholar). is a and a of cellular the of transcription factors at binding or target genes is the of with (or binding often in a single cell type. in LCRs are recognized by the erythroid H. Orkin S.H. Nature. 1993; PubMed Scopus Google Scholar), but also by as as Proc. Natl. Acad. Sci. A. 1993; PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar, K. A. Proc. Natl. Acad. Sci. A. PubMed Scopus Google Scholar). a important in the and promoter is by both an erythroid and the Cell. 1993; PubMed Scopus Google Scholar). the in binding of to an the in or is an and it regulatory in pathways or is a of are and in of Transcription in of a lineage-specific transcription and binding in genes expressed in a cell-specific is a for the as a Although of in cells on the of a transcription to a in of binding a for a to which gene in stem cells and of J. Full Text PDF PubMed Google Scholar) has 1). is that in the of a transcription to a of the hematopoietic lineage in the As are with the that factors a in lineage as to genes to the critical In the of the high that it be a critical in erythroid cells, as GATA motifs are in regulatory elements of erythroid-expressed genes and the is the GATA in In of and erythroid the for cells are by with the M.J. G. Orkin S.H. Genes & Dev. PubMed Scopus Google Scholar). the lymphoid or cells, and K. M. A. A. Cell. Full Text PDF PubMed Scopus Google Scholar) and cells of hematopoietic and lymphoid J. H. Science. PubMed Scopus Google Scholar). a gene with in hematopoietic lineages and aberrantly activated gene in is for erythroid development also for some aspects of R. Orkin S.H. Nature. PubMed Scopus Google of some expressed factors in For of the gene at an but not with development of in which it is expressed G. D. A.M. van M. van M. A. C. Cell. Full Text PDF PubMed Scopus Google Scholar, Y. H. Cell. Full Text PDF PubMed Scopus Google Scholar). of the in of at the yolk sac of that of or M.J. Cell. Full Text PDF PubMed Scopus Google at the of the or be to hematopoiesis progenitor at the fetal is of K. S.H. Cell. 1991; Full Text PDF PubMed Scopus Google Scholar). Although erythroid and lymphoid cells are are as the of an are of a of a required in (or as cells a hematopoietic to that cellular G. M.J. M. F. Orkin S.H. Nature. PubMed Scopus Google some cell-restricted transcription factors to be required lineage commitment. of of on globin expression in are ( in evidence that of the gene in cells globin Y. Proc. Natl. Acad. Sci. A. PubMed Scopus Google Scholar). this hematopoietic of is for of to ( in the is expressed of its a of transcription of the adult gene A. and H. in the of in a target is by a to of to be of lineage selection or at an the study of developmental is gene or may this H. H. K. Science. PubMed Scopus Google Scholar). analysis and in of cells be to hematopoietic development in the is to the G. M.J. M. F. Orkin S.H. Nature. PubMed Scopus Google Scholar). functional may a in to a marked in a lineage in which the is expressed be used as evidence in The lineage for selected factors in hematopoiesis are in Transcription and a cell a single of is a in of suggests that growth factors for and proliferation of and that lineage decisions are through of in the of and and the of lymphoid in are with the not that lineage the in which of a in progenitor cells the additional evidence for the of such factors in controlling commitment. it is to that of a single transcription a cell to its an or lymphoid of lineages of a HSCs or is in is that functional of hematopoietic transcription factors must be considered in the of a cellular of in the cell expression of evidence for an on lineage A. J. 1992; PubMed Scopus Google Scholar). lineage by expression of or and by of cells to J. 1993; PubMed Google Scholar). In this the of H. Cell. Full Text PDF PubMed Scopus Google Scholar). The an as in the of L. Orkin S.H. F. Scholar). The of and in of cells that GATA factors are with respect to this and may a basis for in in this aspects of the cell-restricted factors are cell-specific and to activate an developmental how are lineages to are cell-restricted factors with cell-specific as is that lineage is by a of evidence in of this is of transcription factors is of some genes in cells both and T. T. A. Genes & Dev. 1993; PubMed Scopus Google Scholar). evidence suggests that of its and may of a critical for gene G. A. Genes & Dev. PubMed Scopus Google Scholar). The for a of factors is by transcription In some this such as that of with P.A. H. Orkin S.H. Proc. Natl. Acad. Sci. A. 1993; PubMed Scopus Google Scholar) or with L. W. R. Cell. PubMed Scopus Google Scholar), with H. A. J. R. Proc. Natl. Acad. Sci. A. PubMed Scopus Google Scholar), and with M.J. McKercher S.R. Maki R.A. Cell. 1992; PubMed Scopus Google Scholar). of functional may also cell-restricted such as and or a cell-restricted and such as and ( and H. Cell. in the of and the of a cell-restricted factors be the to are cell-specific factors with cell-specific recent a In the of erythroid to the to with which is by to control M.J. G. Orkin S.H. Genes & Dev. PubMed Scopus Google Scholar). in the cell is by or J. 1993; PubMed Google Scholar). developmental of cells of or the GATA Orkin S.H. Cell. PubMed Google Scholar). These for erythroid or by GATA the required for of cells to the DNA-binding of or M. J. Orkin S.H. Cell. PubMed Google Scholar). As that of may be of for in or the DNA-binding functions binding a with recent evidence through this The of the DNA-binding C. Orkin S.H. Proc. Natl. Acad. Sci. A. 1991; PubMed Scopus Google Scholar) is with the of the of GATA factors in expression of lineage-specific may reflect expression rather functional in the and is to selection a evidence that of is also by of of cells by the of gene is by of A. J. 1992; PubMed Scopus Google Scholar). of expression of is in the erythroid lineage and in A. M. M. G. L. C. Orkin S.H. C. Proc. Natl. Acad. Sci. A. 1992; PubMed Scopus Google Scholar). has been to for of it lymphoid K. M. A. A. Cell. Full Text PDF PubMed Scopus Google Scholar). that in cells the factors for lineages each the expression of the genes be as of a are Although the by which regulatory are to be of of target genes of and of factors are to the decisions of hematopoietic it a to in the of cell Full Text PDF PubMed Scopus Google Scholar, Genes & Dev. PubMed Scopus Google Scholar) may additional in which to the functions of hematopoietic transcription