©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Transcription Factors and Hematopoietic Development (*)

Stuart H. Orkin (§)

From the Division of Hematology/Oncology, Children's Hospital, Dana Farber Cancer Institute, Department of Pediatrics, Harvard Medical School and the Howard Hughes Medical Institute, Boston, Massachusetts 02115

INTRODUCTION
Cis-regulatory Motifs and Transcription Factors
Knockouts and in Vivo Roles of Transcription Factors in Hematopoietic Cells
Hematopoietic Transcription Factors and Lineage Commitment
Reciprocal Relationships and Lineage Selection
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES


INTRODUCTION

Hematopoiesis 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). (^1)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(1, 2) .

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 Factors

Diverse 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(3, 4) . 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(4) . Among lymphoid-expressed genes, promoter (or enhancer) motifs recognized by Ikaros(5) , NF-kappaB proteins, Oct-1 and Oct-2(6, 7) , E2A(8) , and the high mobility group (HMG) factors LEF-1 and TCF-1 (9, 10) have been identified. In myeloid-expressed genes, binding motifs recognized by PU.1(11) , AML1 (or runt)(12) , and C/EBPbeta (13) have been commonly noted.



For each type of binding motif in these lineages, cell-enriched nuclear proteins have been identified. For example, in erythroid cells, the factors GATA-1 and NF-E2 predominate as the GATA-binding and AP-1/NF-E2-binding proteins(14, 15) . In lymphoid cells, GGGAA elements are recognized by Ikaros and its isoforms, as well as members of the NF-kappaB family(16) ; E-boxes are bound by E2A products (E12/47) and octamer sequences by Oct-2. As is evident from Table 1, the cell-specific transcription factors identified do not fall within a single protein class, that is factors of two different zinc-finger classes, bHLH, ets, paired box, and myb families are represented. Thus, preconceptions about the kinds of regulatory factors controlling cell-specific gene expression in a particular cell type would be misleading.

Though it is perhaps not surprising, no single cis-element appears sufficient to establish cell-specific gene expression. For example, erythroid targeting of transgenes in mice requires the combination of at least two motifs of the LCR cores(17) . This alone suggests that cooperative interactions between transcriptional factors are essential in establishing distinct patterns of gene expression (see below). Also, virtually none of the lineage-specific factors are, indeed, restricted to a single cell type. For example, GATA-1, which appears to interact with cis-elements of nearly all erythroid-expressed genes, is also expressed in mast cells, eosinophils, megakaryocytes(18, 19, 20) , and progenitors not yet committed to a single pathway(21) . Moreover, though factors may appear exquisitely hematopoietic-specific (e.g. GATA-1, Ikaros), they are also expressed at selected sites outside the hematopoietic system, such as Sertoli cells of the testis (GATA-1) (22) and the corpus striatum of the brain (Ikaros)(5) . Thus, specificity is a relative concept, and only a combination of components can establish ultimate cellular identity.

A vexing problem encountered when considering the role of individual transcription factors at particular binding sites or target genes is the multiplicity of proteins with similar (or identical) DNA binding specificity often found in a single cell type. AP-1 sequences in LCRs are recognized by the erythroid complex NF-E2 (a p45/p18 heterodimer) (15) , but also by diverse fos/jun family members, as well as ubiquitous -45 NF-E2-related proteins(23, 24, 25) . Likewise, a functionally important CACCC sequence in the human and mouse beta-globin promoter is bound by both an erythroid Krüppel-like protein (EKLF) and the ubiquitous factor Sp1(26) . Whether the in vitro binding of multiple proteins to an element reflects the in vivo situation or is an artifact and if it conveys regulatory significance in fine-tuning transcriptional pathways or is merely a relic of evolution are uncertain.


Knockouts and in Vivo Roles of Transcription Factors in Hematopoietic Cells

The discovery of a lineage-specific transcription factor and cognate binding sites in various genes expressed in a cell-specific manner is only a prerequisite for considering the factor as a candidate regulator. Although transactivation assays of promoter/reporter constructs in heterologous cells offer one perspective on the potential roles of a transcription factor, they fail to provide a relevant in vivo context.

The complexity of proteins binding a given motif begs for a genetic solution, one to which gene targeting in mouse embryonic stem (ES) cells and generation of knockout animals (27) has contributed substantially (Table 1). It is satisfying that in several instances, the knockout of a lineage-restricted transcription factor leads to a selective loss of the relevant hematopoietic lineage in the animal. As such, these findings are compatible with the view that these factors play a role in lineage determination as opposed to merely regulating genes subsequent to the critical decisions. In the case of GATA-1 the presumption was initially high that it would be a critical regulator in erythroid cells, as GATA motifs are consistently found in regulatory elements of erythroid-expressed genes and the protein is the most abundant GATA factor in these cells. In vivo, loss of GATA-1 prevents primitive and definitive erythroid development, although the consequences for definitive cells are blunted by partial redundancy with the related factor, GATA-2(28) . Likewise, mice missing the lymphoid factor Ikaros lack T- or B-lymphoid cells, and their precursors (29) and PU.1-null mice lack cells of disparate hematopoietic lineages, myeloid and lymphoid cells(30) . tal-1/SCL, a gene normally coexpressed with GATA-1 in hematopoietic lineages and aberrantly activated gene in acute T-lymphocytic leukemia, is necessary for erythroid development and, very likely, also for some aspects of myelopoiesis(31) .

More surprisingly, loss of some broadly expressed factors results in lineage-selective deficits. For example, targeted mutation of the E2A gene blocks B-lymphopoiesis at an early stage but does not interfere with development of other tissues in which it is normally expressed (32, 33) . Also, loss of the tal-1/SCL-associated LIM protein rbtn2 results in selective failure of erythropoiesis at the yolk sac stage, reminiscent of that seen upon inactivation of GATA-1 or tal-1/SCL(34) .

Defects at the level of the HSC or early progenitors would be expected to impair hematopoiesis across all lineages. A progenitor defect at the definitive stage (i.e. fetal liver) is evident upon loss of c-myb(35) . Although erythroid and myeloid lymphoid cells are affected, megakaryocytes (which are commonly viewed as the products of an erythroid/myeloid progenitor) are spared. Loss of GATA-2 offers a clear example of a factor required in progenitors (or HSCs), as GATA-2-null cells exhibit a broad hematopoietic deficit, most likely reflecting inadequate responsiveness to cytokines that promote cellular proliferation(36) .

Conversely, some cell-restricted transcription factors appear to be required only after lineage commitment. Effects of loss of p45 NF-E2 on globin expression in vivo are far milder than anticipated, (^2)despite evidence that retroviral inactivation of the gene in mouse erythroleukemia cells prevents globin expression(37) . Nonetheless, this hematopoietic subunit of NF-E2 is essential for maturation of megakaryocytes (the precursors to platelets). (^3)Though the CACCC-binding protein EKLF is expressed throughout all stages of erythropoiesis, its loss produces a stage-specific, gene-selective deficiency: failure of adequate transcription of the adult beta-globin gene^4. Thus, even in the face of multiple CACCC-binding proteins in vivo, a dedicated target is discernible by a genetic test.

Limitations to interpretation of knockout experiments need to be made explicit. First, if loss of function blocks lineage selection or maturation at an early stage, the study of later developmental events is compromised. Tissue-restricted gene inactivation using Flp or Cre recombinases may circumvent this obstacle(38) . Meanwhile, chimera analysis and in vitro differentiation of homozygous ES cells can be employed to examine hematopoietic development in situations where the deficit is lethal to the intact animal(36) . Second, functional redundancy may obscure a legitimate in vivo role. Thus, failure to observe a marked phenotype in a lineage in which the factor is expressed cannot be used as strong evidence against in vivo participation. The lineage requirements for selected factors in hematopoiesis are illustrated in Fig. 1.


Figure 1: Transcription factors essential for hematopoietic development. HSC, pluripotent hematopoietic stem cell; Ly, lymphoid progenitor; M/E, myeloerythroid progenitor.




Hematopoietic Transcription Factors and Lineage Commitment

How a multipotential cell chooses a single pathway of differentiation is a central problem in hematopoiesis. A wealth of data suggests that growth factors principally allow for survival and proliferation of progenitors and that lineage decisions are exercised through transcriptional mechanisms. Loss of embryonic erythropoiesis in the absence of GATA-1, tal-1/SCL, and rbtn2, and the absence of lymphoid precursors in Ikaros-null mice are consistent with the view (but do not prove) that these proteins establish lineage decisions. On the other hand, experiments in which forced overexpression of a particular factor in progenitor cells diverts the differentiation pattern can provide additional evidence for the role of such factors in controlling commitment. While it is perhaps unrealistic to anticipate that introduction of a single transcription factor into a heterologous (non-hematopoietic) cell will lead to its conversion into an erythroblast or lymphoid precursor, induction of specific lineages following introduction of a factor into immortal HSCs or progenitors is reasonable. A caveat inherent in these experiments is that functional attributes of hematopoietic transcription factors must be considered in the context of a preexisting cellular milieu.

Induction of megakaryocyte differentiation in the murine myeloid cell line 416B upon forced expression of GATA-1 provides persuasive evidence for an influence on lineage commitment(39) . This lineage reprogramming was similarly provoked by expression of GATA-2 or GATA-3 and by exposure of cells to 5-azacytidine(40) . In this latter respect, the phenomenon resembles myogenic conversion of fibroblasts(41) . The 416B experiments raise an apparent contradiction, as megakaryocytes develop normally in the absence of GATA-1(42) . The similar activities of GATA-2 and GATA-3 in promoting megakaryocytic differentiation of 416B cells suggest that GATA factors are largely interchangeable with respect to this pathway and may provide a basis for in vivo redundancy in this lineage.

Two aspects warrant discussion. First, if none of the cell-restricted factors are uniquely cell-specific and sufficient to activate an entire developmental program, how are individual lineages specified? Second, to what extent are cell-restricted factors endowed with cell-specific properties (such as activation domains)? It is commonly proposed that lineage determination is regulated by a combinatorial matrix of factors, although published evidence in support of this model is scarce. A clear example of cooperation between transcription factors is activation of some myeloid-specific genes in non-hematopoietic cells expressing both c-myb and C/EBPbeta(43) . Recent evidence suggests that phosphorylation of C/EBPbeta derepresses its activation potential and may constitute part of a critical decision for myeloid gene expression(44) . The need for a combination of two factors is perhaps most dramatically illustrated by multicomponent transcription factor complexes. In some instances, this involves stable dimer formation such as that of p45 NF-E2 with p18 NF-E2 (45) or tal-1 with E2A proteins(46) , tal-1/E2A with rbtn2(47) , and PU.1 with NF-EM5 (48) . Less stable interactions, still of functional relevance, may also occur between two cell-restricted factors, such as GATA-1 and EKLF, or between a cell-restricted and ubiquitous factors, such as GATA-1 and Sp1. (^5)Through the multiplicity of dimer formation and protein-protein interactions the transcriptional impact of a relatively few cell-restricted factors can be greatly amplified.

In considering the second question, to what extent are cell-specific factors endowed with cell-specific properties, recent data pose a dilemma. In the absence of GATA-1, definitive erythroid precursors develop to the proerythroblast stage, apparently due to partial redundancy with GATA-2, which is elevated by >50-fold (relative to control proerythroblasts)(28) . Moreover, in the 416B cell assay megakaryocytic differentiation is fostered by GATA-1, -2, or -3(40) . Finally, partial developmental rescue of GATA-1 minus ES cells occurs following introduction of various constructs, including GATA-3 or the non-hematopoietic GATA protein GATA-4(49) . These findings suggest little intrinsic specificity for erythroid or megakaryocytic differentiation imparted by GATA-1 versus other GATA proteins. Surprisingly, the minimal domain required for megakaryocytic differentiation of 416B cells maps to the DNA-binding domain of GATA-1 or GATA-2(50) . As such, these results suggest that activation domains of GATA-1 may be of less significance for in vivo function than supposed or the DNA-binding domain confers functions beyond DNA binding alone, a hypothesis compatible with recent evidence demonstrating protein-protein interactions mediated through this region. The extraordinary sequence divergence of GATA-1 across species outside the DNA-binding domain (51) is compatible with the results of these biological assays. Hence, the roles of GATA factors in promoting expression of lineage-specific targets may largely reflect their own restricted expression patterns rather than inherent functional differences in the proteins.


Reciprocal Relationships and Lineage Selection

Plasticity is inherent to hematopoiesis. Lineage selection implies a choice between alternate pathways. Indirect evidence hints that activation of one pathway is also accompanied by suppression of another. Upon megakaryocytic differentiation of 416B cells by GATA-1 the appearance of megakaryocyte-specific gene products is paralleled by suppression of myeloid markers(39) . During differentiation of cultured normal progenitors, expression of GATA-1 is up-regulated in the erythroid lineage and reciprocally extinguished in committed myeloid precursors(21) . Finally, Ikaros has been suggested to provide negative signals for differentiation of myeloerythroid lineages, while it promotes lymphoid development(29) . We can speculate, therefore, that in cells beyond the multipotential stage factors specific for different lineages negatively regulate each other. Accordingly, the expression of the desired genes would be ensured, as those of a different pathway are kept silent. Although the precise mechanisms by which these regulatory events are achieved remain to be defined, cross-regulation of lineage-restricted factors, repression of target genes of alternative lineages, and on/off switches of lineage-restricted factors are likely to underlie the binary fate decisions of hematopoietic progenitors. Though it remains a challenge to establish these phenomena in vivo, the availability of new multipotential cell lines(52, 53) may provide additional systems in which to test the biological functions of hematopoietic transcription factors.


FOOTNOTES

*
This minireview will be reprinted in the 1995 Minireview Compendium, which will be available in December, 1995.

§
Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Division of Hematology/Oncology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-735-7910; Fax: 617-735-7262.

(^1)
The abbreviations used are: HSC, hematopoietic stem cell; LCR, locus control region; ES, embryonic stem; bHLH, basic helix-loop-helix.

(^2)
R. Shivdasani et al., manuscript in preparation.

(^3)
R. Shivdasani et al., manuscript in preparation.

(^4)
A. Perkins, A. Sharpe, and S. H. Orkin, manuscript submitted.

(^5)
M. Merika and S. H. Orkin, Mol. Cell. Biol., in press.


ACKNOWLEDGEMENTS

I thank Leonard Zon and Merlin Crossley for helpful discussions during preparation of this review.


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