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316 Part IV Disorders of Hematopoietic Cell Development

More recently, it has been identified that KLF1 promotes terminal specific regulators during early versus late erythroid differentiation or
erythroid maturation also in a noncell-autonomous fashion by regu- during yolk sac versus fetal liver/adult erythropoiesis is demonstrated.
lating expression of DNase IIα, in the central macrophage of fetal However, this does not exclude the involvement of some factors (i.e.,
liver erythroblastic islands thus facilitating digestion of the DNA of SCL, TEL) at both early and late stages of erythropoiesis. In fact,
engulfed pyrenocytes, in the central macrophage of the erythroblastic more recent studies on conditional knockouts have clarified that SCL
island present in mouse fetal liver. 525,526 exerts two different levels of control in the development of the hemo-
Intrinsic control of erythroid differentiation also is exerted by poietic system. First, SCL is required for the determination event that
genes that, until repressed, prevent terminal cell maturation. The induces one (or few) mesenchymal cell(s) to become a hematopoietic
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most studied of these genes is ID1, which as its name indicates, stem cell(s) in the early embryos. After this initial event has taken
inhibits differentiation along almost all mesenchymal cell lineages, place, its presence becomes dispensable, as demonstrated by the fact
including the erythroid lineage. 528,529 ID1 appears to act between that conditional SCL deletion in the adult animals impairs only
GATA1 and EKLF by preventing EKLF from executing its program. erythropoiesis and megakaryocytopoiesis. 197,538
Because common transcription factors are present in erythroid With information from innovative applications of molecular
and megakaryocytic cells, and bipotent erythroid/megakaryocytic approaches becoming available at a fast pace, the list of regulators
progenitors exist both in vitro (in the form of cell lines) and in with a biologic impact on hematopoiesis/erythropoiesis not only
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vivo, exciting insights regarding subtleties in the molecular control is continuously expanding but is starting to fill the gap between
of these two lineages by the same transcription factors have sur- the individual transcription factors and the epigenetic control of
faced. Modified gene-targeting strategy (“knockdown”) of GATA1 erythroid cells. Actively expressed genes are localized in areas on
uncovered a largely unanticipated role of this transcription factor in the chromosome in an open configuration. The DNA switch from
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the control of proliferation and maturation of megakaryocytes. In a closed to an open configuration is determined by the tightness of
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addition to GATA1, other important transcription factors essential its binding to the histones by which it is surrounded. A series of
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for terminal megakaryocytic development are NF-E2 and its enzymes regulates the chromosome configuration state by modifying
partner mafG. 531 either the DNA (cytosine methylation mediated by specific meth-
Nevertheless, the fact that several regulators are necessary for ylases) or the histones (e.g., histone acetyltransferase [HAT] and
primitive (yolk sac), as opposed to definitive (fetal liver and bone deacetylase [HDAC], polycomb repressive complexes). HAT exerts
marrow), erythropoiesis provides evidence that molecular control a positive control (promoting the formation of an open configura-
between these two hemopoietic sites is different and may include tion state), whereas methylases and HDAC exert a negative control
both ubiquitous and hematopoietic-specific factors. In fact, evidence (inducing a closed chromatin configuration state) on gene expression.
suggests that GATA1 transcription is differentially regulated in yolk Once the chromatin is in an open configuration state, appropriate
sac cells compared to fetal liver erythroid cells, with alternative enzymatic complexes (e.g., polymerases, spliceosomes) are recruited
promoter use and an additional intron element requirement for to the locus for appropriate expression to occur. Because of their
promoter activation in fetal liver cells. 532 ability to recognize specific DNA sequences, transcription factors play
In addition to transcription factors/oncogenes influencing an important role in the recruitment of the epigenetic and/or tran-
erythropoiesis, targeted ablation and naturally existing mutations scriptional protein machinery to a specific locus. The link between
of hematopoietic growth factor receptors, especially of the tyrosine epigenetic and transcriptional control of gene expression in erythroid
kinase family, have disclosed important insights into the control cells is emerging. The first global methylation status of erythroid cells
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of erythropoiesis. Whereas deletion of the vascular endothelial as they mature has been determined. The relationship between
growth factor (VEGF)/flk-1 receptor affects both endothelial and chromatin architecture and transcription factor occupancy in the loci
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533
hematopoietic development through its presumed presence in the encoding key erythrocyte membrane proteins has been established.
hemangioblast, the common endothelial/hematopoietic stem cell, In addition to binding GATA1, FOG-1 is also capable of binding
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mutations affecting the tyrosine kinase KIT receptor (present in NuRD, a complex that contains HDAC1. The multicomplex
hematopoietic cells) or of its ligand KL (present in stromal cells) GATA1/FOG-1/NuRD is responsible for appropriate activation/
seem to predominantly affect erythropoiesis in the fetal liver and repression of several erythroid specific genes, including the GATA2-
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the adult animal. Mice with KIT mutations (W mutations) leading GATA1 switch occurring at early stages of erythroid development.
to absence of or compromised kinase activity and steel mice with Recently, a complex formed by the class II HDAC HDAC5, GATA1,
543
mutations of KL have disproportionate and severe reduction of the EKLF, and ERK was identified in human erythroblasts. Based on
numbers of late erythroid progenitors, CFU-E, and differentiated the observation that this complex was not detected in megakaryocytes
534
erythroid precursors resulting in anemia. Studies showing cross- and that the function of class II HDAC is to chaperone other proteins
phosphorylation of EPOR following activation of KIT/KL signaling to the nucleus, this novel complex was defined as nuclear remodeling
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may be relevant to the effect. Mutations or targeted ablations of shuttle erythroid (NuRSERY). By balancing the level of GATA1
some downstream signaling substrates for KIT or other receptors and EKLF during terminal erythroid maturation, NuRSERY may
(i.e., SHP2 phosphatase or gp130) seem to produce a hematopoietic represent at least one of the mechanisms that links the extrinsic
picture not unlike the one produced by receptor mutations. 535,536 (ERK phosphorylation by KL) to the intrinsic (transcription factor
Taken together, these studies have significantly expanded our concentration) control of erythropoiesis.
understanding of the molecular basis of hematopoietic cell develop- Genome-wide analyses have recently detailed the sequence of
ment in general and of erythropoiesis in particular. The emerging epigenetic events that regulates the expression of erythroid specific
picture is that certain genes, such as SCL, are absolutely required for genes during the process of terminal erythroid maturation. Erythroid-
hematopoietic development, whereas other genes, such as GATA2, specific enhancers and promoters are already in an active configuration
c-Myb, CBF, TEL, and some downstream signal transducing mol- at the progenitor levels. 544,545 There is little difference in the enhancer
ecules such as gp30 and SHP2, are responsible for expansion and activation profile of fetal and adult erythroid progenitors. Surprisingly
maintenance of a normal pool of fetal liver and adult hematopoietic this difference is related to binding of cofactors, such as the interferon
progenitors. The participation of many of these molecules in multi- regulatory factors 2 and 6 that are essential for activation of adult
component molecular complexes with protein/protein and protein/ erythroid programs but not to binding of master erythroid regulators
DNA interactions (i.e., LM02/Lbd1/SCL/E2A/GATA), during the such as GATA1. During erythroid maturation, the expression of
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early proliferative stages of hematopoiesis may underlie their role in these genes is mainly regulated posttranscriptionally (mRNA stability
the proliferation and maintenance of immature progenitor/precursor and splicing and binding to the ribosome translational machinery).
pools in erythropoiesis. Other genes such as GATA1, its partner Erythroid-specific micro- 546,547 and long- 548,549 noncoding RNAs may
FOG-1, and EKLF are necessary to direct high levels of function play important roles in the posttranscriptional regulation of erythroid
of erythroid-specific genes in cells already committed to terminal genes at late stages of maturation. This regulation may represent
differentiation. Thus a hierarchical requirement in the expression of another layer of complexity. In fact, increased expression of LIN28B,