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Transcriptional Control of Erythropoiesis: Emerging Mechanisms and Principles

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Transcriptional Control of Erythropoiesis: Emerging Mechanisms and Principles Oncogene (2007) 26, 6777–6794 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Transcriptional control of erythropoiesis: emerging mechanisms and principles S-I Kim and EH Bresnick Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Medical Sciences Center, Madison, WI, USA Transcriptional networks orchestrate fundamental bio- leads to the development and progression of specific logical processes, including hematopoiesis, in which leukemias (Gilliland et al., 2004; Rosenbauer and hematopoietic stem cells progressively differentiate into Tenen, 2007). Whereas the focus of this review is on specific progenitors cells, which in turn give rise to the transcriptional mechanisms that underlie red blood cell diverse blood cell types. Whereas transcription factors development, the process termed erythropoiesis, the recruit coregulators to chromatin, leading to targeted fundamental principles emerging from these studies chromatin modification and recruitment of the transcrip- have broad relevance in diverse systems. tional machinery, many questions remain unanswered Since a host of transcriptional regulators and signal- regarding the underlying molecular mechanisms. Further- ing pathways that control erythropoiesis have already more, how diverse cell type-specific transcription factors been identified, major efforts are focused on elucidating function cooperatively or antagonistically in distinct the underlying molecular mechanisms. Canonical trans- cellular contexts is poorly understood, especially since criptional mechanisms involve sequence-specific binding genes in higher eukaryotes commonly encompass broad of trans-acting factors (transcription factors) to DNA chromosomal regions (100 kb and more) and are littered motifs termed cis-elements in chromatin, followed by with dispersed regulatory sequences. In this article, we recruitment of additional regulatory proteins (coregula- describe an important set of transcription factors and tors) via direct protein–protein interactions (Kadonaga, coregulators that control erythropoiesis and highlight 2004). Coregulators typically exist as large multiprotein emerging transcriptional mechanisms and principles. It is complexes and either mediate activation (coactivators) not our intent to comprehensively survey all factors or repression (corepressors) (Bresnick et al., 2006; Lee implicated in the transcriptional control of erythropoiesis, and Workman, 2007). Certain coregulator complexes but rather to underscore specific mechanisms, which have mediate both activation and repression in a context- potential to be broadly relevant to transcriptional control dependent manner (Crispino et al., 1999; Rogatsky in diverse systems. et al., 2002). It is instructive to classify coregulators as Oncogene (2007) 26, 6777–6794; doi:10.1038/sj.onc.1210761 chromatin remodeling or chromatin modifying enzymes, based on whether they lack or have the capacity, Keywords: erythropoiesis; chromatin; transcription; respectively, to post-translationally modify histones that epigenetic mark form the octameric core of the nucleosome. Chromatin remodeling enzymes utilize ATP in a biochemical reaction that modifies nucleosome structure and alters nucleosome positioning (Saha et al., 2006). Since chromatin can be a formidable impediment to trans- Introduction cription factor access to nucleosomal DNA (Hager et al., 1993), remodeling enzymes regulate transcription The differentiation of hematopoietic stem cells (HSCs) factor access to chromatin. In addition, as nucleosomal into specific progenitor cells, and ultimately into diverse filaments condense into higher-order structures (Felsen- blood cell types, is intricately controlled by intercellular feld and Groudine, 2003), remodeling enzyme-depen- and intracellular signaling mechanisms (Kaushansky, dent chromatin structure transitions almost certainly 2006; Mikkola and Orkin, 2006). These mechanisms regulate higher-order chromatin folding. commonly target transcriptional regulators, which in In contrast to remodeling enzymes, chromatin mod- turn establish complex transcriptional networks. Dysre- ifying enzymes catalyse a plethora of histone post- gulation of signaling and transcriptional mechanisms translational modifications, including acetylation, methylation, phosphorylation, ubiquitination, sumoyla- tion and ADP ribosylation, which are termed epigenetic Correspondence: Dr EH Bresnick, Department of Pharmacology, marks (Allfrey et al., 1964; Fischle et al., 2003). Such University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, 385 Medical Sciences Center, Madison, WI 53706, modifications are particularly prevalent within the USA. conserved N-terminal core histone tails, but also occur E-mail: [email protected] within the central globular domain (Berger, 2007; Transcriptional control of erythropoiesis S-I Kim and EH Bresnick 6778 Bernstein et al., 2007; Kouzarides, 2007). In certain subdomains (Forsberg et al., 2000b; Kiekhaefer et al., cases, epigenetic marks regulate chromatin structure 2002; Bulger et al., 2003). directly. For example, histone acetylation counteracts Recent work with the b-globin system has provided higher-order chromatin folding with purified, reconsti- important insights into perhaps the most fundamental tuted chromatin templates in vitro (Tse et al., 1998). In aspect of transcriptional control, how trans-acting addition, specific epigenetic marks function as ligands to factors recognize and occupy functional sites in chro- attract additional regulatory factors to the chromatin matin (Bresnick et al., 2006). cis-elements that mediate (Marmorstein, 2001; Fischle et al., 2003). Protein modules transcription factor binding to chromatin are typically present in transcriptional regulatory factors, including the short sequence motifs of 5–10 base pairs, and such bromodomain that recognizes acetyl-lysine (Dhalluin motifs occur at a high frequency throughout genomes, et al., 1999; Jacobson et al., 2000; Owen et al., 2000), simply based on the statistical distribution of nucleo- bind histones bearing specific epigenetic marks. tides. The development of the chromatin immunopreci- In addition to the canonical mechanisms noted above, pitation (ChIP) assay to measure protein occupancy at certain transcription factors retain functionality upon endogenous chromatin sites in living cells has provided a disabling their sequence-specific DNA binding activity, powerful technology for analysing how transcription indicating the importance of DNA binding-independent factors select functional sites in the genome (Orlando mechanisms in certain contexts (Reichardt et al., 1998; et al., 1997; Johnson and Bresnick, 2002; Im et al., 2004; Porcher et al., 1999; Tuckermann et al., 1999). Given Kirmizis and Farnham, 2004). that transcriptional complexes assembled at promoters Extensive analyses of chromatin occupancy by the and distal regulatory elements, such as enhancers and hematopoietic zinc-finger protein GATA-1, which is locus control regions (LCRs), often contain a large discussed below in detail, revealed that only a small cohort of factors that engage in a multitude of protein– fraction of high-affinity GATA motifs are occupied in protein interactions (Bresnick et al., 2006; Dean, 2006), chromatin (Johnson et al., 2002, 2007; Grass et al., 2003, it seems reasonable that certain transcription factors can 2006; Pal et al., 2004b; Im et al., 2005; Martowicz et al., integrate into such complexes without a critical DNA 2005). Intriguingly, the cell type-specific coregulator binding activity requirement. Such tethering might also Friend of GATA-1 (FOG-1), which mediates certain permit stable transcription factor interactions at low- biological functions of GATA-1 (Tsang et al., 1997, affinity motifs, which otherwise would not be occupied. 1998), facilitates GATA-1 occupancy at certain, but not However, considerably less is known about transcrip- all, chromatin target sites (Letting et al., 2004; Pal et al., tion factor tethering mechanisms vs DNA binding- 2004a). We refer to this FOG-1 activity as chromatin dependent mechanisms. occupancy facilitator (COF) activity. Thus, mechanisms Important principles underlying transcriptional con- responsible for the selective recognition of a small subset trol in higher eukaryotes have regularly emerged from of motifs represent a crucial primary mode of transcrip- mechanistic studies on the regulation of the b-like globin tional control, and specific protein–protein interactions gene cluster, a commonly used model system to influence this decision-making process. Subsequent to elucidate cell type-specific and developmental-stage transcription factor occupancy of chromatin, a multi- specific transcriptional mechanisms (Bank, 2006; Bres- tude of regulatory events, including coregulator recruit- nick et al., 2006). Studies with this system have led to ment, coregulator-dependent chromatin structure multiple seminal discoveries including (1) the concept of transitions, dynamics of transcription factor and cor- an LCR, a transcriptional regulatory element that egulator interactions with the template, and interactions activates a linked gene proportional to template copy between these components and RNA Polymerase II (Pol number and independent of the chromosomal integra- II) dictate the magnitude and kinetics of the transcrip- tion site (Forrester et al., 1987; Grosveld et al., 1987); (2) tional response. identification of the founding member of the
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