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- logical processes, including hematopoiesis, in which hematopoietic stem cells progressively differentiate into specific progenitors cells, which in turn give rise to the diverse blood cell types. Whereas transcription factors recruit coregulators to chromatin, leading to targeted chromatin modification and recruitment of the transcrip- tional machinery, many questions remain unanswered regarding the underlying molecular mechanisms. Further- more, how diverse cell type-specific transcription factors function cooperatively or antagonistically in distinct cellular contexts is poorly understood, especially since genes in higher eukaryotes commonly encompass broad chromosomal regions (100kb and more) and are littered with dispersed regulatory sequences. In this article, we describe an important set of transcription factors and coregulators that control erythropoiesis and highlight emerging transcriptional mechanisms and principles. It is not our intent to comprehensively survey all factors implicated in the transcriptional control of erythropoiesis, but rather to underscore specific mechanisms, which have potential to be broadly relevant to transcriptional control in diverse systems. Oncogene (2007) 26, 6777–6794; doi:10.1038/sj.onc.1210761 Keywords: erythropoiesis; chromatin; transcription; epigenetic mark Introduction The differentiation of hematopoietic stem cells (HSCs) into specific progenitor cells, and ultimately into diverse blood cell types, is intricately controlled by intercellular and intracellular signaling mechanisms (Kaushansky, 2006; Mikkola and Orkin, 2006). These mechanisms commonly target transcriptional regulators, which in turn establish complex transcriptional networks. Dysre- gulation of signaling and transcriptional mechanisms leads to the development and progression of specific leukemias (Gilliland et al., 2004; Rosenbauer and Tenen, 2007). Whereas the focus of this review is on transcriptional mechanisms that underlie red blood cell development, the process termed erythropoiesis, the fundamental principles emerging from these studies have broad relevance in diverse systems. Since a host of transcriptional regulators and signal- ing pathways that control erythropoiesis have already been identified, major efforts are focused on elucidating the underlying molecular mechanisms. Canonical trans- criptional mechanisms involve sequence-specific binding of trans-acting factors (transcription factors) to DNA motifs termed cis-elements in chromatin, followed by recruitment of additional regulatory proteins (coregula- tors) via direct protein–protein interactions (Kadonaga, 2004). Coregulators typically exist as large multiprotein complexes and either mediate activation (coactivators) or repression (corepressors) (Bresnick et al., 2006; Lee and Workman, 2007). Certain coregulator complexes mediate both activation and repression in a context- dependent manner (Crispino et al., 1999; Rogatsky et al., 2002). It is instructive to classify coregulators as chromatin remodeling or chromatin modifying enzymes, based on whether they lack or have the capacity, respectively, to post-translationally modify histones that 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- cription factor access to nucleosomal DNA (Hager et al., 1993), remodeling enzymes regulate transcription factor access to chromatin. In addition, as nucleosomal filaments condense into higher-order structures (Felsen- feld and Groudine, 2003), remodeling enzyme-depen- dent chromatin structure transitions almost certainly regulate higher-order chromatin folding. In contrast to remodeling enzymes, chromatin mod- ifying enzymes catalyse a plethora of histone post- translational modifications, including acetylation, methylation, phosphorylation, ubiquitination, sumoyla- tion and ADP ribosylation, which are termed epigenetic marks (Allfrey et al., 1964; Fischle et al., 2003). Such modifications are particularly prevalent within the conserved N-terminal core histone tails, but also occur within the central globular domain (Berger, 2007; Correspondence: Dr EH Bresnick, Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, 385 Medical Sciences Center, Madison, WI 53706, USA. E-mail: ehbresni@wisc.edu Oncogene (2007) 26, 6777–6794 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc