Summary Genome-scale studies have revealed extensive, cell type-specific co-localization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B celllineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These locations serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. Together with analyses of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs.

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The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key players in a wide array of developmental processes. Over 240 HLH proteins have been identified to date in organisms ranging from the yeast Saccharomyces cerevisiae to humans (6). Studies in Xenopus laevis, Drosophila melanogaster, and mice have convincingly demonstrated that HLH proteins are intimately involved in developmental events such as cellular differentiation, lineage commitment, and sex determination. In yeast, HLH proteins regulate several important metabolic pathways, including phosphate uptake and phospholipid biosynthesis (19,67,112). In multicellular organisms, HLH factors are required for a multitude of important developmental processes, including neurogenesis, myogenesis, hematopoiesis, and pancreatic development (12,86,127,179). The purpose of this review is to examine the structure and functional properties of HLH proteins.E-box sites: elements mediating cell-type-specific gene transcription. Gene transcription of the immunoglobulin heavychain (IgH) gene has long been known to be regulated, in part, by a cis-acting DNA element known as the IgH intronic enhancer (109,156). By in vivo methylation protection assays, a number of sites were identified in both the IgH and the kappa light-chain gene enhancers which were specifically protected in B cells but not in nonlymphoid cells (41). These elements shared a signature motif which consisted of the core hexanucleotide sequence, CANNTG, and were subsequently dubbed E boxes (41). A total of five E-box elements are present in the IgH gene enhancer: E1, E2, E3, E4, and E5. The Ig kappa enhancer also contains three cannonical E boxes, designated E1, E2, and E3. E-box sites have been subsequently found in B-cell-specific promoter and enhancer elements, including a subset of Ig light-chain gene promoters, the IgH and Ig light-chain 3Ј enhancers, and, more recently, the 5 promoter (110,118,156).E-box elements have also been identified in promoter and enhancer elements that regulate muscle-, neuron-, and pancreas-specific gene expression. For example, in muscle, the muscle creatine kinase gene, acetylcholine receptor genes ␣ and ␦, and the myosin light-chain gene all require E-box elements for full activity (27,51,85). A number of genes whose expression is limited to the pancreas also require E-box sites for proper expression. The insulin and somatostatin genes, for example, contain E-box sites that, when multimerized, are sufficient to regulate pancreatic ␤-cell-specific gene expression (168). More recently, E-box regulatory sites have been identified in a number of neuron-specific genes, including the opsin, hippocalcin, beta 2 subunit of the neuronal nicotinic acetylcholine receptor, and muscarinic acetylcholine receptor genes (1, 21, 52, 125).E-box sites: cognate recognition sequence for HLH proteins. Two proteins, termed E12 and E47, were originally identified as binding to the E2/E5 site (65, 102). They have a region of homology with the Drosophila Daughterless protein, the...

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