The myocyte enhancer factor 2 (MEF2) transcription factor acts as a lynchpin in the transcriptional circuits that control cell differentiation and organogenesis. The spectrum of genes activated by MEF2 in different cell types depends on extracellular signaling and on co-factor interactions that modulate MEF2 activity. Recent studies have revealed MEF2 to form an intimate partnership with class IIa histone deacetylases, which together function as a point of convergence of multiple epigenetic regulatory mechanisms. We review the myriad roles of MEF2 in development and the mechanisms through which it couples developmental, physiological and pathological signals with programs of cell-specific transcription. IntroductionThe formation of specialized cell types and their integration into different tissues and organs during development requires the interpretation of extracellular signals by components of the transcriptional apparatus and through the subsequent activation of cascades of regulatory and structural genes by combinations of widely expressed and cell type-restricted transcription factors. The myocyte enhancer factor 2 (MEF2) transcription factor plays central roles in the transmission of extracellular signals to the genome and in the activation of the genetic programs that control cell differentiation, proliferation, morphogenesis, survival and apoptosis of a wide range of cell types.Recent studies in mice and fruit flies have revealed upstream signaling systems that control MEF2 expression and activity, and downstream effector genes that mediate the actions of MEF2 throughout development, as well as in adult tissues. These studies point to MEF2 having a central role as a mediator of epigenetic regulatory mechanisms that involve changes in chromatin configurations and the modulation of microRNAs. Here we review the mechanisms that govern MEF2 activity and discuss commonalities in the functions of MEF2 as a regulator of differentiation of diverse cell types. The requirement of MEF2 for the differentiation of seemingly unrelated cell types from multiple lineages points to MEF2 being a key component of the regulatory codes that are required for metazoan development.The MEF2 family MEF2 proteins belong to the evolutionarily ancient MADS (MCM1, agamous, deficiens, SRF) family of transcription factors (Shore and Sharrocks, 1995). Saccharomyces cerevisiae, Drosophila and Caenorhabditis elegans possess a single Mef2 gene, whereas vertebrates have four -Mef2a, b, c and d. The N-termini of MEF2 factors contain a highly conserved MADS-box and an immediately adjacent motif termed the MEF2 domain ( Fig. 1), which together mediate dimerization, DNA binding, and co-factor interactions (Black and Olson, 1998;McKinsey et al., 2002a). The C-terminal regions of MEF2 proteins, which function as transcriptional activation domains, are subject to complex patterns of alternative splicing and are divergent among family members (Fig. 1).MEF2 proteins bind to the consensus DNA sequence YTA(A/T) 4 TAR as homo-or heterodimers (Andres e...

Histone deacetylases (HDACs) tighten chromatin structure and repress gene expression through the removal of acetyl groups from histone tails. The class I HDACs, HDAC1 and HDAC2, are expressed ubiquitously, but their potential roles in tissue-specific gene expression and organogenesis have not been defined. To explore the functions of HDAC1 and HDAC2 in vivo, we generated mice with conditional null alleles of both genes. Whereas global deletion of HDAC1 results in death by embryonic day 9.5, mice lacking HDAC2 survive until the perinatal period, when they succumb to a spectrum of cardiac defects, including obliteration of the lumen of the right ventricle, excessive hyperplasia and apoptosis of cardiomyocytes, and bradycardia. Cardiac-specific deletion of either HDAC1 or HDAC2 does not evoke a phenotype, whereas cardiac-specific deletion of both genes results in neonatal lethality, accompanied by cardiac arrhythmias, dilated cardiomyopathy, and up-regulation of genes encoding skeletal muscle-specific contractile proteins and calcium channels. Our results reveal cell-autonomous and non-cell-autonomous functions for HDAC1 and HDAC2 in the control of myocardial growth, morphogenesis, and contractility, which reflect partially redundant roles of these enzymes in tissue-specific transcriptional repression.[Keywords: Heart development; histone deacetylase; transcription] Supplemental material is available at http://www.genesdev.org.

The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and ketogenesis become major energy sources. Here, we show that fibroblast growth factor 21 (FGF21), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferatoractivated receptor ␥ coactivator protein-1␣ (PGC-1␣), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1␣ expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship between FGF21 and PGC-1␣ and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.lipid metabolism ͉ liver ͉ gluconeogenesis ͉ glycogenolysis ͉ ketogenesis I n mammals, the liver plays a crucial role in maintaining systemic energy balance during fasting and starvation through coordinate effects on carbohydrate and lipid metabolism. During the early stages of fasting, the liver mobilizes glucose from its glycogen stores. As fasting progresses and glycogen reserves are depleted, the liver oxidizes fat to provide both energy for gluconeogenesis and substrate for ketogenesis. This synchronization of hepatic lipid and carbohydrate metabolism is critical for the normal fasting response; disruption of either one of these pathways has profound effects on the other (1-4).Hormones such as glucagon, catecholamines, and glucocorticoids have important roles in controlling substrate utilization and maintaining energy balance during fasting. Recently, the hormone fibroblast growth factor 21 (FGF21) was shown to be induced in the liver during fasting (5-7). FGF21 is an unusual FGF family member in that it lacks the conventional heparinbinding domain (8) and thus can diffuse away from its tissue of origin and function as a hormone. FGF21 signals through cell-surface receptors composed of classic FGF receptors complexed with ␤-klotho, a membrane-spanning protein (9-14). Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor ␣ (PPAR␣) (5-7). FGF21 has diverse metabolic actions that include stimulating hepatic fatty acid oxidation and ketogenesis (5,6,15) and blocking the growth hormone signaling pathway (16). FGF21 also sensitizes mice to torpor, a short-term hibernation-like state of regulated hypothermia (6). Pharmacologic administration of FGF21 to insulin-resistant rodents and monkeys improves glucose tolerance and reduces plasma insulin and triglyceride concentrations (15,17).Peroxisome proliferator-activated receptor ␥ coactivator protein-1␣ (PGC-1␣) is a transcriptional coactivator ...