The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is currently uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via PGC1α and PPARα. Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a novel therapeutic strategy for disorders of lipid metabolism.

Histone methylation is crucial for regulating chromatin structure, gene transcription and the epigenetic state of the cell. LSD1 is a lysine-specific histone demethylase that represses transcription by demethylating histone H3 on lysine 4 (ref. 1). The LSD1 complex contains a number of proteins, all of which have been assigned roles in events upstream of LSD1-mediated demethylation 2-4 apart from BHC80 (also known as PHF21A), a plant homeodomain (PHD) finger-containing protein. Here we report that, in contrast to the PHD fingers of the bromodomain PHD finger transcription factor (BPTF) and inhibitor of growth family 2 (ING2), which bind methylated H3K4 (H3K4me3) 5,6 , the PHD finger of BHC80 binds unmethylated H3K4 (H3K4me0), and this interaction is specifically abrogated by methylation of H3K4. The crystal structure of the PHD finger of BHC80 bound to an unmodified H3 peptide has revealed the structural basis of the recognition of H3K4me0. Knockdown of BHC80 by RNA inhibition results in the de-repression of LSD1 target genes, and this repression is restored by the reintroduction of wild-type BHC80 but not by a PHD-finger mutant that cannot bind H3. Chromatin immunoprecipitation showed that BHC80 and LSD1 depend reciprocally on one another to associate with chromatin. These findings couple the function of BHC80 to that of LSD1, and indicate that unmodified H3K4 is part of the 'histone code' 7 . They further raise the possibility that the generation and recognition of the unmodified state on histone tails in general might be just as crucial as post-translational modifications of histone for chromatin and transcriptional regulation. © 2007 Nature Publishing GroupCorrespondence and requests for materials should be addressed to Y.S. (E-mail: yshi@hms.harvard.edu) and X.C. (E-mail: xcheng@emory.edu).. † Present address: Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy. * These authors contributed equally to this work.Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author InformationThe X-ray structure of the BHC80 PHD domain in complex with the H3 tail peptide has been deposited to PDB as 2PUY.Reprints and permissions information is available at www.nature.com/reprints.The authors declare no competing financial interests. Recent studies have identified a subset of PHD fingers that bind methyl lysine 5,6,8,9 . To investigate the role of BHC80, a PHD finger-containing protein (Fig. 1a) of the LSD1 corepressor complex, in transcriptional repression, we determined whether BHC80 also binds histone tails through its PHD finger. As shown in Fig. 1b, BHC80 binds the first 21 residues of histone H3 (lane 3), but not residues 21-44 or histones H4, H2A or H2B (lanes 4, 8-11). Unexpectedly, the BHC80-H3 interaction is disrupted by methylation of K4, but is insensitive to modifications at K9 or K14 (Fig. 1b, lanes 5-7 and Supplementary Fig. 1a). Native BHC80 in the LSD1 complex also binds H3K4me0, and this binding is similarly ...

SummaryThe transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism.