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Nat Commun. 2019 Aug 9;10(1):3623. doi: 10.1038/s41467-019-11568-0.

MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat.

Author information

1
Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
2
Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, 97074, Germany.
3
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
4
Hartwell Center, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
5
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
6
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
7
Department of Anatomy and Neurobiology, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
8
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
9
Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. sandra.dazzo@stjude.org.

Abstract

Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.

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