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

Ida Annunziata, Diantha Vlekkert, Elmar Wolf, David Finkelstein, Geoffrey Neale, Eda Machado, Rosario Mosca, Yvan Campos, Heather Tillman, Martine F. Roussel, Jason Andrew Weesner, Leigh Ellen Fremuth, Xiaohui Qiu, Min-Joon Han, Gerard C. Grosveld and Alessandra d’Azzo ()
Additional contact information
Ida Annunziata: St. Jude Children’s Research Hospital
Diantha Vlekkert: St. Jude Children’s Research Hospital
Elmar Wolf: University of Würzburg
David Finkelstein: St. Jude Children’s Research Hospital
Geoffrey Neale: Hartwell Center, St. Jude Children’s Research Hospital
Eda Machado: St. Jude Children’s Research Hospital
Rosario Mosca: St. Jude Children’s Research Hospital
Yvan Campos: St. Jude Children’s Research Hospital
Heather Tillman: St. Jude Children’s Research Hospital
Martine F. Roussel: St. Jude Children’s Research Hospital
Jason Andrew Weesner: St. Jude Children’s Research Hospital
Leigh Ellen Fremuth: St. Jude Children’s Research Hospital
Xiaohui Qiu: St. Jude Children’s Research Hospital
Min-Joon Han: St. Jude Children’s Research Hospital
Gerard C. Grosveld: St. Jude Children’s Research Hospital
Alessandra d’Azzo: St. Jude Children’s Research Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11568-0

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