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

Author

Listed:
  • 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
    University of Tennessee Health Science Center)

  • Leigh Ellen Fremuth

    (St. Jude Children’s Research Hospital
    University of Tennessee Health Science Center)

  • 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)

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.

Suggested Citation

  • 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 El, 2019. "MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11568-0
    DOI: 10.1038/s41467-019-11568-0
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    Cited by:

    1. Xiao Han & Lijuan Liu & Saihua Huang & Wenfeng Xiao & Yajing Gao & Weitao Zhou & Caiyan Zhang & Hongmei Zheng & Lan Yang & Xueru Xie & Qiuyan Liang & Zikun Tu & Hongmiao Yu & Jinrong Fu & Libo Wang & , 2023. "RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Mei Luo & Lin Ye & Ruimin Chang & Youqiong Ye & Zhao Zhang & Chunjie Liu & Shengli Li & Ying Jing & Hang Ruan & Guanxiong Zhang & Yi He & Yaoming Liu & Yu Xue & Xiang Chen & An-Yuan Guo & Hong Liu & L, 2022. "Multi-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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