4.8 Article

TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

Journal

CELL REPORTS
Volume 33, Issue 6, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2020.108371

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Funding

  1. National Institutes of Health [R01 DK097485, U19 AI109725, U19 AI142784]
  2. Center for the Study of Inflammatory Bowel Disease [P30 DK043351, R35 GM122547]

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Transcription factor EB (TFEB) activates lysosomal biogenesis genes in response to environmental cues. Given implications of impaired TFEB signaling and lysosomal dysfunction in metabolic, neurological, and infectious diseases, we aim to systematically identify TFEB-directed circuits by examining transcriptional responses to TFEB subcellular localization and stimulation. We reveal that steady-state nuclear TFEB is sufficient to activate transcription of lysosomal, autophagy, and innate immunity genes, whereas other targets require higher thresholds of stimulation. Furthermore, we identify shared and distinct transcriptional signatures between mTOR inhibition and bacterial autophagy. Using a genome-wide CRISPR library, we find TFEB targets that protect cells from or sensitize cells to lysosomal cell death. BHLHE40 and BHLHE41, genes responsive to high, sustained levels of nuclear TFEB, act in opposition to TFEB upon lysosomal cell death induction. Further investigation identifies genes counter-regulated by TFEB and BHLHE40/41, adding this negative feedback to the current understanding of TFEB regulatory mechanisms.

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