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Deciphering the Transcriptional Logic of TFEB activation in cell identity and cancer

Periodic Reporting for period 1 - EpiTFeb (Deciphering the Transcriptional Logic of TFEB activation in cell identity and cancer)

Reporting period: 2018-04-01 to 2020-03-31

Using a systems biology approach it has been determined that lysosomal biogenesis and function are globally regulated at the transcriptional level by the transcription factor EB (TFEB). This discovery has opened an entirely new field of investigation and generated considerable interest both in the cell biology and medical fields. Major steps forward have been made towards the understanding of the mechanisms underlying TFEB-mediated regulation of lysosomal biogenesis. However, in spite of these efforts, major knowledge gaps still remain. One of the most important issues is to identify ways to induce TFEB activity and avoid the risks of side effects. While, acute TFEB overexpression and induction of the CLEAR network ameliorates disease progression in several models of disease, constitutively enhanced TFEB activity and sustained induction of autophagy have been associated with several human cancers, indicating that fine-tuning TFEB activity (e.g. with a pulsatile regimen) is imperative for its use as a therapeutic tool.
Transcriptional regulation is a crucial process not only to instruct developmental transitions but also to coordinate organismal cellular processes under homeostasis and stress. The proposed project aims at providing a systematic dissection of the molecular and developmental cues responsible for TFEB transcriptional regulation, an aspect that is still missing.
Overall, the project performed so far provided:
- a deep characterization of the transcriptional repertoire of different cell types under specific stimuli (i.e. starvation and induction of differentiation);
- the identification of bonafide TFEB transcriptional regulators;
- functional validation of candidate transcription factors.
During the specific report period, I leveraged my previous observations showing that TFEB expression is highly variable across different tissues and cell lines and differentially tuned upon nutrient availability and that TFEB regulatory regions are differentially enriched at enhancer markers based on the cell identity in order to deepen the mechanisms​ ​underlying​ ​TFEB​ ​transcriptional​ ​regulation​.
Indeed, I identified transcription factors that drive TFEB expression and characterized the mode of actions of these factors. Moreover, by using genomic approaches, I was able to establish the relationship between the genomic sequences and the regulatory activity of TFEB cis-regulatory elements.
The proposed project greatly contributed to the definition of the transcriptional landscape of TFEB and provided a novel​ ​and​ ​yet​ ​unexplored​ ​angle​ ​to​ ​revise​ ​its​ ​contribution​ ​in​ ​diseases​ ​where​ ​the​ ​lysosome​ ​function​ ​is​ ​impaired. Indeed, ​modulation of its expression and activity represents an attractive therapeutic strategy to treat those diseases​ ​that​ ​could​ ​potentially​ ​benefit​ ​from​ ​promoting​ ​intracellular​ ​clearance.z