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

Información del proyecto

EpiTFeb

Identificador del acuerdo de subvención: 799002

DOI

10.3030/799002

Proyecto finalizado el 1 Septiembre 2019

Fecha de la firma de la CE 14 Marzo 2018

Fecha de inicio 1 Abril 2018

Fecha de finalización 28 Abril 2020

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 180 277,20

Aportación de la UE

€ 180 277,20

Coordinado por

FONDAZIONE TELETHON ETS
Italy

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

Período documentado: 2018-04-01 hasta 2020-03-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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

WP1 and WP2 are illustrated in the picture