EpiTFeb · Deciphering the Transcriptional Logic of TFEB activation in cell identity and cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-04-01 → 2020-04-28
- EU contribution
- €180,277
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Deciphering the Transcriptional Logic of TFEB activation in cell identity and cancer
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.
Data: CORDIS, © European Union
Project objective
The discovery that lysosomal biogenesis is subjected to a global transcriptional control and that the transcription factor TFEB is the primary driving force for the coordinated expression of lysosomal genes has empowered intense investigations on the molecular mechanisms regulating cellular homeostasis. Modulation of TFEB expression and activity is therefore crucial in cellular adaptation to a wide variety of internal stresses and environmental fluctuations. While many studies have been focused on TFEB post-translational modifications and on how they can affect its subcellular localization and function, little attention has been given to how TFEB expression is regulated at the transcriptional level across different cell types and nutritional states hampering the capacity of fully benefit from its powerful properties.By using genomic approaches and induced-pluripotent stem cell-based systems, I aim to define the regulatory architecture of TFEB activation across a broad range of cellular contexts. This will allow understanding how different regulatory mechanisms result in a cell-selective ability to preserve homeostasis and respond to various stress conditions. Specifically, I will: i) define the cell-specific dynamics of TFEB expression; ii) expose novel TFEB transcriptional regulators; iii) identify the transcriptional mechanisms underlying aberrant TFEB activation in cancer. The proposed project will be essential to define the transcriptional landscape of TFEB and will also provide a novel and yet unexplored angle to revise its contribution in disease settings where the lysosome function is impaired.
Original text from CORDIS.
Participants
- FONDAZIONE TELETHON ETS · ROMACoordinatorItaly
Links
Data: CORDIS, © European Union