Diet induced stress and epigenetic control of circadian clock regulation

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Project Description

The majority of our physiological and metabolic processes are coordinated by an internal clock, which has evolved as an adaptive response to the daily light-dark cycles. Thus, several physiological and behavioral activities display an oscillatory rhythmic period of 24 hours. This highly conserved molecular mechanism is achieved through a specific program of gene expression, characterized by a complex interaction between clock-core proteins, chromatin remodelers and epigenetic events associated with the oscillatory nature of circadian transcriptional activity in the genome. Clock disruption leads to a wide spectrum of severe health problems associated including chronic metabolic disorders, muscle waste and cardiopathies. Recent evidence revealed that each cell and organ possesses an intrinsic clock and that coordination between central versus peripheral clocks is key for health. The underlying mechanisms that regulate the intrinsic clock vs and its integration/interdependence on diet-induced stress are largely unknown. In this study we propose to investigate the role of chromatin cell memory mechanisms for intrinsic clock transcriptional regulation and their functional interplay with diet indices metabolic stress. We will focus on the mechanistic role of Polycomb group proteins (PcG) mediated cell memory system on circadian regulation and in particular the PRC2-Ezh1 complex, and its role in supporting intrinsic clock functions both in gene silencing and activation in post-mitotic skeletal muscle. The outcome of this study will shed light on novel fundamental mechanistic aspects underlying clock regulation, relevant for high societal impact diseases, with the dual scope of improving health policies and indicating possible novel therapeutic approaches.
Program - BioScience
Division - Biological and Environmental Sciences and Engineering
Field of Study - ​Epigenetics

About the
Researcher

Valerio Orlando

Professor, Bioscience

Valerio Orlando
​The epigenome constitutes the chromosomal molecular interface that allows the genome to interact with the environment. The epigenome enables cells to learn, remember and maintain their functional states throughout life and enable organisms to integrate environmental signals.

Prof. Orlando's lab is interested in investigating the chromatin mediated fundamental mechanisms that control cell identity and plasticity. These include signaling to chromatin regulation and nuclear organization by Polycomb proteins, the role of ncRNA-protein interactions in transcriptional regulation, Epigenomics and how this relates for development, transdifferentiation and adaptation (e.g. Metabolism), in particular in stress conditions.

Furthermore, as part of the mechanistic plastic properties of the genome in response to developmental and environmental cues, Prof. Orlando's lab also investigates the epigenetic regulation of the expression and dynamics of transposable elements and their role in cell differentiation and epigenomic biodiversity.

Desired Project Deliverables

​Unraveling the mechanistic role of PRC2-Ezh1 mediated control of circadian clock regulation in protecting and adapting skeletal muscle cells from high fat and fasting-induced metabolic stress.​