Chromatin Control of Autophagy
Lead Research Organisation:
Newcastle University
Department Name: Inst for Cell and Molecular Biosciences
Abstract
The overall objective of this project is to determine the role of chromatin in regulation of autophagy. Autophagy is an evolutionary conserved lysosomal degradation pathway of diverse intracellular macromolecular components, such as membranes, protein aggregates and organelles. Autophagy is essential for survival, differentiation, development and cellular homeostasis. Autophagy dysfunction has been strongly linked with cellular and organismal aging and it is associated with age-related pathologies, such as neurodegenerative diseases.
Besides non-selective degradation, autophagy is also involved in selective, ubiquitin-dependent degradation of proteins. How specificity in autophagic selective degradation is achieved is not well understood. Recent studies have provided evidence for epigenetic, chromatin control of autophagy. Nevertheless, the role and function of chromatin organization and chromatin-regulatory factors in autophagy remains largely unclear. The fundamental repeating unit of chromatin is the nucleosome, which consists of 147bp of DNA wrapped around a histone octamer. Nucleosomes compact the genome and serve as hubs for signal integration for nuclear functions. Chromatin modifying enzymes are essential epigenetic regulators, altering the nucleosome structure, shaping the chromatin landscape in a spatiotemporal fashion and impacting all aspects of nuclear biology.
Our preliminary analysis revealed specific chromatin regulators that mediate selective autophagic degradation. This project will test the hypothesis that epigenetic control defines a new signaling pathway between nuclear and lysosomal autophagic responses involved in the aging process.
Specifically, we will address the following timely questions:
- How is the dynamic chromatin landscape altered during autophagy induction, contributing to selective autophagy?
- How is chromatin regulation integrated in the autophagic response, controlling the timely and efficient destruction of proteins?
- How does epigenetic control of autophagy promotes nuclear functions, cellular physiology and aging?
To delineate the role of chromatin regulation of autophagy and aging we will apply a powerful combination of genomics and proteomics together with biochemical, genetic and cell biology assays, using budding yeast and mammalian cells as model systems. This combination of unbiased systems biology and molecular approaches will reveal the physical and functional interface between chromatin control and autophagy response and elucidate the molecular underpinnings of this novel homeostasis pathway.
Besides non-selective degradation, autophagy is also involved in selective, ubiquitin-dependent degradation of proteins. How specificity in autophagic selective degradation is achieved is not well understood. Recent studies have provided evidence for epigenetic, chromatin control of autophagy. Nevertheless, the role and function of chromatin organization and chromatin-regulatory factors in autophagy remains largely unclear. The fundamental repeating unit of chromatin is the nucleosome, which consists of 147bp of DNA wrapped around a histone octamer. Nucleosomes compact the genome and serve as hubs for signal integration for nuclear functions. Chromatin modifying enzymes are essential epigenetic regulators, altering the nucleosome structure, shaping the chromatin landscape in a spatiotemporal fashion and impacting all aspects of nuclear biology.
Our preliminary analysis revealed specific chromatin regulators that mediate selective autophagic degradation. This project will test the hypothesis that epigenetic control defines a new signaling pathway between nuclear and lysosomal autophagic responses involved in the aging process.
Specifically, we will address the following timely questions:
- How is the dynamic chromatin landscape altered during autophagy induction, contributing to selective autophagy?
- How is chromatin regulation integrated in the autophagic response, controlling the timely and efficient destruction of proteins?
- How does epigenetic control of autophagy promotes nuclear functions, cellular physiology and aging?
To delineate the role of chromatin regulation of autophagy and aging we will apply a powerful combination of genomics and proteomics together with biochemical, genetic and cell biology assays, using budding yeast and mammalian cells as model systems. This combination of unbiased systems biology and molecular approaches will reveal the physical and functional interface between chromatin control and autophagy response and elucidate the molecular underpinnings of this novel homeostasis pathway.
Organisations
| Description | Autophagy is a complex biological pathway which has been identified to function in a wide range of human diseases, cancers and also play a role in natural aging. Better understanding the Autophagy pathway can therefore offer potential therapeutics for a wide range of medically relevant conditions. An area of study not well understood is how epigenetic processes regulate Autophagy and more generally control metabolic stress response. My work has discovered that the INO80 chromatin remodeling complex, an evolutionary conserved epigenetic regulator, allows survival in conditions of metabolic stress by promoting the autophagy. This is the first time that this complex has been shown to be involved with autophagy. More specifically, I have discovered that a group of genes, called the COS genes, must be up-regulated in order for selective autophagy to function. This up-regulation is dependent on INO80 complex counteracting sirtuin-dependent epigenetic suppression these genes. In summary I have identified a novel epigenetic pathway regulating selective autophagy, centered around the COS gene family and their regulation by sirtuins and chromatin remodeling by INO80 |
| Exploitation Route | With the identification of new regulatory mechanism of autophagy, it is now possible to begin research into strategies for controlling these for therapeutic benefits. For example, INO80 complex is over-expressed in many cancers and the reasons for this are yet unknown. This work leads to new hypotheses for the role of INO80 in cancer, for example that it may support the cancer in dealing with metabolic stress that would otherwise be toxic to a cell. Future work will need to identify whether INO80 controls autophagy in higher eukaryotes and whether this is through a similar mechanism. |
| Sectors | Pharmaceuticals and Medical Biotechnology |