Chromatin Regulation by CHD1 in Metabolism and Aging

The DNA of each cell from fungi, plants and animals is stored in the cell nucleus in the form of chromatin. Chromatin is a highly ordered structure enabling the condensation of the long DNA molecules to fit into the limited space of the nucleus. At the same time chromatin is a powerful regulator of genome activity as it generally impedes access to the DNA, thereby regulating transcription, replication or repair of the genetic information. Chromatin structure can be modulated by various means, including the action of chromatin remodelling enzymes that alter histone-DNA interactions in an energy dependent process. The highly conserved chromodomain-helicase-DNA binding protein 1 (CHD1) is known as an ATP-dependent chromatin remodelling factor that also acts as a nucleosome assembly factor in vitro and in vivo. While the mechanistic details of CHD1s remodelling activity as well as its contribution to cellular transcription have been studied in some detail, its biological roles at the level of a complex organism are not well understood. In the fly, we have shown that Chd1 deletion leads to intestinal immunodeficiency and to an altered gut microbiome. Preliminary results revealed reduced lifespan, signs of premature aging and aberrant insulin/IGF and TOR signaling pathway activity in the absence of CHD1. With this proposal, we plan to elucidate the nature and extent of the contribution of CHD1 to basic metabolism and life- and healthspan regulation in Drosophila melanogaster. We will employ a combination of genetic, biochemical, behavioural and omics approaches (i) to examine, if the phenotypic defects observed in Chd1-deficient flies are rooted in defects during embryonic and larval development, or if they are caused by the loss of CHD1 in the adult; (ii) to perform a comprehensive analysis of different aspects of metabolism, physiology and behaviour of Chd1-mutant flies, and (iii) to investigate the molecular changes behind the observed phenotypes. Given the sparse knowledge about the contribution of ATP-dependent chromatin remodelling mechanisms to basic metabolism and life- and healthspan regulation in complex organisms, results from the proposed project will help to fill gaps in our understanding of these processes. In light of the high degree of conservation of the mechanisms that govern the regulation of metabolism and aging, insights into these processes obtained from the current project may help to better understand the molecular parameters underlying human metabolic diseases, such as diabetes, obesity or eating disorders.

The project focused on studying the physiological role of the molecular motor protein CHD1. Specifically, we aimed to determine whether CHD1 helps to create and preserve a healthy chromatin structure within cells. Our research, which used the fruit fly as a model system, revealed that deleting the CHD1 gene caused issues with maintaining chromatin integrity in brain cells. We found that CHD1's ability to incorporate the H3.3 histone variant is responsible for the observed defects in the CHD1 mutant. Histones are proteins that, together with DNA, form a highly structured complex called chromatin. Chromatin protects DNA from damage and enables the correct activation and inactivation of genes. During gene transcription, some histones may be lost and require replacement by proteins like CHD1. Brain cells are especially reliant on replacing regular histones with variant H3.3 and therefore on CHD1. Defects in CHD1 result in increasingly disordered chromatin and severely disrupted transcription. This results in phenotypes such as severely disturbed feeding behaviour, increased inflammation, and disturbed metabolism, ultimately significantly shortening the lifespan of the flies. Furthermore, our studies have revealed an important role of CHD1 in the sensory perception of the fly. Additionally, mutations in the mammalian counterpart of the fly protein affect the cognitive abilities of mice by severely reducing long-term spatial memory. CHD1 proteins are highly similar across different organisms, suggesting that they may have a similar role in humans.