The Drosophila Huntington's disease gene ortholog dhtt influences chromatin regulation during development

Abstract

Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG expansion mutation in HTT, the gene encoding huntingtin. Evidence from both human genotype-phenotype relationships and mouse model systems suggests that the mutation acts by dysregulating some normal activity of huntingtin. Recent work in the mouse has revealed a role for huntingtin in epigenetic regulation during development. Here, we examine the role of the Drosophila huntingtin ortholog (dhtt) in chromatin regulation in the development of the fly. Although null dhtt mutants display no overt phenotype, we found that dhtt acts as a suppressor of position-effect variegation (PEV), suggesting that it influences chromatin organization. We demonstrate that dhtt affects heterochromatin spreading in a PEV model by modulating histone H3K9 methylation levels at the heterochromatin-euchromatin boundary. To gain mechanistic insights into how dhtt influences chromatin function, we conducted a candidate genetic screen using RNAi lines targeting known PEV modifier genes. We found that dhtt modifies phenotypes caused by knockdown of a number of key epigenetic regulators, including chromatin-associated proteins, histone demethylases (HDMs) and methyltransferases. Notably, dhtt strongly modifies phenotypes resulting from loss of the HDM dLsd1, in both the ovary and wing, and we demonstrate that dhtt appears to act as a facilitator of dLsd1 function in regulating global histone H3K4 methylation levels. These findings suggest that a fundamental aspect of huntingtin function in heterochromatin/euchromatin organization is evolutionarily conserved across phyla.

Studying polyglutamine diseases in Drosophila

“…A similar although milder spindle phenotype has also been observed in dhtt-ko flies 257 . Furthermore, resonating with observations from early mammalian studies 258 , analysis of dhtt null flies has revealed a potential involvement of dhtt in epigenetic control, as dhtt shows genetic interactions with heterochromatin genes and components of chromatin remodeling complex and can facilitate the global demethylation of histone H3K4 259 . These findings suggest that HTT has conserved functions in regulating mitotic spindle orientation and epigenetic regulation.…”

Characterization of axonal transport defects inDrosophilaHuntingtin mutants

“…Previous studies have implicated Htt in a variety of biological processes, including neurogenesis (Ben M’Barek et al, 2013), mitotic spindle orientation (Godin et al, 2010), chromatin organization (Dietz et al, 2015; Seong et al, 2010), macroautophagy (Rui et al, 2015), iron import (Lumsden, Henshall, Dayan, Lardelli, & Richards, 2007) cargo transport (Gauthier et al, 2004; Trushina et al, 2004) and synaptic plasticity (Choi et al, 2014). Here we demonstrate that Drosophila dhtt −/− mutants display defects in axonal transport of cargos in vivo .…”

The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington’s Disease

“…Figure 2 contains a model that represents a possible mechanism of how this domain interacts with the rest of the N-terminal huntingtin protein in humans, not in Drosophila . Interestingly, the htt protein sequence is highly conserved between the Drosophila species, suggesting a common biological function in the fruit fly [76,77], and a key tool to study the main functions of this protein in this animal model. Similar to vertebrates, htt protein is transported bi-directionally in Drosophila’s axons, where it is associated with several proteins that receive the name of huntingtin associate proteins (HAP), with HAP40 being a key regulator of endocytosis, a critical factor for HD development in humans [78].…”