Epigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a

Kramer, Jamie M.; Kochinke, Korinna; Oortveld, Merel A. W.; Marks, Hendrik; Krämer, Daniela; Jong, Eiko K. de; Asztalos, Zoltán; Westwood, J. Timothy; Stunnenberg, Hendrik G.; Sokolowski, Marla B.; Keleman, Krystyna; Zhou, Huiqing; Bokhoven, Hans van; Schenck, Annette

doi:10.1371/journal.pbio.1000569

Cited by 194 publications

(217 citation statements)

References 67 publications

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“…26 Habituation of the startle jump response towards repeated lightoff stimuli of 3-7-day-old individual male flies was tested in two independent 16-unit light-off jump habituation systems. A total of 32 flies (16 flies/system) were simultaneously exposed to series of 100 short (15 ms) light-off pulses with a 1 s inter-pulse interval.…”

Section: Light-off Jump Reflex Habituationmentioning

confidence: 99%

“…31,32 Using the light-off jump reflex habituation, we have previously identified learning deficits in number of Drosophila ID models. 9,24,26 Two independent inducible RNAi lines targeting the Drosophila WAC orthologue CG8949 (vdrc48307 and vdrc107328) and their corresponding genetic background control lines (vdrc60000 and vdrc60100) were obtained (Vienna Drosophila RNAi Center 22 ) and fly stocks were kept under standard conditions. Expression of CG8949 was specifically downregulated in neurons using the UAS-Gal4 system.…”

Section: Panneuronal Knockdown Of the Drosophila Wac Orthologue Resulmentioning

confidence: 99%

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De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

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Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

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Section: Light-off Jump Reflex Habituationmentioning

confidence: 99%

Section: Panneuronal Knockdown Of the Drosophila Wac Orthologue Resulmentioning

confidence: 99%

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

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“…The fruit fly, Drosophila melanogaster, contains a single ortholog of G9a and EHMT1. Loss of Drosophila EHMT/G9a also causes several behavioral and cognitive defects, including altered larval locomotory behavior, loss of habituation, and defects in STM and LTM (78). These studies further underscore that H3K9 methylation is an important mechanism in cognition and behavior (Figure 1).…”

Section: Histone Methylationmentioning

confidence: 68%

“…However, these studies do not reveal the true mechanism or extent of gene regulation in learning and memory. Some studies have used a genome wide approach to determine how epigenetic regulators influence gene expression in the brain (30,57,64,77,78). Genome wide mRNA profiling has been performed in animals that have mutations in epigenetic regulators that are known to cause learning and memory defects.…”

Section: Targets Of Epigenetic Control In Learning and Memorymentioning

confidence: 99%

“…This also suggested that learning and memory may be disrupted by inappropriate activation of genes in the brain. Genome wide analysis of EHMT/G9a target genes in a Drosophila model with cognitive defects, revealed enrichment for neuronal genes with known roles in learning and memory, suggesting that G9a does have the potential to target more specific learning and memory processes (78). However, it remains to be seen whether Drosophila EHMT/G9a target genes are misregulated in the brain during learning and memory.…”

Section: Targets Of Epigenetic Control In Learning and Memorymentioning

confidence: 99%

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Epigenetic regulation of memory: implications in human cognitive disorders

Kramer

2013

BioMolecular Concepts

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Epigenetic modification of chromatin structure is an important mechanism in the regulation of gene expression. Recent studies have shown that dynamic regulation of chromatin structure occurs in response to neuronal stimulation associated with learning and memory. Learning-induced chromatin modifications include DNA methylation, histone acetylation, histone phosphorylation and histone methylation. Studies in animal models have used genetic and pharmacological methods to manipulate the epigenetic machinery in the brain during learning and memory formation. In general, these studies suggest that epigenetic regulation of chromatin structure is essential for long term memory (LTM) consolidation, which is known to require new gene transcription. Analysis of animal models has also implicated epigenetic mechanisms in impaired cognition associated with aging, neurodegenerative disease, and intellectual disability (ID). Recently, it has been shown that a subset of ID disorders and autism are caused by disruption of specific chromatin modification complexes that are involved in nuclear hormone receptor mediated transcriptional regulation. This review provides an overview of chromatin modifications that are implicated in learning and memory and discusses the role of chromatin modifying proteins in learning-induced transcriptional regulation and human cognitive disorders.

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