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Fig. 6 | Clinical Epigenetics

Fig. 6

From: BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model

Fig. 6

Proposed model describing the effects of BETi PFI-1 and JQ1 in C9BAC cultures and mice. PFI-1 and JQ1 are highly potent pan-BETi and antagonize BET family members BRD4 > BRD2/3 > BRDT. a Treatment of primary cortical cultures from C9BAC mice with PFI-1 (5 μM for 24 h) enhances the expression of the human C9ORF72 gene in neurons, leading to increases in C9ORF72 transcripts, reduction in poly(GP) aggregates, and accumulation of RNA foci. The methylation of the human C9ORF72 gene promoter region represents an enrichment of several repressive histone modifications, including H3K9me3 and H3K27me3 in the histone tails of the depicted nucleosomes. Higher-order DNA structures, called G-quadruplexes, found in the G4C2 hexanucleotide repeat expansions (HRE) of the C9ORF72 gene body are also shown. For simplicity only BET family member BRD4 is shown and the ET domain omitted. b Treatment of 6-month-old C9BAC mice with JQ1 (i.p. 0.5 mg/kg/day for 7 days) rescues hippocampal-dependent cognitive spatial memory, as measured by the object location memory (OLM) task

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Clinical Epigenetics

ISSN: 1868-7083

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