Transcriptional regulation of neurodevelopmental and metabolic pathways by the psychiatric illness candidate gene NPAS3
Abstract
The basic helix-loop-helix PAS domain transcription factor gene NPAS3 is a risk
factor for psychiatric disorders. A knockout mouse model also exhibits behavioural
and adult neurogenesis deficits consistent with human illness. To define the location
and mechanism of NPAS3 aetiopathology immunofluorescent and transcriptomic
approaches were used.
Npas3 was co-localised with Dcx, but not other neurogenesis markers, in the
hippocampal subgranular zone - the site of adult neurogenesis. This implied that
NPAS3 might be involved in maturing, rather than proliferating, neuronal precursor
cells. Microarray analysis revealed that the transcriptional activities of NPAS3 and
its truncated form (C-terminal deletion) in the HEK293 cell line are sensitive to
circadian rhythm context. The most highly up-regulated NPAS3 target gene, VGF,
encodes secretory peptides with established roles in neurogenesis, depression and
schizophrenia. VGF was one of many NPAS3 target genes also shown to be
regulated by the SOX family of transcription factors, suggesting an overlap in
neurodevelopmental pathways. The transcriptional repression of multiple glycolytic
genes indicated that NPAS3 has a second role in metabolic regulation. This finding
was also confirmed by collaboration with a metabolomics research group at the
University of Strathclyde.
SOX11, a transcription factor known to play a role in neuronal and glial cell
differentiation, was shown to be down-regulated by NPAS3. The set of genes
targeted by SOX11 and their ontologies were deduced by a microarray analysis in a SOX11 overexpressing HEK293 cell line. Regulated genes include a previously
established SOX11 target, known markers of neurogenesis as well as genes
implicated in neuropsychiatric disorders. Multiple histone and zinc finger genes are
regulated by SOX11, many of which were located in two clusters on chromosomes 6
and 19. The chromosome 6 cluster lies within a region of the genome showing the
strongest genetic association with schizophrenia. SOX11 may alter localised
expression competence and its targets induce a complex programme of chromatin
remodelling and downstream gene expression changes to achieve the mature
neuronal phenotype.
This thesis details how transcription factors are involved in biological processes
linked to psychiatric illness. The dual neurodevelopmental and metabolic aspects of
NPAS3 activity described here increase our understanding of aspects of neurogenesis
relevant to mental illness and may explain the innate and medication-induced
susceptibility to diabetes reported in psychiatric patients.