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HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells.

ABSTRACT: Schizophrenia is a common psychiatric disorder and caused by a combination of environmental, social and genetic factors. Histone deacetylases (HDACs) can translate epigenetic effects to the genome by modifying chromatin structure and gene expression. Inappropriate activity of HDACs is associated with cancer, cardiovascular and neurological diseases, and HDAC inhibitors are shown to improve the derivation of induced pluripotent stem (iPS) cells and to modulate cell lineage differentiation during brain development. We demonstrate that one of the HDAC genes, HDAC9, is hemizygously deleted in a small proportion of schizophrenia patients, and is widely expressed in mouse brain including areas where the neuropathology of schizophrenia is found. High levels of expression are observed in the hippocampus, layers II/III and V of the cerebral cortex, prefrontal and medial prefrontal cortex, piriform and cingulum cortex, basolateral amygdaloid nuclei and choroid plexus. HDAC9 protein is found in the cell body as well as in nerve fibers. Importantly, HDAC9 is not expressed in adult neural stem cells, glia, astrocytes, or oligodendrocytes, but expressed exclusively in post-mitotic and mature neurons. Our data suggest that HDAC9 may play a crucial role in neuronal function of adult brain.

SUBMITTER: Lang B

PROVIDER: S-EPMC3643384 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells.

Lang Bing B Alrahbeni Tahani Mohammed A TM Clair David St DS Blackwood Douglas H DH McCaig Colin D CD Shen Sanbing S

American journal of stem cells 20110818 1

Schizophrenia is a common psychiatric disorder and caused by a combination of environmental, social and genetic factors. Histone deacetylases (HDACs) can translate epigenetic effects to the genome by modifying chromatin structure and gene expression. Inappropriate activity of HDACs is associated with cancer, cardiovascular and neurological diseases, and HDAC inhibitors are shown to improve the derivation of induced pluripotent stem (iPS) cells and to modulate cell lineage differentiation during ...[more]

PMID: 23671795

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Project description:BackgroundProtein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.Methodology/principal findingsWe have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia.Conclusions/significanceWe found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.

Project description:Understanding the mechanisms by which neurons are generated and specified, and how they integrate into functional circuits is key to being able to treat disorders of the nervous system and acute brain trauma. Much of what we know about neuronal differentiation has been studied in developing embryos, but differentiation steps may be very different during adult neurogenesis. For this reason, we compared the transcriptomes of newly differentiated neurons in zebrafish embryos and adults.Using a 4tU RNA labeling method, we isolated and sequenced mRNA specifically from cells of one day old embryos and adults expressing the transgene HA-uprt-mcherry under control of the neuronal marker elavl3. By categorizing transcript products into different protein classes, we identified similarities and differences of gene usage between adult and embryonic neuronal differentiation. We found that neurons in the adult brain and in the nervous system of one day old embryos commonly use transcription factors - some of them identical - during the differentiation process. When we directly compared adult differentiating neurons to embryonic differentiating neurons, however, we found that during adult neuronal differentiation, the expression of neuropeptides and neurotransmitter pathway genes is more common, whereas classical developmental signaling through secreted molecules like Hedgehog or Wnt are less enriched, as compared to embryonic stages.We conclude that both adult and embryonic differentiating neurons show enriched use of transcription factors compared to surrounding cells. However, adult and embryonic developing neurons use alternative pathways to differentiate. Our study provides evidence that adult neuronal differentiation is distinct from the better characterized embryonic neuronal differentiation process. This important insight and the lists of enriched genes we have identified will now help pave the way to a better understanding of the mechanisms of embryonic and adult neuronal differentiation and how to manipulate these processes.

Project description:BackgroundMicroRNAs (miRNAs) are a large group of RNAs that play important roles in regulating gene expression and protein translation. Several studies have indicated that some miRNAs are specifically expressed in human, mouse and zebrafish tissues. For example, miR-1 and miR-133 are specifically expressed in muscles. Tissue-specific miRNAs may have particular functions. Although previous studies have reported the presence of human, mouse and zebrafish tissue-specific miRNAs, there have been no detailed reports of rat tissue-specific miRNAs. In this study, Home-made rat miRNA microarrays which established in our previous study were used to investigate rat neural tissue-specific miRNAs, and mapped their target genes in rat tissues. This study will provide information for the functional analysis of these miRNAs.ResultsIn order to obtain as complete a picture of specific miRNA expression in rat neural tissues as possible, customized miRNA microarrays with 152 selected miRNAs from miRBase were used to detect miRNA expression in 14 rat tissues. After a general clustering analysis, 14 rat tissues could be clearly classified into neural and non-neural tissues based on the obtained expression profiles with p values < 0.05. The results indicated that the miRNA profiles were different in neural and non-neural tissues. In total, we found 30 miRNAs that were specifically expressed in neural tissues. For example, miR-199a was specifically expressed in neural tissues. Of these, the expression patterns of four miRNAs were comparable with those of Landgraf et al., Bak et al., and Kapsimani et al. Thirty neural tissue-specific miRNAs were chosen to predict target genes. A total of 1,475 target mRNA were predicted based on the intersection of three public databases, and target mRNA's pathway, function, and regulatory network analysis were performed. We focused on target enrichments of the dorsal root ganglion (DRG) and olfactory bulb. There were four Gene Ontology (GO) functions and five KEGG pathways significantly enriched in DRG. Only one GO function was significantly enriched in the olfactory bulb. These targets are all predictions and have not been experimentally validated.ConclusionOur work provides a global view of rat neural tissue-specific miRNA profiles and a target map of miRNAs, which is expected to contribute to future investigations of miRNA regulatory mechanisms in neural systems.

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HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells.

Publications

HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells.

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