Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome

Girdhar, Kiran; Hoffman, Gabriel E.; Jiang, Yan; Brown, Leanne; Kundaković, Marija; Hauberg, Mads E.; Francoeur, Nancy; Wang, Ying-Chih; Shah, Hardik; Kavanagh, David; Zharovsky, Elizabeth; Jacobov, Rivka; Wiseman, Jennifer; Park, Royce; Johnson, Jessica; Kassim, Bibi; Sloofman, Laura; Mattei, Eugenio; Weng, Zhiping; Sieberts, Solveig K.; Peters, Mette A.; Harris, Brent T.; Lipska, Barbara K.; Sklar, Pamela; Roussos, Panos; Akbarian, Schahram

doi:10.1038/s41593-018-0187-0

Cited by 127 publications

(141 citation statements)

References 72 publications

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“…We also examined heritability of psychiatric disorders and behavioral traits and identified a preferential enrichment in neuronal enhancers. An earlier study comparing neuronal and non-neuronal regulatory regions in the cortex found a similar neuronal enrichment for schizophrenia risk variants (81). In addition, we found an enrichment of schizophreniarisk variants in promoters for neurons, oligodendrocytes and astrocytes, however, whether this reflects contributions of glial to disease or is indicative of a general neural dysfunction remains to be tested.…”

Section: Discussionsupporting

confidence: 59%

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Nott¹,

Holtman²,

Coufal

et al. 2019

Preprint

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Identification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants. AbstractUnique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring ADrisk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function. of neurons, microglia, astrocytes, oligodendrocytes and other cell types that reside within the brain (1-4). In contrast, transcriptional mechanisms that control their developmental and functional properties in health and disease remain less well understood. Studies in animal models have provided deep insights into conserved processes, but significant differences between species often limit the translatability of findings in model systems to humans (5).Genome-wide association studies (GWASs) provide a genetic approach to identifying molecular pathways involved in complex traits and diseases by defining associations between genetic variants and phenotypes of interest (6, 7). Large-scale GWASs have discovered hundreds of single nucleotide polymorphisms (SNPs) that are associated with the risk of neurological and psychiatric disorders. The vast majority of disease-risk genetic variants are located in non-coding regions of the genome (7) and the specific cell type (s) in which the disease-risk variants are active is often unclear. Furthermore, linkagedisequilibrium between disease-risk variants at GWAS significant loci complicates the identification of causal variants. Collectively, these limitations have hindered the assignment and interpretation of disease-risk genes.GWAS-identified risk variants that are located in non-coding regions of the genome can exert phenotypic effects through several mechanisms, including perturbation of transcriptional enhancers and promoters (6). While promoters provide the essential sites of transcriptional initiation of mRNAs, they are frequently not sufficient to direct appropriate developmental and signal-dependent levels of gene expression (8,9). This additional information is provided by enhancers, short regions of DNA that, when bound by transcription factors, enhance mRNA expression from target promoters. Enhancers can reside hundreds of thousands of base pairs away from their target gene and their function is generally consid...

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Section: Discussionsupporting

confidence: 59%

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Nott¹,

Holtman²,

Coufal

et al. 2019

Preprint

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“…A number of the M-PTSD specific functional enrichments are also highly plausible; for example, enrichment H3K27 acetylation peaks from a gene-set derived from DLPFC neurons (Girdhar et al, 2018), known to have a role in stress models and neuropsychiatric disorders (McEwen et al, 2015), including PTSD (Maddox et al, 2018). Our results highlight a potential shared genetic basis between olfaction and M-PTSD, in line with previous findings of differential olfactory 5 identification in individuals with combat-related M-PTSD compared to healthy controls (Vasterling et al, 2000); olfactory triggers for PTSD intrusion symptoms (Daniels and Vermetten, 2016); olfactory-based treatments for PTSD (Aiken and Berry, 2015); and the key role of olfaction in fear conditioning in animal models (Morrison et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

Huckins

Breen

Chatzinakos

et al. 2019

Preprint

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PTSD has significant genetic heritability; however, it is unclear how genetic risk influences tissue-specific gene expression. We used brain and non-brain transcriptomic imputation models to impute genetically regulated gene expression (GReX) in 9,087 PTSD-cases and 23,811 controls and identified thirteen significant GReX-PTSD associations. The results suggest 5 substantial genetic heterogeneity between civilian and military PTSD cohorts. The top studywide significant PTSD-association was with predicted downregulation of the Small Nuclear Ribonucleoprotein U11/U12 Subunit 35 (SNRNP35) in the BA9 region of the prefrontal cortex (PFC) in military cohorts. In peripheral leukocytes from 175 U.S. Marines, the observed PTSD differential gene expression correlated with the predicted blood GReX differences for these 10 individuals, and deployment stress downregulated SNRNP35 expression, primarily in Marines with post-deployment PTSD. SNRNP35 is a subunit of the minor spliceosome complex and SNRNP35 knockdown in cells validated its functional importance in U12-intron splicing. Finally, mimicking acute activation of the endogenous stress axis in mice downregulated PFC Snrnp35 expression. 15 Huckins et al. 4

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“…It is established that different cell-types exhibit distinct epigenetic landscapes 28 and therefore, bulk tissue data must be evaluated in a context of its underlying cellular composition [29][30][31] . In order to estimate the relative cellular composition in our ChIP-seq data, we used an approach similar to the one described by Mancarci et al 30 .…”

Section: Cell Composition Is a Major Source Of Variation In Bulk Tissmentioning

confidence: 99%

“…In order to estimate the relative cellular composition in our ChIP-seq data, we used an approach similar to the one described by Mancarci et al 30 . Briefly, we intersected genomic H3K27ac binding sites differentiating between NeuN-positive and NeuN-negative brain cells 28 with the list of brain cell-type specific marker-genes 30 to obtain genomic H3K27ac cell-type marker sites. The first principal component of reads aligned to the marker sites was used to obtain Marker Site Profiles (MSPs) which serve as a proxy for the relative abundance of the corresponding cell-types across the samples.…”

Section: Cell Composition Is a Major Source Of Variation In Bulk Tissmentioning

confidence: 99%

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Genome-wide dysregulation of histone acetylation in the Parkinson’s disease brain

Toker

Sundaresan

Tysnes

et al. 2019

Preprint

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Parkinson disease (PD) is a complex neurodegenerative disorder of largely unknown etiology. While several genetic risk factors have been identified, the involvement of epigenetics in the pathophysiology of PD is mostly unaccounted for. We conducted a histone acetylome-wide association study in PD, using brain tissue from two independent cohorts of cases and controls. Immunoblotting revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. Chromatin immunoprecipitation sequencing (ChIP-seq) further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon, with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Our findings strongly suggest that dysregulation of histone acetylation plays an important role in the pathophysiology of PD and identify novel epigenetic signatures associated with the disease.

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Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome

Cited by 127 publications

References 72 publications

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

Genome-wide dysregulation of histone acetylation in the Parkinson’s disease brain

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