Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data

Mancarci, B. Ogan; Toker, Lilah; Tripathy, Shreejoy J.; Li, Brenna; Rocco, Brad R.; Sibille, Etienne; Pavlidis, Paul

doi:10.1523/eneuro.0212-17.2017

Cited by 139 publications

(168 citation statements)

References 89 publications

(119 reference statements)

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“…It is also possible that some of the GluN2C+/NeuN-/GFAP- cells include oligodendrocytes or other glial cell populations. Overall, these results are consistent with the findings of RNA-seq transcriptomes for the cerebral cortex [33,34]. From these studies, GluN2C mRNA from the cerebral cortex was much more highly expressed in astrocytes than in oligodendrocytes, microglia, and neurons.…”

Section: Discussionsupporting

confidence: 90%

In the Telencephalon, GluN2C NMDA Receptor Subunit mRNA is Predominately Expressed in Glial Cells and GluN2D mRNA in Interneurons

et al. 2018

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N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the brain with high concentrations in the telencephalon where they modulate synaptic plasticity, working memory, and other functions. While the actions of the predominate GluN2 NMDAR subunits, GluN2A and GluN2B are relatively well understood, the function of GluN2C and GluN2D subunits in the telencephalon is largely unknown. To better understand the possible role of GluN2C subunits, we used fluorescence in situ hybridization (FISH) together with multiple cell markers to define the distribution and type of cells expressing GluN2C mRNA. Using a GluN2C-KO mouse as a negative control, GluN2C mRNA expression was only found in non-neuronal cells (NeuN-negative cells) in the hippocampus, striatum, amygdala, and cerebral cortex. For these regions, a significant fraction of GFAP-positive cells also expressed GluN2C mRNA. Overall, for the telencephalon, the globus pallidus and olfactory bulb were the only regions where GluN2C was expressed in neurons. In contrast to GluN2C, GluN2D subunit mRNA colocalized with neuronal and not astrocyte markers or GluN2C mRNA in the telencephalon (except for the globus pallidus). GluN2C mRNA did, however, colocalize with GluN2D in the thalamus where neuronal GluN2C expression is found. These findings strongly suggest that GluN2C has a very distinct function in the telencephalon compared to its role in other brain regions and compared to other GluN2-containing NMDARs. NMDARs containing GluN2C may have a specific role in regulating L-glutamate or D-serine release from astrocytes in response to L-glutamate spillover from synaptic activity.

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Section: Discussionsupporting

confidence: 90%

In the Telencephalon, GluN2C NMDA Receptor Subunit mRNA is Predominately Expressed in Glial Cells and GluN2D mRNA in Interneurons

et al. 2018

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

confidence: 99%

“…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 . 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.…”

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%

“…Peaks were annotated to all genes for which they intersected a region between 5kb upstream from their TSS to the end of their 5'UTR. In the next step, we intersected the genes with DARs between glia and neurons with expression-based cortical marker gene lists based on NeuroExpresso database 30 . The DARs were next reassigned to specific glial and neuronal cells if they were annotated to genes defined as cell-type specific based on NeuroExpresso.…”

Section: Calculation Of Marker Site Profiles (Msp)mentioning

confidence: 99%

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

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et al. 2019

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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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Neuronal loss drives differentially expressed protein‐pathways in the PSP globus pallidus

Dick

Johanson

Tzoulis

2023

Clinical & Translational Med

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Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data

Abstract: Visual Abstract

Cited by 139 publications

References 89 publications

In the Telencephalon, GluN2C NMDA Receptor Subunit mRNA is Predominately Expressed in Glial Cells and GluN2D mRNA in Interneurons

In the Telencephalon, GluN2C NMDA Receptor Subunit mRNA is Predominately Expressed in Glial Cells and GluN2D mRNA in Interneurons

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

Neuronal loss drives differentially expressed protein‐pathways in the PSP globus pallidus

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