Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential Biomarkers
Microglial cells form a context-dependent network of brain immunoeffector cells. Despite their indispensable roles, unresolved questions exist around biomarker discovery relevant to their cellular localization, self-renewing potential, and brain developmental dynamics. To resolve the existent gap in...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Neurology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fneur.2018.00266/full |
| _version_ | 1818110741113208832 |
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| author | R. Ayana Shailja Singh Shailja Singh Soumya Pati |
| author_facet | R. Ayana Shailja Singh Shailja Singh Soumya Pati |
| author_sort | R. Ayana |
| collection | DOAJ |
| description | Microglial cells form a context-dependent network of brain immunoeffector cells. Despite their indispensable roles, unresolved questions exist around biomarker discovery relevant to their cellular localization, self-renewing potential, and brain developmental dynamics. To resolve the existent gap in the annotation of candidate biomarkers, we conducted a meta-analysis of brain cells using available high-throughput data sets for deciphering microglia-specific expression profiles. We have identified 3,290 significant genes specific to microglia and further selected the top 20 dysregulated genes on the basis of p-value and log2FC. To this list, we added 7 known microglia-specific markers making the candidate list comprising 27 genes for further downstream analyses. Next, we established a connectome of these potential markers with their putative protein partners, which demonstrated strong associations of upregulated genes like Dedicator of cytokinesis 2 (DOCK2) with early/mature microglial markers such as Sphingosine kinase 1 (SPHK1), CD68, and CD45. To elucidate their respective brain anatomical location, we deconvoluted the BrainSpan Atlas expression data. This analysis showed high expression of the majority of candidate genes in microglia-dense regions (Amygdala, Hippocampus, Striatum) in the postnatal brain. Furthermore, to decipher their localized expression across brain ages, we constructed a developmental dynamics map (DDM) comprising extensive gene expression profiles throughout prenatal to postnatal stages, which resulted in the discovery of novel microglia-specific gene signatures. One of the interesting readout from DDM is that all the microglia-dense regions exhibit dynamic regulation of few genes at 37 post conception week (pcw), the transition period between pre- and postnatal stages. To validate these findings and correlate them as potential biomarkers, we analyzed the expression of corresponding proteins in hESC-derived human microglia precursors. The cultured microglial precursors showed expression of Pentraxin 3 (PTX3) and SPHK1 as well as several known markers like CD68, Allograft inflammatory factor 1 (AIF1/IBA1). In summary, this study has furnished critical insights into microglia dynamics across human brain ages and cataloged potential transcriptomic fingerprints that can be further exploited for designing novel neurotherapeutics. |
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| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-11T02:51:58Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-fc6e4a0c5d9248b28a48591f012cf7872022-12-22T01:23:16ZengFrontiers Media S.A.Frontiers in Neurology1664-22952018-04-01910.3389/fneur.2018.00266335533Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential BiomarkersR. Ayana0Shailja Singh1Shailja Singh2Soumya Pati3Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Lucknow, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Lucknow, IndiaSpecial Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Lucknow, IndiaMicroglial cells form a context-dependent network of brain immunoeffector cells. Despite their indispensable roles, unresolved questions exist around biomarker discovery relevant to their cellular localization, self-renewing potential, and brain developmental dynamics. To resolve the existent gap in the annotation of candidate biomarkers, we conducted a meta-analysis of brain cells using available high-throughput data sets for deciphering microglia-specific expression profiles. We have identified 3,290 significant genes specific to microglia and further selected the top 20 dysregulated genes on the basis of p-value and log2FC. To this list, we added 7 known microglia-specific markers making the candidate list comprising 27 genes for further downstream analyses. Next, we established a connectome of these potential markers with their putative protein partners, which demonstrated strong associations of upregulated genes like Dedicator of cytokinesis 2 (DOCK2) with early/mature microglial markers such as Sphingosine kinase 1 (SPHK1), CD68, and CD45. To elucidate their respective brain anatomical location, we deconvoluted the BrainSpan Atlas expression data. This analysis showed high expression of the majority of candidate genes in microglia-dense regions (Amygdala, Hippocampus, Striatum) in the postnatal brain. Furthermore, to decipher their localized expression across brain ages, we constructed a developmental dynamics map (DDM) comprising extensive gene expression profiles throughout prenatal to postnatal stages, which resulted in the discovery of novel microglia-specific gene signatures. One of the interesting readout from DDM is that all the microglia-dense regions exhibit dynamic regulation of few genes at 37 post conception week (pcw), the transition period between pre- and postnatal stages. To validate these findings and correlate them as potential biomarkers, we analyzed the expression of corresponding proteins in hESC-derived human microglia precursors. The cultured microglial precursors showed expression of Pentraxin 3 (PTX3) and SPHK1 as well as several known markers like CD68, Allograft inflammatory factor 1 (AIF1/IBA1). In summary, this study has furnished critical insights into microglia dynamics across human brain ages and cataloged potential transcriptomic fingerprints that can be further exploited for designing novel neurotherapeutics.http://journal.frontiersin.org/article/10.3389/fneur.2018.00266/fullSPHK1agemicroglia stem cell-like progenitorsPTX3transcriptomic analysisamygdala |
| spellingShingle | R. Ayana Shailja Singh Shailja Singh Soumya Pati Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential Biomarkers Frontiers in Neurology SPHK1 age microglia stem cell-like progenitors PTX3 transcriptomic analysis amygdala |
| title | Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential Biomarkers |
| title_full | Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential Biomarkers |
| title_fullStr | Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential Biomarkers |
| title_full_unstemmed | Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential Biomarkers |
| title_short | Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia-Specific Potential Biomarkers |
| title_sort | deconvolution of human brain cell type transcriptomes unraveled microglia specific potential biomarkers |
| topic | SPHK1 age microglia stem cell-like progenitors PTX3 transcriptomic analysis amygdala |
| url | http://journal.frontiersin.org/article/10.3389/fneur.2018.00266/full |
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