Cell-Type-Specific Analysis of Molecular Pathology in Autism Identifies Common Genes and Pathways Affected Across Neocortical Regions

2020 ◽  
Vol 57 (5) ◽  
pp. 2279-2289 ◽  
Author(s):  
Dmitry Velmeshev ◽  
Marco Magistri ◽  
Emilia Maria Cristina Mazza ◽  
Patrick Lally ◽  
Nathalie Khoury ◽  
...  
2020 ◽  
Author(s):  
Emily A. McGlade ◽  
Gerardo G. Herrera ◽  
Kalli K. Stephens ◽  
Sierra L. W. Olsen ◽  
Sarayut Winuthayanon ◽  
...  

AbstractOne of the endogenous estrogens, 17β-estradiol (E2) is a female steroid hormone secreted from the ovary. It is well established that E2 causes biochemical and histological changes in the uterus. The oviduct response to E2 is virtually unknown in an in vivo environment. In this study, we assessed the effect of E2 on each oviductal cell type, using an ovariectomized-hormone-replacement mouse model, single cell RNA-sequencing (scRNA-seq), in situ hybridization, and cell-type-specific deletion in mice. We found that each cell type in the oviduct responded to E2 distinctively, especially ciliated and secretory epithelial cells. The treatment of exogenous E2 did not drastically alter the transcriptomic profile from that of endogenous E2 produced during estrus. Moreover, we have identified and validated genes of interest in our datasets that may be used as cell- and region-specific markers in the oviduct. Insulin-like growth factor 1 (Igf1) was characterized as an E2-target gene in the mouse oviduct and was also expressed in human Fallopian tubes. Deletion of Igf1 in progesterone receptor (Pgr)-expressing cells resulted in female subfertility, partially due to an embryo developmental defect and embryo retention within the oviduct. In summary, we have shown that oviductal cell types are differentially regulated by E2 and support gene expression changes that are required for normal embryo development and transport in mouse models.


2007 ◽  
Vol 21 (5) ◽  
Author(s):  
Ronald M. Lynch ◽  
Roger Barthelson ◽  
Julia Cates ◽  
Heddwen L. Brooks ◽  
David W. Galbraith

2020 ◽  
Author(s):  
Xiao Qin ◽  
Jahangir Sufi ◽  
Petra Vlckova ◽  
Pelagia Kyriakidou ◽  
Sophie E. Acton ◽  
...  

Abstract Organoids are powerful biomimetic tissue models. Despite their increasing popularity, no existing methods are suitable for cell-type specific analysis of post-translational modification (PTM) signalling networks in organoids. Here we report a multivariate mass cytometry (MC) protocol for single-cell analysis of cell-type specific PTM signalling in organoid monocultures and organoids co-cultured with stromal and immune cells. Thiol-reactive Organoid Barcoding in situ (TOBis) was developed to facilitate high-throughput comparison of signalling networks between organoid cultures. Taken together, our protocol enables high-throughput multivariate PTM signalling analysis of healthy and cancerous organoids at the single-cell level.


Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 51 ◽  
Author(s):  
Rashaun S. Wilson ◽  
Angus C. Nairn

Cell-type-specific analysis has become a major focus for many investigators in the field of neuroscience, particularly because of the large number of different cell populations found in brain tissue that play roles in a variety of developmental and behavioral disorders. However, isolation of these specific cell types can be challenging due to their nonuniformity and complex projections to different brain regions. Moreover, many analytical techniques used for protein detection and quantitation remain insensitive to the low amounts of protein extracted from specific cell populations. Despite these challenges, methods to improve proteomic yield and increase resolution continue to develop at a rapid rate. In this review, we highlight the importance of cell-type-specific proteomics in neuroscience and the technical difficulties associated. Furthermore, current progress and technological advancements in cell-type-specific proteomics research are discussed with an emphasis in neuroscience.


2019 ◽  
Author(s):  
Daniel W Kennedy ◽  
Nicole M White ◽  
Miles C Benton ◽  
Rodney A Lea ◽  
Kerrie Mengersen

MotivationEpigenome-wide studies are often performed using heterogeneous methylation samples, especially when there is no prior information as to which cell-types are disease associated. While much work has been done in ascertaining cell-type fractions and removing cell-type heterogeneity variation, relatively little work has been done in identifying cell-type specific variation in heterogeneous samples.ResultsIn this paper, we present a Bayesian model-based approach for making cell-type specific inferences in heterogeneous settings, by using a logit-Normal sampling distribution and incorporating a priori knowledge of cell-type lineage. The method is applied to the detection of cell-type specific sex effects in methylation, where cell-type information is present as an independent verification of the results. Panels derived from this method contained more loci where CD8+T, CD19+B and Natural Killer cell-types were differentially methylated. The analysis suggests that an ensemble approach with this method included could be used for discovering cell-type specific methylation changes.Availabilityhttps://github.com/danwkenn/Bayes_CDM


2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Brittany P. Todd ◽  
Michael S. Chimenti ◽  
Zili Luo ◽  
Polly J. Ferguson ◽  
Alexander G. Bassuk ◽  
...  

Abstract Background Traumatic brain injury (TBI) is a leading cause of death and disability that lacks neuroprotective therapies. Following a TBI, secondary injury response pathways are activated and contribute to ongoing neurodegeneration. Microglia and astrocytes are critical neuroimmune modulators with early and persistent reactivity following a TBI. Although histologic glial reactivity is well established, a precise understanding of microglia and astrocyte function following trauma remains unknown. Methods Adult male C57BL/6J mice underwent either fluid percussion or sham injury. RNA sequencing of concurrently isolated microglia and astrocytes was conducted 7 days post-injury to evaluate cell-type-specific transcriptional responses to TBI. Dual in situ hybridization and immunofluorescence were used to validate the TBI-induced gene expression changes in microglia and astrocytes and to identify spatial orientation of cells expressing these genes. Comparative analysis was performed between our glial transcriptomes and those from prior reports in mild TBI and other neurologic diseases to determine if severe TBI induces unique states of microglial and astrocyte activation. Results Our findings revealed sustained, lineage-specific transcriptional changes in both microglia and astrocytes, with microglia showing a greater transcriptional response than astrocytes at this subacute time point. Microglia and astrocytes showed overlapping enrichment for genes related to type I interferon signaling and MHC class I antigen presentation. The microglia and astrocyte transcriptional response to severe TBI was distinct from prior reports in mild TBI and other neurodegenerative and neuroinflammatory diseases. Conclusion Concurrent lineage-specific analysis revealed novel TBI-specific transcriptional changes; these findings highlight the importance of cell-type-specific analysis of glial reactivity following TBI and may assist with the identification of novel, targeted therapies.


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