Multi-species single-cell transcriptomic analysis of ocular compartment regulons

Gautam, Pradeep; Hamashima, Kiyofumi; Chen, Ying; Zeng, Yingying; Makovoz, Bar; Parikh, Bhav Harshad; Lee, Hsin Yee; Lau, Katherine Anne; Su, Xinyi; Wong, Raymond Ching-Bong; Chan, Woon‐Khiong; Hu, Li; Blenkinsop, Timothy A.; Loh, Yuin Han

doi:10.1038/s41467-021-25968-8

Cited by 65 publications

(79 citation statements)

References 60 publications

(70 reference statements)

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“…(C) For functional analysis follow-up, top genetic hits were prioritized based on different criteria such as being the causal gene at the locus (presence of coding variants), the rave variants (RV) identified being enriched in Q1 patients, the gene playing a role in a biological pathway associated with AMD pathophysiology, and providing a potential biomarker opportunity. For the top hits, gene expression in human retina or RPE/choroid (bulk RNA sequencing, data from Orozco et al 34 ) and in different human ocular cell types (single cell RNA sequencing, data from Gautam et al 35 ) were also analyzed. AR: autosomal recessive; FPLD5: Familial Partial Lipodystrophy type 5.…”

Section: Resultsmentioning

confidence: 99%

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Kim

Stockwell²,

Qin³

et al. 2022

Preprint

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Background: The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. Methods: AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro. Results: We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes. Conclusions: As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.

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Section: Resultsmentioning

confidence: 99%

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Kim

Stockwell²,

Qin³

et al. 2022

Preprint

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“…It is recovered as a heterodimer with KRT5 and form the cytoskeleton of epithelial cells [27,28]. Gautam et al, using multi-species single-cell transcriptomic analysis of human eye, KRT 14 was expressed in corneal epithelial cells [29]. However, previous studies did not perform deeper investigation in POAG.…”

Section: Discussionmentioning

confidence: 99%

Screening of Primary Open-Angle Glaucoma Diagnostic Markers based on Immune-related Genes and Immune Infiltration

Zhang

Suo

Dai

et al. 2022

Preprint

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PURPOSE. Primary open-angle glaucoma (POAG) continues to be a poorly understood disease. Performing bioinformatics analyses of optic nerve (ON) and trabecular meshwork (TM) gene expression data in order to further elucidate the immune-related genes of POAG and identify candidate target genes for treatment.METHODS. We performed a gene analysis of publicly available microarray data, namely, the GSE27276-GPL2507, GSE2378-GPL8300, GSE9944-GPL8300, GSE9944-GPL571 datasets from Gene Expression Omnibus database. The obtained datasets were used as input for parallel pathway analyses. Based on Random Forest and Support vector machine (SVM) analysis to screen the key genes, significantly changed pathways were clustered into functional categories and the results were further investigated. CIBERSORT was used to evaluate infiltration of immune cells in POAG tissues. A network visualizing the differences between the POAG and normal was created. GO and KEGG enrichment analyses were performed using the Metascape database. We divided the differential mRNA into up-regulated and down-regulated groups, and predicted the drug targeting of the differential genes through the Connectivity Map (CMap) database.RESULTS. A total of 49 differentially expressed genes, including 19 downregulated genes and 30 upregulated genes, were detected. Five genes (KRT14, HBB, ACOX2, HEPH and KRT13) were significantly changed. The results showed that the expression profiles of drug disturbances such as avrainvillamide-analysis-3, cytochalasin-D, NPI-2358, oxymethylone and vinorelbine were negatively correlated with the expression profiles of disease disturbances. It indicated that these drugs may reduce or even reverse the POAG disease state.CONCLUSION. This study provides an overview of the processes involved in the molecular pathogenesis of POAG in the ON and TM. The findings provide a new understanding of the molecular mechanism of POAG from the perspective of immunology.

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“…Such strategy is particularly attractive when we consider the potential heterogeneity of the CSC compartment. This strategy was employed by Gautam et al (2021) to generate a multispecies cell roadmap for human and porcupine ocular compartments. The ability to use organoids and enrich for stem cell like progenitors offers new possibilities to further decode CSCs.…”

Section: Probing the Cellular Niche: Technological Advancesmentioning

confidence: 99%

Uncovering Pharmacological Opportunities for Cancer Stem Cells—A Systems Biology View

Correia

Weiskittel

Ung

et al. 2022

Front. Cell Dev. Biol.

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Cancer stem cells (CSCs) represent a small fraction of the total cancer cell population, yet they are thought to drive disease propagation, therapy resistance and relapse. Like healthy stem cells, CSCs possess the ability to self-renew and differentiate. These stemness phenotypes of CSCs rely on multiple molecular cues, including signaling pathways (for example, WNT, Notch and Hedgehog), cell surface molecules that interact with cellular niche components, and microenvironmental interactions with immune cells. Despite the importance of understanding CSC biology, our knowledge of how neighboring immune and tumor cell populations collectively shape CSC stemness is incomplete. Here, we provide a systems biology perspective on the crucial roles of cellular population identification and dissection of cell regulatory states. By reviewing state-of-the-art single-cell technologies, we show how innovative systems-based analysis enables a deeper understanding of the stemness of the tumor niche and the influence of intratumoral cancer cell and immune cell compositions. We also summarize strategies for refining CSC systems biology, and the potential role of this approach in the development of improved anticancer treatments. Because CSCs are amenable to cellular transitions, we envision how systems pharmacology can become a major engine for discovery of novel targets and drug candidates that can modulate state transitions for tumor cell reprogramming. Our aim is to provide deeper insights into cancer stemness from a systems perspective. We believe this approach has great potential to guide the development of more effective personalized cancer therapies that can prevent CSC-mediated relapse.

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Multi-species single-cell transcriptomic analysis of ocular compartment regulons

Cited by 65 publications

References 60 publications

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Screening of Primary Open-Angle Glaucoma Diagnostic Markers based on Immune-related Genes and Immune Infiltration

Uncovering Pharmacological Opportunities for Cancer Stem Cells—A Systems Biology View

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