Single-cell multiome of the human retina and deep learning nominate causal variants in complex eye diseases

Wang, Sean K.; Nair, Surag; Li, Rui; Kraft, Katerina; Pampari, Anusri; Patel, Aman; Kang, Je-Won; Luong, Christy; Kundaje, Anshul; Chang, Howard Y.

doi:10.1016/j.xgen.2022.100164

Cited by 31 publications

(42 citation statements)

References 66 publications

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“…To investigate RGC migration in the developing retina, we sourced available human fetal and adult retina single-cell RNA sequencing data to explore which pro-migratory signals are upregulated during RGC development. 32,33 There are two major neuron migration patterns in retinal and cerebral development: radial and tangential. 50 Tangential migration means that neurons follow the axis perpendicular to the tissue's apico-basal axis (XY plane), but this rarely occurs in the vertebrate retina, 51 where most neurons and progenitors travel radially.…”

Section: Resultsmentioning

confidence: 99%

“…Single-cell RNA sequencing data analysis and identification of targets. The data analysis was performed using the obtained datasets from Wang et al for human adult retina, 32 and Sridhar et al for fetal (FD59, FD82, FD105) and hPSC-derived retinal organoids (OD45, OD60). 33 The data remaining after quality control filtering were analyzed in RStudio v. 1.4.1717 (R 4.1.1) using the Seurat package (v. 4.1.0).…”

Section: Maintenance Of Human Stem Cells and Human Rgc Differentiationmentioning

confidence: 99%

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Introduced chemokine gradients guide transplanted and regenerated retinal neurons toward their natural position in the retina

Soucy

Todd

Kryukov

et al. 2022

Preprint

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Ongoing cell replacement studies and clinical trials have demonstrated the need to control donor and newborn cell behavior within their target tissue. Here we present a methodology to guide stem cell-derived and endogenously regenerated neurons by engineering the microenvironment. Being an ″approachable part of the brain,″ the eye provides a unique opportunity to study donor neuron fate, migration, and integration within the central nervous system. Glaucoma and other optic neuropathies lead to the permanent loss of retinal ganglion cells (RGCs) - the neurons in the retina that transfer all visual information from the eye to the brain. Cell transplantation and transdifferentiation strategies have been proposed to restore RGCs, and one of the significant barriers to successful RGC integration into the existing retinal circuitry is cell migration towards their natural position in the retina. Here we describe a framework for identifying, selecting, and applying chemokines to direct cell migration in vivo within the retina. We have performed an in silico analysis of the single-cell transcriptome of the developing human retina and identified six receptor-ligand candidates to guide stem cell-derived or newborn neurons. The lead candidates were then tested in functional in vitro assays for their ability to guide stem cell-derived RGCs. For the in vivo studies, donor and newborn neurons were differentiated in human and mouse retinal organoids or endogenously reprogrammed with proneuronal transcription factors, respectively. An exogenous stromal cell-derived factor-1 (SDF1) gradient led to a 2.7-fold increase in donor RGC migration into the ganglion cell layer and a 3.3-fold increase in the displacement of newborn RGCs out of the inner nuclear layer. Furthermore, by altering the migratory profile of donor RGCs toward multipolar migration, overall migration was improved in mature retinal tissues. Together, these results highlight the ability and importance of engineering the tissue microenvironment and the individual cells for research and clinical applications in gene and cell therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Maintenance Of Human Stem Cells and Human Rgc Differentiationmentioning

confidence: 99%

Introduced chemokine gradients guide transplanted and regenerated retinal neurons toward their natural position in the retina

Soucy

Todd

Kryukov

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Second, we collected retina H3K27ac HiChIP loops 23 to annotate all credible variants with spatially proximal genes. We found that three credible variants supported by HiChIP loops linked to different genes, and they were located in the eye enhancer regions or Müller cell/astrocyte open chromatin peaks according to single-cell multiome profiles.…”

Section: Resultsmentioning

confidence: 99%

“…If yes, eQTL harboring genes (eGenes) were selected. 2) Is the locus located in the open chromatin peaks from retina H3K27ac HiChIP data 23 ? If yes, causal genes were anchor-targeted genes.…”

Section: Methodsmentioning

confidence: 99%

“…We applied MAGMA 43 to evaluate whether specific ocular cell types showed significant heritability enrichment for traits based on ASSET one-sided summary statistics. MAGMA also requires gene average expression level across cell types derived from single-cell RNA sequencing (scRNA-seq) and single-cell multi-omics sequencing data of anterior chamber angle or retina/choroid 20; 21; 23; 44-46 ( Table S2 ). We additionally downloaded the raw data and determined the average expression values per cell type for each dataset using Cell Ranger 47 and the R package Seurat 48 unless the information was available.…”

Section: Methodsmentioning

confidence: 99%

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Genome-wide analysis of genetic pleiotropy and causal genes across three age-related ocular disorders

Yao

Yang

Han

et al. 2022

Preprint

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Purpose: Genome-wide association studies (GWAS) have revealed plenty of putative loci of ocular disorders, and the relationship among ocular disorders manifesting vision loss has been widely studied. However, genetic pleiotropy correlations remain unknown in eye diseases. Methods: The GWAS summary statistics of age-related macular disorder (AMD), cataract and glaucoma were leveraged to dissect the genetic pleiotropy from three aspects: genomic pleiotropy, regional pleiotropy and variant-level pleiotropy. A meta-analysis using three approaches was performed. Cell types related to disease risk were unveiled using retina and anterior chamber angle single cell RNA (scRNA) seq profiles and retina single cell ATAC (scATAC) seq data. Causal pleiotropic genes of the above three diseases were prioritized base on the colocalization between retina-specific/cell-type-specific annotations and credible sets. In addition, we assessed the protein-protein network of candidate causal genes as well as the druggability. Results: Genetic correlations were corroborated and eleven pleiotropic regions were identified between the pairs of AMD, cataract and glaucoma. Ten pleiotropic loci were jointly identified, including three pleiotropic loci intersecting with retina-specific eQTL SNPs and enhancer regions as well as six pleiotropic loci resided in HiChIP loops or cell-type-specific peaks. Six loci were replicated using the Finggen GWAS data of corresponding diseases. Muller cell, astrocyte, vascular endothelium and fibroblast were identified in cell-type trait association analysis. Through the strategy we have formulated, thirty genes causally associated with three traits were prioritized, which enriched in the pathways of nerve development and cell communication. Conclusions: The genetic pleiotropy of AMD, cataract and glaucoma was detailedly characterized in our study which provides potential drug targets for ocular disorders.

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eQTL studies: from bulk tissues to single cells

Zhang

Zhao

2023

Journal of Genetics and Genomics

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Single-cell multiome of the human retina and deep learning nominate causal variants in complex eye diseases

Cited by 31 publications

References 66 publications

Introduced chemokine gradients guide transplanted and regenerated retinal neurons toward their natural position in the retina

Introduced chemokine gradients guide transplanted and regenerated retinal neurons toward their natural position in the retina

Genome-wide analysis of genetic pleiotropy and causal genes across three age-related ocular disorders

eQTL studies: from bulk tissues to single cells

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