Nucleome Dynamics during Retinal Development [scRNA-seq/scATAC-seq_Mm]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE164044 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:Single cell RNA-sequencing shows cell type specific expression of genes in the retina. Single cell ATAC-sequencing of the wild type retina at multiple stages revealed that chromatin in the Vsx2 CRC SE, a stage- and cell type-specific core regulatory circuit super-enhancer (CRC-SE) upstream of the Vsx2 gene, was only open in bipolar cells in Region3 in adult retina. Chromatin in Region0 was open in retinal progenitor cells in E14.5 retina.
2021-11-16 | GSE169262 | GEO
Project description:The nuclei of rod photoreceptors in mice and other nocturnal species have an unusual inverted chromatin structure with centrally located heterochromatin that helps to focus light and improve photosensitivity. To gain a deeper understanding of this unique nuclear organization of rod photoreceptors, we have carried out Hi-C on retina at 3 stages of development and on purified rod photoreceptors. Predicted looping interactions from the Hi-C data were validated with fluorescent in situ hybridization (FISH). We discovered that a subset of genes important for retinal development, cancer and stress response in the retina are localized to the facultative heterochromatin domain in a developmental stage– and cell type–specific manner. We used machine learning to develop an algorithm based on our chromatin Hidden Markov Modeling (chromHMM) of retinal development to predict heterochromatin domains and study their dynamics during retinogenesis. FISH data for 264 genomic loci were used to train and validate the algorithm. These integrated data (https://pecan.stjude.cloud/retinalnucleome) were used to identify a developmental stage- and cell type-specific core regulatory circuit super-enhancer (CRC-SE) upstream of the Vsx2 gene that is required for bipolar neuron expression. Deletion of the Vsx2 CRC-SE in mice led to the loss of bipolar neurons in the retina.
2019-09-05 | GSE135465 | GEO
Project description:Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of transcription factor Vsx2 in a developmental stage- and cell-type specific manner. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of one Vsx2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease.
2024-06-04 | GSE268990 | GEO
Project description:Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify key cis-regulatory features that mediate the transcriptomic and functional differences between them. We generated open chromatin maps and transcriptome profiles of mouse ON and OFF bipolar cells isolated by fluorescence-activated cell sorting (FACS) and compared them to similar data from rod and cone photoreceptors. We found that photoreceptors and bipolar cells have divergent transcriptional profiles, and yet share remarkably similar cis-regulatory grammars. The predominant cis-regulatory motifs in the enhancers of both cell classes are K50 homeodomain binding sites, which are required for activity. These motifs are bound by two transcription factors (TFs), CRX and OTX2, which are expressed in both photoreceptors and bipolar cells. In contrast, cell type-specific open chromatin regions are distinguished by enrichment of E-box motifs in bipolar cells, and Q50 homeodomain motifs in photoreceptors. In bipolar cells, Q50 motifs are thought to mediate repression of photoreceptor-specific genes through the bipolar-specific TF VSX2. We show that converting selected K50 motifs to Q50 motifs represses reporter expression in bipolar cells, while photoreceptor expression is maintained. These findings suggest that partitioning of Q50 motifs within cell type-specific CREs was likely a critical step in the divergence of the bipolar transcriptome from that of photoreceptors, facilitating the emergence of the complex interneuronal circuitry of the vertebrate retina.
2019-10-16 | GSE131625 | GEO
Project description:Bhlhe23 is a transcription factor that is required for the maturation and survival of retinal rod bipolar cells in mice. In the Bhlhe23-/- retina, rod bipolar cells are born in normal numbers, then die by apoptosis from postnatal day 8. We identified genes that were likely to be important to rod bipolar cell development and survival by identifying genes that were significantly differentially expressed in the transcriptome of the Bhlhe23-/- mouse retina compared with wild type retina at postnatal day 7. just before the onset of rob bipolar cell death.
2017-09-20 | E-MTAB-6071 | biostudies-arrayexpress
Project description:Bhlhe23 is a transcription factor that is required for the maturation and survival of retinal rod bipolar cells in mice. In the adult Bhlhe23-/- retina, rod bipolar cells are almost completely absent. We identified genes that were likely to be important to rod bipolar cell maintenance and function by identifying genes that were significantly down-regulated in the transcriptome of adult Bhlhe23-/- mouse retina compared with wild type retina.
2017-09-20 | E-MTAB-6069 | biostudies-arrayexpress
Project description:The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
2022-07-13 | GSE196104 | GEO
Project description:The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
2022-07-13 | GSE196103 | GEO
Project description:The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
2022-07-13 | GSE196097 | GEO
Project description:Diverse cell types can be reprogrammed into pluripotent stem cells by ectopic expression of Oct4 (Pou5f1), Klf4, Sox3 and Myc. Many of these induced pluripotent stem cells (iPSCs) retain an epigenetic memory of their cellular origins and this in turn may bias their subsequent differentiation. Differentiated neurons are difficult to reprogram and there has not been a systematic side-by-side characterization of reprogramming efficiency or epigenetic memory across different neuronal subtypes. We have recently developed a new method for reprogramming retinal neurons and successfully reprogrammed rod photoreceptors from the murine retina. Here we extended our retinal reprogramming to cone photoreceptors, bipolar neurons, amacrine/horizontal cell interneurons and Müller glia at two different stages of development. We scored the efficiency of reprogramming across all 5 retinal cell types at each developmental stage and we measured retinal differentiation from each iPSC line using a quantitative standardized scoring system called STEM-RET. We discovered that the rod photoreceptors and bipolar neurons had the lowest reprogramming efficiency but iPSCs derived from rods and bipolar cells had the best retinal differentiation. Epigenetic memory was analyzed by characterizing DNA methylation and performing ChIP-seq for 8 histone marks, Brd4, PolII and CTCF. The epigenetic data were integrated with RNA-Seq data from each iPSC line. Retinal cell types with a greater epigenetic barrier to reprogramming (rods and bipolars) are more likely to retain epigenetic memory of their cellular origins. In addition, we identified biomarkers of iPSCs that are predictive of retinal differentiation. This work will have implications for selection of cell populations for cell based therapy and for using reprogramming of purified cell populations to advance our understanding of the role of the epigenome in normal differentiation.
2018-01-28 | GSE109712 | GEO