Epigenetic control of gene regulation during development and disease: A view from the retina

Corso-Díaz, Ximena; Jaeger, Catherine; Chaitankar, Vijender; Swaroop, Anand

doi:10.1016/j.preteyeres.2018.03.002

Cited by 107 publications

(116 citation statements)

References 389 publications

(508 reference statements)

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“…Studies of the CMZ have primarily focused on zebrafish and Xenopus models to determine genetic pathways required for RSC identity 2,14-16 and to characterize the epigenetic networks which regulate RSC function 17,18 . By comparison, the mechanisms mediating RSC maintenance in vivo remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Whether an analogous structure exists in mammals is debated, but there are distinct, progenitor-like cells in the periphery of the retina that are active during embryogenesis 7-9 . Mammalian RSCs can also be isolated from the adult ciliary margin, cultured in vitro, and stimulated to produce retinal neurons 10-13 .However, this activity has not been demonstrated in the mature mammalian retinae in vivo.Studies of the CMZ have primarily focused on zebrafish and Xenopus models to determine genetic pathways required for RSC identity 2,14-16 and to characterize the epigenetic networks which regulate RSC function 17,18 . By comparison, the mechanisms mediating RSC maintenance in vivo remain unknown.…”

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confidence: 99%

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dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

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The ciliary marginal zone (CMZ) of the zebrafish retina contains a population of actively proliferating resident stem cells, which generate retinal neurons throughout life. The maintenance methyltransferase, dnmt1, is expressed within the CMZ. Loss of dnmt1 function results in gene misregulation and cell death in a variety of developmental contexts, however, its role in retinal stem cell (RSC) maintenance is currently unknown. Here, we demonstrate that zebrafish dnmt1 s872 mutants possess severe defects in RSC maintenance within the CMZ. Using a combination of immunohistochemistry, in situ hybridization, and a transgenic reporter assay, our results demonstrate a requirement for dnmt1 activity in the regulation of RSC proliferation, gene expression and in the repression of endogenous retroelements (REs). Ultimately, cell death is elevated in the dnmt1 -/-CMZ, but in a p53-independent manner. Using a transgenic reporter for RE transposition activity, we demonstrate increased transposition in the dnmt1 -/-CMZ. Taken together our data identify a critical role for dnmt1 function in RSC maintenance in the vertebrate eye. Introduction:The distal region of the vertebrate retina, termed the ciliary marginal zone (CMZ), contains a population of resident retinal stem cells (RSCs). The CMZ remains proliferative throughout the life of fish, but it proliferates to a more limited extent during the lifetime of amphibians and birds 1-6 . Whether an analogous structure exists in mammals is debated, but there are distinct, progenitor-like cells in the periphery of the retina that are active during embryogenesis 7-9 . Mammalian RSCs can also be isolated from the adult ciliary margin, cultured in vitro, and stimulated to produce retinal neurons 10-13 .However, this activity has not been demonstrated in the mature mammalian retinae in vivo.Studies of the CMZ have primarily focused on zebrafish and Xenopus models to determine genetic pathways required for RSC identity 2,14-16 and to characterize the epigenetic networks which regulate RSC function 17,18 . By comparison, the mechanisms mediating RSC maintenance in vivo remain unknown. In studies of RSCs, the zebrafish has been advantageous given that it possesses a highly active RSC population and is tractable for genetic and pharmacological manipulations, transgenesis and in vivo imaging 19,20 .DNA methylation, a frequently studied epigenetic modification, is the process through which a methyl group is added to the fifth carbon of cytosine nucleotides and is commonly found at CpG dinucleotide sequences 21 . Members of the family of DNA methyltransferase (Dnmt) enzymes 22,23 catalyze this epigenetic modification. Dnmt1 serves as a maintenance methyltransferase, copying the methylation pattern from parent to daughter strand during DNA replication and its function is required for cell cycle progression [24][25][26] . Loss of Dnmt1 function results in genomic hypomethylation 27-29 and in developmental contexts and specific organ systems, this often compromises progenitor cell maintenance 24...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

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“…Thus, particular attention will be paid to those studies performed at early stages using genetic models in vivo. Other excellent reviews have set the focus on the system‐level analysis, either in vivo or using organoids, of main retinal diseases such as macular degeneration and retinitis pigmentosa . As a preliminary statement, it is important to note that the assembly of GRNs is complex and we just started gathering enough information to have a minimal understanding of their architecture.…”

Section: Introductionmentioning

confidence: 99%

“…Other excellent reviews have set the focus on the system-level analysis, either in vivo or using organoids, of main retinal diseases such as macular degeneration and retinitis pigmentosa. [15][16][17] As a preliminary statement, it is important to note that the assembly of GRNs is complex and we just started gathering enough information to have a minimal understanding of their architecture. Despite the advances in the systemic identification of many network nodes and edges, the field is still going through an exploratory phase that follows the pace of recent technological innovations, ranging from RNA-seq to singlecell ATAC-seq.…”

Section: Introductionmentioning

confidence: 99%

Retina Development in Vertebrates: Systems Biology Approaches to Understanding Genetic Programs

Buono

Martı́nez-Morales

2020

BioEssays

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The ontogeny of the vertebrate retina has been a topic of interest to developmental biologists and human geneticists for many decades. Understanding the unfolding of the genetic program that transforms a field of progenitors cells into a functionally complex and multi‐layered sensory organ is a formidable challenge. Although classical genetic studies succeeded in identifying the key regulators of retina specification, understanding the architecture of their gene network and predicting their behavior are still a distant hope. The emergence of next‐generation sequencing platforms revolutionized the field unlocking the access to genome‐wide datasets. Emerging techniques such as RNA‐seq, ChIP‐seq, ATAC‐seq, or single cell RNA‐seq are used to characterize eye developmental programs. These studies provide valuable information on the transcriptional and cis‐regulatory profiles of precursors and differentiated cells, outlining the trajectories that connect each intermediate state. Here, recent systems biology efforts are reviewed to understand the genetic programs shaping the vertebrate retina.

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“…Rods and cones are produced by retinal progenitor cells (RPCs), with cones generally produced earlier in development than rods, from RPCs that express the TFs Otx2, Olig2 , and Oc1 23–26 These and other TFs with essential roles in RPCs, rods, or cones have been identified 27,28 . In addition to Otx2 , a close homologue, Crx , is required for normal gene expression in both rods and cones 29–31 .…”

Section: Introductionmentioning

confidence: 99%

Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types

Nadadur

Perez-Cervantes

Lonfat

et al. 2019

Preprint

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39Identification of the cis-regulatory elements (CREs) that regulate gene expression in 40 specific cell types is critical for defining the gene regulatory networks (GRNs) that 41 control normal physiology and disease states. We previously utilized non-coding RNA 42 (ncRNA) profiling to define CREs that comprise a GRN in the adult mouse heart 1 . Here, 43we applied ncRNA profiling to the mouse retina in the presence and absence of Nrl, a 44 rod photoreceptor-specific transcription factor required for rod versus cone 45 photoreceptor cell fate. Differential expression of Nrl-dependent ncRNAs positively 46 correlated with differential expression of Nrl-dependent local genes. Two distinct Nrl-47 dependent regulatory networks were discerned in parallel: Nrl-activated ncRNAs were 48 enriched for accessible chromatin in rods but not cones whereas Nrl-repressed ncRNAs 49were enriched for accessible chromatin in cones but not rods. Furthermore, differential 50Nrl-dependent ncRNA expression levels quantitatively correlated with photoreceptor cell 51 type-specific ATAC-seq read density. Direct assessment of Nrl-dependent ncRNA-52 defined loci identified functional cone photoreceptor CREs. This work supports 53 differential ncRNA profiling as a platform for identifying context-specific regulatory 54 elements and provides insight into the networks that define photoreceptor cell types. 55 contexts and its ability to distinguish activated and repressed elements has not been 79 examined. 80Here, we applied the differential ncRNA approach to identify regulatory elements 81 that are active in either of two specific cell types, rod and cone photoreceptors, in the 82 mouse retina. Rod photoreceptors are active in dim light and constitute the most 83 abundant retinal cell type, comprising ~80% of all mouse retinal cells and 95% of human 84 photoreceptors 11,12 . In contrast, cone photoreceptors are active in bright light and 85 mediate high-acuity vision and color vision. Their critical role in daylight vision makes 86 them a desirable cell type to replace from stem cells, or to target for gene therapy, in 87 diseases that lead to blindness 13 . An understanding of the GRNs that control cone 88 versus rod fate is essential for understanding both normal retinal biology and for cone 89 replacement, as has been recently demonstrated for rods in mice [14][15][16][17][18][19] . In addition, gene 90 therapy vectors that require expression specifically in rods and/or cones would benefit 91 from a broader range of validated photoreceptor CREs 20-22 . 92Rods and cones are produced by retinal progenitor cells (RPCs), with cones 93 generally produced earlier in development than rods, from RPCs that express the TFs 94Otx2, Olig2, and Oc1 23-26 . These and other TFs with essential roles in RPCs, rods, or 95 cones have been identified 27,28 . In addition to Otx2, a close homologue, Crx, is required 96 for normal gene expression in both rods and cones [29][30][31] . In contrast, Nrl, a basic leucine 97 zipper TF, is expressed only in rods and is ...

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Epigenetic control of gene regulation during development and disease: A view from the retina

Cited by 107 publications

References 389 publications

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Retina Development in Vertebrates: Systems Biology Approaches to Understanding Genetic Programs

Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types

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