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

ABSTRACT: Complex biological processes, such as organogenesis and homeostasis, are stringently regulated by genetic programs that are fine-tuned by epigenetic factors to establish cell fates and/or to respond to the microenvironment. Gene regulatory networks that guide cell differentiation and function are modulated and stabilized by modifications to DNA, RNA and proteins. In this review, we focus on two key epigenetic changes - DNA methylation and histone modifications - and discuss their contribution to retinal development, aging and disease, especially in the context of age-related macular degeneration (AMD) and diabetic retinopathy. We highlight less-studied roles of DNA methylation and provide the RNA expression profiles of epigenetic enzymes in human and mouse retina in comparison to other tissues. We also review computational tools and emergent technologies to profile, analyze and integrate epigenetic information. We suggest implementation of editing tools and single-cell technologies to trace and perturb the epigenome for delineating its role in transcriptional regulation. Finally, we present our thoughts on exciting avenues for exploring epigenome in retinal metabolism, disease modeling, and regeneration.

SUBMITTER: Corso-Diaz X

PROVIDER: S-EPMC6054546 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Corso-Díaz Ximena X Jaeger Catherine C Chaitankar Vijender V Swaroop Anand A

Progress in retinal and eye research 20180312

Complex biological processes, such as organogenesis and homeostasis, are stringently regulated by genetic programs that are fine-tuned by epigenetic factors to establish cell fates and/or to respond to the microenvironment. Gene regulatory networks that guide cell differentiation and function are modulated and stabilized by modifications to DNA, RNA and proteins. In this review, we focus on two key epigenetic changes - DNA methylation and histone modifications - and discuss their contribution to ...[more]

PMID: 29544768

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Project description:AimIdentification of genes that contribute to secondary palate development provide a better understanding of the etiology of palatal clefts. Gene-expression profiling of the murine palate from gestational days 12-14 (GD12-14), a critical period in palate development, identified Sox4 as a differentially expressed gene. In this study, we have examined if the differential expression of Sox4 in the palate is due to changes in DNA methylation.Materials & methodsIn situ hybridization analysis was used to localize the expression of Sox4 in the developing murine secondary palate. CpG methylation profiling of a 1.8-kb upstream region of Sox4 in the secondary palate from GD12-14 and transfection analysis in murine embryonic maxillary mesenchymal cells using Sox4 deletion, mutant and in vitro methylated plasmid constructs were used to identify critical CpG residues regulating Sox4 expression in the palate.ResultsSpatiotemporal analysis revealed that Sox4 is expressed in the medial edge epithelium and presumptive rugae-forming regions of the palate from GD12 to GD13. Following palatal shelf fusion on GD14, Sox4 was expressed exclusively in the epithelia of the palatal rugae, structures that serve as signaling centers for the anteroposterior extension of the palate, and that are thought to serve as neural stem cell niches. Methylation of a 1.8-kb region upstream of Sox4, containing the putative promoter, completely eliminated promoter activity. CpG methylation profiling of the 1.8-kb region identified a CpG-poor region (DMR4) that exhibited significant differential methylation during palate development, consistent with changes in Sox4 mRNA expression. Changes in the methylation of DMR4 were attributed primarily to CpGs 83 and 85.ConclusionOur studies indicate that Sox4 is an epigenetically regulated gene that likely integrates multiple signaling systems for mediating palatal fusion, palatal extension and/or the maintenance of the neural stem cell niche in the rugae.

Project description:Epigenetic modifications are heritable changes in gene expression without changes in DNA sequence. DNA methylation has been implicated in the control of several cellular processes including differentiation, gene regulation, development, genomic imprinting and X-chromosome inactivation. Methylated cytosine residues at CpG dinucleotides are commonly associated with gene repression; conversely, strategic loss of methylation during development could lead to activation of lineage-specific genes. Evidence is emerging that bone development and growth are programmed; although, interestingly, bone is constantly remodelled throughout life. Using human embryonic stem cells, human fetal bone cells (HFBCs), adult chondrocytes and STRO-1(+) marrow stromal cells from human bone marrow, we have examined a spectrum of developmental stages of femur development and the role of DNA methylation therein. Using pyrosequencing methodology we analysed the status of methylation of genes implicated in bone biology; furthermore, we correlated these methylation levels with gene expression levels using qRT-PCR and protein distribution during fetal development evaluated using immunohistochemistry. We found that during fetal femur development DNA methylation inversely correlates with expression of genes including iNOS (NOS2) and COL9A1, but not catabolic genes including MMP13 and IL1B. Furthermore, significant demethylation was evident in the osteocalcin promoter between the fetal and adult developmental stages. Increased TET1 expression and decreased expression of DNA (cytosine-5-)-methyltransferase 1 (DNMT1) in adult chondrocytes compared to HFBCs could contribute to the loss of methylation observed during fetal development. HFBC multipotency confirms these cells to be an ideal developmental system for investigation of DNA methylation regulation. In conclusion, these findings demonstrate the role of epigenetic regulation, specifically DNA methylation, in bone development, informing and opening new possibilities in development of strategies for bone repair/tissue engineering.

Project description:BackgroundBetween embryonic day 12 and postnatal day 21, six major neuronal and one glia cell type are generated from multipotential progenitors in a characteristic sequence during mouse retina development. We investigated expression patterns of retina transcripts during the major embryonic and postnatal developmental stages to provide a systematic view of normal mouse retina development,ResultsA tissue-specific cDNA microarray was generated using a set of sequence non-redundant EST clones collected from mouse retina. Eleven stages of mouse retina, from embryonic day 12.5 (El2.5) to postnatal day 21 (PN21), were collected for RNA isolation. Non-amplified RNAs were labeled for microarray experiments and three sets of data were analyzed for significance, hierarchical relationships, and functional clustering. Six individual gene expression clusters were identified based on expression patterns of transcripts through retina development. Two developmental phases were clearly divided with postnatal day 5 (PN5) as a separate cluster. Among 4,180 transcripts that changed significantly during development, approximately 2/3 of the genes were expressed at high levels up until PN5 and then declined whereas the other 1/3 of the genes increased expression from PN5 and remained at the higher levels until at least PN21. Less than 1% of the genes observed showed a peak of expression between the two phases. Among the later increased population, only about 40% genes are correlated with rod photoreceptors, indicating that multiple cell types contributed to gene expression in this phase. Within the same functional classes, however, different gene populations were expressed in distinct developmental phases. A correlation coefficient analysis of gene expression during retina development between previous SAGE studies and this study was also carried out.ConclusionThis study provides a complementary genome-wide view of common gene dynamics and a broad molecular classification of mouse retina development. Different genes in the same functional clusters are expressed in the different developmental stages, suggesting that cells might change gene expression profiles from differentiation to maturation stages. We propose that large-scale changes in gene regulation during development are necessary for the final maturation and function of the retina.

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

Publications

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

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