Abstract

Retinal neurogenesis is driven by concerted actions of transcription factors, some of which are expressed in a continuum and across several cell subtypes throughout development. While seemingly redundant, many factors diversify their regulatory outcome on gene expression, by coordinating variations in chromatin landscapes to drive divergent retinal specification programs. Recent studies have furthered the understanding of the epigenetic contribution to the progression of age-related macular degeneration, a leading cause of blindness in the elderly. The knowledge of the epigenomic mechanisms that control the acquisition and stabilization of retinal cell fates and are evoked upon damage, holds the potential for the treatment of retinal degeneration. Herein, this review presents the state-of-the-art approaches to investigate the retinal epigenome during development, disease, and reprogramming. A pipeline is then reviewed to functionally interrogate the epigenetic and transcriptional networks underlying cell fate specification, relying on a truly unbiased screening of open chromatin states. The related work proposes an inferential model to identify gene regulatory networks, features the first footprinting analysis and the first tentative, systematic query of candidate pioneer factors in the retina ever conducted in any model organism, leading to the identification of previously uncharacterized master regulators of retinal cell identity, such as the nuclear factor I, NFI. This pipeline is virtually applicable to the study of genetic programs and candidate pioneer factors in any developmental context. Finally, challenges and limitations intrinsic to the current next-generation sequencing techniques are discussed, as well as recent advances in super-resolution imaging, enabling spatio-temporal resolution of the genome.

Highlights

  • The eye, the primary sense organ for vision, is often seen as an extension of the brain, and a model system to study the central nervous system

  • Five different cell types in the murine retina and derivative iPSCs lines were produced in mosaic co-cultures with post-natal retinal pellets; the iPSCs lines were compared at two developmental stages for their ability to regenerate retinal organoids and to display cellular pliancy [99], that is, predisposition to undergo reprogramming by the acquisition of epigenetically active states

  • Following this first evidence by footprinting analysis showing that transcription factors (TFs) binding is directly affected in human photoreceptors and retinal pigmented epithelium (RPE) during macular degeneration [226], subsequent studies have investigated the impact of genome-wide associated variants and possible single nucleotide polymorphisms on TF mediated regulatory networks and binding sites in the human retina [70,235]

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Summary

Introduction

The eye, the primary sense organ for vision, is often seen as an extension of the brain, and a model system to study the central nervous system. Traditionally adopted to scan retinal thickness in agerelated macular degeneration and glaucoma can be used to monitor other neurological conditions, such as multiple sclerosis and Parkinson’s disease [23–26], for which visual acuity tests can be leveraged, involving measuring low-contrast letter acuity, the speed of rapid number naming and rapid picture naming [27–29]. Understanding the molecular mechanisms that underpin retinal neurogenesis and degeneration leading to visual dysfunction holds promise for the early neurological diagnosis and potential treatment of neurodegenerative diseases. Several model organisms have been leveraged to investigate the retinogenesis, retinal degeneration, and differences in the regenerative capacity of the retina, leading to a compendium of data over genetics, epigenetic master regulators of cell fate identity, and related gene regulatory networks. I will discuss challenges and limitations intrinsic to current next-generation sequencing techniques

Temporal Patterning in the Retina
Molecular Staging and Taxonomic Classification of the Developing Retina
Temporal Patterning from an Epigenomic Perspective
A Fine Balance between Reprogramming Capacity and Epigenetic Memory
Lhx2 Is Required for the Regionalization of the Optic
Lhx2 Is Expressed in Neuro-Epithelial, Bipotent Progenitors That Give Rise to
Lhx2 and Its Neurogenic Potential
Lhx2 as a Transcriptional Determinant of Cell Fate Identity
Chromatin Regulators in Retinal Development
Footprinting Analysis and Competition for Nucleosome Occupancy by Predicted
Expanding the Therapeutic Portfolio from Gene Editing to Genome Editing towards Personalized Medicine
Agnostic Approaches to Restore the Visual Function, from Prosthetics to Autologous Cell Replacement
Chasing the Secret to Youth
The 4D Genome
Findings
Conclusions and Future Perspectives
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