Gene regulatory networks controlling temporal patterning, neurogenesis, and cell-fate specification in mammalian retina

Lyu, Pin; Hoang, Thanh; Santiago, Clayton; Thomas, Eric D.; Timms, Andrew E.; Appel, Haley; Gimmen, Megan Y.; Le, Nguyet; Jiang, Lizhi; Kim, Dong Won; Chen, Siqi; Espinoza, David; Telger, Ariel E.; Weir, Kurt; Clark, Brian S.; Cherry, Timothy J.; Qian, Jiang; Blackshaw, Seth

doi:10.1016/j.celrep.2021.109994

Cited by 62 publications

(46 citation statements)

References 101 publications

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“…Expression patterns for most of the retinal TFs have been extensively characterized [ 36 , 113 , 114 , 115 , 116 , 117 , 118 , 119 ]. Nonetheless, the specific mechanisms by which TFs coordinate epigenetic changes across retinal development remain elusive, since the direct assessment of binding sites is limited to select cases, such as for CRX, OTX2, and RORB, NFI, NRL, or MEF2D [ 120 , 121 , 122 , 123 , 124 , 125 ], whereas most of these mechanisms are inferred [ 69 , 98 , 126 , 127 , 128 , 129 ].…”

Section: Temporal Patterning In the Retinamentioning

confidence: 99%

“…While transcriptional and epigenetic descriptors do not necessarily address the mechanistic aspects of cell fate determination in the retina, the advent of single-cell sequencing has allowed, at least, to resolve such molecular complexity, by deconvolving the cell type specificity of regulatory elements that could not otherwise be discerned from conventional bulk sequencing [ 98 , 124 ].…”

Section: Temporal Patterning In the Retinamentioning

confidence: 99%

“…Subsequent work from the same group [ 124 ] has heavily relied on this first inferential model [ 75 ], when constructing gene regulatory networks. The original work does not set a stringent limit to pair peak-to-transcription start sites (TSS), since it enables probabilistic assignment of a given peak up to 5000 bp upstream the TSS, 1000 bp downstream for up to 1,000,000 bp maximum extension.…”

Section: The Epigenome: a Pandora’s Boxmentioning

confidence: 99%

“…Moreover, it incorporates H3K27ac marks since enhancers can span across megabases of distance from the TSS. A lack of integration with enhancer marks and the overall stringency in peak-to-TSS pairing adopted in the subsequent work, that is upstream 100 kb or downstream 100 kb of the intergenic peaks [ 124 ], may lead to proximity-related biases and false-negative assignments. In the subsequent work, prediction of cell type-specific TFs binding in cis -regulatory elements [ 124 ] also relies on the pairing of TF binding sites based on footprinting scores with corresponding stage-matched TF expression, as proposed in the original work [ 75 ].…”

Section: The Epigenome: a Pandora’s Boxmentioning

confidence: 99%

“…Last, but not least, what is here referred to as “feedback TF pairs” [ 124 ] arises from the fundamental observation described in the original work [ 75 ] that TFs can exhibit mutually epistatic and/or steric dependencies and that integration of ChIP-seq, with ATAC-seq and RNA-seq in conditional knock out conditions for any given TF, can address that.…”

Section: The Epigenome: a Pandora’s Boxmentioning

confidence: 99%

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Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives

Zibetti

2022

Cells

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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.

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