Recently Evolved Enhancers Emerge with High Interindividual Variability and Less Frequently Associate with Disease

Castelijns, Bas; Baak, Mirna; Geeven, Geert; Vermunt, Marit W.; Wiggers, Caroline R.M.; Timpanaro, Ilia Sarah; Kondova, Ivanela; Laat, Wouter de; Creyghton, Menno P.

doi:10.1016/j.celrep.2020.107799

Cited by 9 publications

(9 citation statements)

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“…Even though disease-related variants seem to be preferentially associated with evolutionarily conserved enhancers [ 339 , 340 , 341 , 342 ], species-specific differences across TF binding patterns [ 341 ] and enhancers divergence do occur [ 342 , 343 , 344 ]. Furthermore, enhancers dispensability despite conservation [ 219 , 345 , 346 ] or functional repurposing [ 347 ], may partially explain the failures of a given TF to recapitulate the regenerative response upon injury observed in other species.…”

Section: Current Challengesmentioning

confidence: 99%

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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Section: Current Challengesmentioning

confidence: 99%

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

Zibetti

2022

Cells

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“…Moreover, in a selected group of primates-mostly chimpanzees and macaques-changes in histone mark enrichments are associated with gene expression differences [15][16][17][18] . Several studies have also targeted the appearance of human-specific methylation [19][20][21][22][23] patterns and active promoters and enhancers in different anatomical structures and cell types [11][12][13][14][15] . All these studies have proven that comparative epigenomics is a powerful tool to investigate the evolution of RE 24,25 .…”

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confidence: 99%

Epigenomic profiling of primate lymphoblastoid cell lines reveals the evolutionary patterns of epigenetic activities in gene regulatory architectures

et al. 2021

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Changes in the epigenetic regulation of gene expression have a central role in evolution. Here, we extensively profiled a panel of human, chimpanzee, gorilla, orangutan, and macaque lymphoblastoid cell lines (LCLs), using ChIP-seq for five histone marks, ATAC-seq and RNA-seq, further complemented with whole genome sequencing (WGS) and whole genome bisulfite sequencing (WGBS). We annotated regulatory elements (RE) and integrated chromatin contact maps to define gene regulatory architectures, creating the largest catalog of RE in primates to date. We report that epigenetic conservation and its correlation with sequence conservation in primates depends on the activity state of the regulatory element. Our gene regulatory architectures reveal the coordination of different types of components and highlight the role of promoters and intragenic enhancers (gE) in the regulation of gene expression. We observe that most regulatory changes occur in weakly active gE. Remarkably, novel human-specific gE with weak activities are enriched in human-specific nucleotide changes. These elements appear in genes with signals of positive selection and human acceleration, tissue-specific expression, and particular functional enrichments, suggesting that the regulatory evolution of these genes may have contributed to human adaptation.

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“…However, the meaning and relevance of this observation seems unclear. While genome-wide studies discussed above present interesting observations on a link between evolution of human regulome and SCZ and ADSs, it is also important to stress that the species-specific, recently evolved enhancers are variable between individuals and tend to have minor impact on gene expression ( Castelijns et al, 2020 ). Altogether these observations reinforce the need for extensive functional validation of the human specific and disease associated regulatory variants in the human genome.…”

Section: Human Accelerated Cis -Regulatory Element...mentioning

confidence: 99%

“…However, to achieve an in-depth understanding of the contribution of non-coding sequences to NDs (and any other diseases for that matter) it will be essential to improve assemblies and annotations of the NHP genomes ( Nurk et al, 2022 ; Vollger et al, 2022 ). Likewise, it will be beneficial to include a larger cohort of human and NHP genomes in the analysis ( Castelijns et al, 2020 ), and improve protocols of in-vitro and in-vivo systems to assess the contribution of genetic variants in distinct cell types present in the human brain.…”

Section: Summary—perspectives and Future Avenues For Researchmentioning

confidence: 99%

Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia

Duński

Pękowska

2022

Front. Genet.

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The unique qualities of the human brain are a product of a complex evolutionary process. Evolution, famously described by François Jacob as a “tinkerer,” builds upon existing genetic elements by modifying and repurposing them for new functions. Genetic changes in DNA may lead to the emergence of new genes or cause altered gene expression patterns. Both gene and regulatory element mutations may lead to new functions. Yet, this process may lead to side-effects. An evolutionary trade-off occurs when an otherwise beneficial change, which is important for evolutionary success and is under strong positive selection, concurrently results in a detrimental change in another trait. Pleiotropy occurs when a gene affects multiple traits. Antagonistic pleiotropy is a phenomenon whereby a genetic variant leads to an increase in fitness at one life-stage or in a specific environment, but simultaneously decreases fitness in another respect. Therefore, it is conceivable that the molecular underpinnings of evolution of highly complex traits, including brain size or cognitive ability, under certain conditions could result in deleterious effects, which would increase the susceptibility to psychiatric or neurodevelopmental diseases. Here, we discuss possible trade-offs and antagonistic pleiotropies between evolutionary change in a gene sequence, dosage or activity and the susceptibility of individuals to autism spectrum disorders and schizophrenia. We present current knowledge about genes and alterations in gene regulatory landscapes, which have likely played a role in establishing human-specific traits and have been implicated in those diseases.

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Recently Evolved Enhancers Emerge with High Interindividual Variability and Less Frequently Associate with Disease

Cited by 9 publications

References 58 publications

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

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

Epigenomic profiling of primate lymphoblastoid cell lines reveals the evolutionary patterns of epigenetic activities in gene regulatory architectures

Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia

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