Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions

Girskis, Kelly M.; Stergachis, Andrew B.; DeGennaro, Ellen M; Doan, Ryan; Qian, Xuyu; Johnson, Matthew B.; Wang, Peter P.; Sejourne, Gabrielle M.; Nagy, Martina; Pollina, Elizabeth A.; Sousa, André M. M.; Shin, Taehwan; Kenny, Connor; Scotellaro, Julia L.; Debo, Brian; Gonzalez, Dilenny M.; Rento, Lariza M.; Yeh, Rebecca C.; Song, Janet; Beaudin, Marc; Fan, Jean; Kharchenko, Peter V.; Šestan, Nenad; Greenberg, Michael E.; Walsh, Christopher A.

doi:10.1016/j.neuron.2021.08.005

Cited by 134 publications

(133 citation statements)

References 87 publications

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“…It is challenging to identify cis -regulatory elements, such as enhancers, encoded in the genome through sequence analyses and computational methods alone [ 53 ]. Major efforts have been made to find ways of identifying and characterizing enhancers and their properties on a genome-wide and individual basis, which is important to facilitate our ability to decode regulatory information embedded in the genome [ 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. While many development specific enhancers, including some of those discovered in the Hox clusters, are evolutionarily conserved [ 35 , 61 , 62 , 63 ], many adult or tissue-specific enhancers can be highly variable across species [ 64 , 65 ].…”

Section: Regulatory Featuresmentioning

confidence: 99%

Transcriptional Regulation and Implications for Controlling Hox Gene Expression

Afzal

Krumlauf

2022

JDB

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Hox genes play key roles in axial patterning and regulating the regional identity of cells and tissues in a wide variety of animals from invertebrates to vertebrates. Nested domains of Hox expression generate a combinatorial code that provides a molecular framework for specifying the properties of tissues along the A–P axis. Hence, it is important to understand the regulatory mechanisms that coordinately control the precise patterns of the transcription of clustered Hox genes required for their roles in development. New insights are emerging about the dynamics and molecular mechanisms governing transcriptional regulation, and there is interest in understanding how these may play a role in contributing to the regulation of the expression of the clustered Hox genes. In this review, we summarize some of the recent findings, ideas and emerging mechanisms underlying the regulation of transcription in general and consider how they may be relevant to understanding the transcriptional regulation of Hox genes.

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Section: Regulatory Featuresmentioning

confidence: 99%

Transcriptional Regulation and Implications for Controlling Hox Gene Expression

Afzal

Krumlauf

2022

JDB

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“…Human accelerated regions (HARs) are genomic regions well conserved in nonhuman primates but with a high rate of mutation in humans (Hubisz & Pollard, 2014). Around 50% of HARs (genomic sequences quickly evolved in the recent human lineage) have been predicted to function as regulatory enhancers (Capra et al., 2013; Girskis et al., 2021; Uebbing et al., 2021). Many HARs are in the proximity of genes important in brain development, including GLI2, GLI3, and TBR1, suggesting a role in proliferation and differentiation during cortical development (Won et al., 2019).…”

Section: Regulation Of Gene Expression Levels and Patternsmentioning

confidence: 99%

“…HARs have been recently shown to extensively rewire the expression pattern of PPP1R17 in the developing primate cortex, where it is expressed in progenitor cells in OSVZ and ISVZ. This gene shortens the cell cycle, promotes the transient amplification of progenitor cells, and delays neuronal differentiation, suggesting a central role in primate corticogenesis of this HAR‐regulated gene (Girskis et al., 2021). PPP1R17 is not expressed in ferret or mouse NPCs, further highlighting the key role of regulatory mechanisms in cortical evolution.…”

Section: Regulation Of Gene Expression Levels and Patternsmentioning

confidence: 99%

Evolution of genetic mechanisms regulating cortical neurogenesis

Espinós

Fernández‐Ortuño

Negri

et al. 2022

Developmental Neurobiology

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The size of the cerebral cortex increases dramatically across amniotes, from reptiles to great apes. This is primarily due to different numbers of neurons and glial cells produced during embryonic development. The evolutionary expansion of cortical neurogenesis was linked to changes in neural stem and progenitor cells, which acquired increased capacity of self-amplification and neuron production. Evolution works via changes in the genome, and recent studies have identified a small number of new genes that emerged in the recent human and primate lineages, promoting cortical progenitor proliferation and increased neurogenesis. However, most of the mammalian genome corresponds to noncoding DNA that contains gene-regulatory elements, and recent evidence precisely points at changes in expression levels of conserved genes as key in the evolution of cortical neurogenesis. Here, we provide an overview of basic cellular mechanisms involved in cortical neurogenesis across amniotes, and discuss recent progress on genetic mechanisms that may have changed during evolution, including gene expression regulation, leading to the expansion of the cerebral cortex.

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“…We obtained the DHS tracks from ENCODE 58 and Roadmap Epigenome 32 . We also obtained tracks from fetal neuron, neuro-progenitor cells, and fetal brain from Girskis et al 59 For a complete list of the tracks and how to access them see Table S5. For most of the analyses involving DHS we used the broad peak calls with an FDR of 0.01 of fetal brain from sample E081 from Roadmap Epigenome 32 , unless otherwise stated.…”

Section: Dnase Hypersensitivity Tracksmentioning

confidence: 99%

Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

Maury

Jones

Seplyarskiy

et al. 2022

Preprint

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Schizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and maternal factors, such as infection and immune activation, have been implicated, but how these two strikingly different mechanisms might converge on the same phenotype is unknown. During development, cells accumulate somatic, mosaic mutations in ways that can be shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (267x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide sSNV compared to controls (p < 2e-10). Remarkably, mosaic T>G mutations and CpG transversions (CpG>GpG or CpG>ApG) were 79- and 62-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ, but not in controls. The pattern of T>G mutations resembles mutational processes in cancer attributed to oxidative damage that is sterically blocked from DNA repair by transcription factors (TFs) bound to damaged DNA. The CpG transversions similarly suggest unfinished DNA demethylation resulting in abasic sites that can also be blocked from repair by bound TFs. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. We call this prenatal mutational process skiagenesis (from the Greek skia, meaning shadow), as these mutations occur in the shadow of bound TFs. Skiagenesis reflects as-yet unidentified prenatal factors and is associated with SCZ risk in a subset (~13%) of cases. In turn, mutational disruption of key TFBS active in fetal brain is well positioned to create SCZ-specific gene dysregulation in concert with germline risk genes. Skiagenesis provides a fingerprint for exploring how epigenomic regulation and prenatal factors such as maternal infection or immune activation may shape the developmental mutational landscape of human brain.

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Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions

Cited by 134 publications

References 87 publications

Transcriptional Regulation and Implications for Controlling Hox Gene Expression

Transcriptional Regulation and Implications for Controlling Hox Gene Expression

Evolution of genetic mechanisms regulating cortical neurogenesis

Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

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