Rewiring of human neurodevelopmental gene regulatory programs by Human Accelerated Regions (HARs)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA749292 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15228900_1.fastq.gz | Fastqsanger.gz | |||
| SRR15228900_2.fastq.gz | Fastqsanger.gz | |||
| SRR15228887_1.fastq.gz | Fastqsanger.gz | |||
| SRR15228887_2.fastq.gz | Fastqsanger.gz | |||
| SRR15228888_1.fastq.gz | Fastqsanger.gz |
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Project description:Human Accelerated Regions (HARs) are the fastest-evolving regions of the human genome and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity of >3,100 HARs in massively parallel reporter assays (MPRAs), demonstrating that many HARs appear to act as neural enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity.
2021-07-24 | GSE180714 | GEO
Project description:Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.
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Project description:Human Accelerated Regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with an automated pipeline and an alignment of 251 mammalian genomes. Combining deep-learning with chromatin capture experiments in human and chimpanzee neural progenitor cells, we discovered a significant enrichment of HARs in topologically associating domains (TADs) containing human-specific genomic variants that change three-dimensional (3D) genome organization. Differential gene expression between humans and chimpanzees at these loci suggests rewiring of regulatory interactions between HARs and neurodevelopmental genes. Thus, comparative genomics together with models of 3D genome folding revealed enhancer hijacking as an explanation for the rapid evolution of HARs.
2022-12-21 | GSE183137 | GEO
Project description:Human neurodevelopmental samples
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Project description:Comparative characterization of human accelerated regions in neurons
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Project description:Human accelerated regions (HARs) are evolutionarily conserved sequences that acquired human-specific nucleotide changes and reside in genomic regions associated with unique human traits and disease. The majority of HARs (96%) are noncoding, a few of which have been shown to be functional enhancers. Here, we comprehensively tested human and chimpanzee sequences of HARs (N=714) for enhancer activity using a lentivirus-based massively parallel reporter assay (lentiMPRA) in human and chimpanzee iPSC derived neural progenitors at two differentiation time points. We found that 43% (306/714) function as enhancers and over two-thirds (204/306) showed consistent differences in activity between human and chimpanzee sequences across conditions. We also tested all possible permutations of substitutions in seven HARs and found significant positive and negative interactions. Our study provides a comprehensive resource of functional neurodevelopmental HAR enhancers and shows that multiple interacting sites drive evolutionary activity differences.
2018-02-17 | GSE110758 | GEO
Project description:Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees. HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation. However, their target genes and functional contributions to human brain development remain largely uncharacterized. Here, we elucidate the cis-regulatory functions of HARs in human and chimpanzee induced pluripotent stem cell (iPSC)-induced excitatory neurons. Using genomic and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologs for functional characterization via single-cell CRISPRi, and demonstrated their species-specific gene regulatory functions. Our findings reveal diverse functional outcomes of HAR-mediated cis-regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPSC pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we use prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons. Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.
2024-11-12 | GSE269798 | GEO
Project description:Human accelerated regions (HARs) are evolutionarily conserved sequences that acquired human-specific nucleotide changes and reside in genomic regions associated with unique human traits and disease. The majority of HARs (96%) are noncoding, a few of which have been shown to be functional enhancers. Here, we comprehensively tested human and chimpanzee sequences of HARs (N=714) for enhancer activity using a lentivirus-based massively parallel reporter assay (lentiMPRA) in human and chimpanzee iPSC derived neural progenitors at two differentiation time points. We found that 43% (306/714) function as enhancers and over two-thirds (204/306) showed consistent differences in activity between human and chimpanzee sequences across conditions. We also tested all possible permutations of substitutions in seven HARs and found significant positive and negative interactions. Our study provides a comprehensive resource of functional neurodevelopmental HAR enhancers and shows that multiple interacting sites drive evolutionary activity differences.
2018-02-17 | GSE110759 | GEO
Project description:Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees. HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation. However, their target genes and functional contributions to human brain development remain largely uncharacterized. Here, we elucidate the cis-regulatory functions of HARs in human and chimpanzee induced pluripotent stem cell (iPSC)-induced excitatory neurons. Using genomic and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologs for functional characterization via single-cell CRISPRi, and demonstrated their species-specific gene regulatory functions. Our findings reveal diverse functional outcomes of HAR-mediated cis-regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPSC pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we use prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons. Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.
2024-11-12 | GSE222112 | GEO
Project description:Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees. HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation. However, their target genes and functional contributions to human brain development remain largely uncharacterized. Here, we elucidate the cis-regulatory functions of HARs in human and chimpanzee induced pluripotent stem cell (iPSC)-induced excitatory neurons. Using genomic and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologs for functional characterization via single-cell CRISPRi, and demonstrated their species-specific gene regulatory functions. Our findings reveal diverse functional outcomes of HAR-mediated cis-regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPSC pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we use prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons. Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.
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