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Massively Parallel Genetic Disruption of Enhancers Active During Human Corticogenesis

ABSTRACT: Massively Parallel Genetic Disruption of Enhancers Active During Human Corticogenesis

PROVIDER: PRJNA577450 | ENA |

REPOSITORIES: ENA

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Massively Parallel Genetic Disruption of Enhancers Active During Human Corticogenesis

Project description:Changes in gene regulation have been linked to the expansion of the human cerebral cortex and to neurodevelopmental disorders. However, the biological effects of genetic variation within developmental regulatory elements on human corticogenesis are not well understood. We used sgRNA-Cas9 genetic screens in human neural stem cells (hNSCs) to disrupt 10,674 expressed genes and 2,227 enhancers active in the developing human cortex and determine the resulting effects on cellular proliferation. Gene disruptions affecting proliferation were enriched for genes associated with risk for human neurodevelopmental phenotypes including primary microcephaly and autism spectrum disorder. Although disruptions in enhancers had overall weaker effects on proliferation than gene disruptions, we identified enhancer disruptions that severely perturbed hNSC self-renewal. Disruptions in Human Accelerated Regions and Human Gain Enhancers, regulatory elements implicated in the evolution of the human brain, also perturbed hNSC proliferation, establishing a role for these elements in human neurodevelopment. Integrating proliferation phenotypes with chromatin interaction maps revealed regulatory relationships between enhancers and target genes that contribute to neurogenesis and potentially to human cortical evolution.

2019-12-03 | GSE138823 | GEO

Mapping of copy-number alterations with massively parallel sequencing

Project description:This SuperSeries is composed of the following subset Series: GSE12019: Fine-scale mapping of copy-number alterations with massively parallel sequencing GSE13372: High-resolution mapping of copy-number alterations with massively parallel sequencing Refer to individual Series

2008-11-13 | E-GEOD-13373 | biostudies-arrayexpress

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Project description:Massively Parallel Genetic Disruption of Enhancers Active During Human Corticogenesis

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Massively Parallel Reporter Assay of human-specific substitutions in neurodevelopmental enhancers

Project description:We performed a Massively Parallel Reporter Assay (MPRA) to screen >30,000 human-specific substitutions in ChIP-seq-identified Human Gain Enhancers (HGEs) and Human Accelerated Regions (HARs), highly conserved non-coding regions that show accelerated sequence evolution in humans. After comparing human and chimpanzee reference alleles, we used a second MPRA to deconvolute individual substitutions within differentially active enhancers from substitutions in the same fragment and from other variants (human segregating variants or chimpanzee-specific variants) to isolate their specific effects on enhancer activity.

2019-11-26 | GSE140983 | GEO

Massively Parallel Reporter Assay of human-specific substitutions in neurodevelopmental enhancers

Project description:Massively Parallel Reporter Assay of human-specific substitutions in neurodevelopmental enhancers

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Systematic dissection of regulatory motifs in 2,000 predicted human enhancers using a massively parallel reporter assay

2013-03-15 | GSE33367 | GEO

Systematic dissection of regulatory motifs in 2,000 predicted human enhancers using a massively parallel reporter assay

Project description:We employ a massively parallel reporter assay (MPRA) to measure the ex vivo activities of hundreds of K562 and HepG2 enhancers with known transcription factor motif instances. For seven selected motifs that correspond to known or predicted activators and repressors in the two cell types, we make directed modifications of the bases corresponding to these motifs and observe the changes in enhancer activity. Reporter mRNA-seq from HepG2 and K562 cells transfected with a ~55,000-plex MPRA plasmid pool containing 5,418 mutated human enhancer sequences, each linked to 10 distinct 10-nt tags. The reporter mRNA tags facilitate quantitation of their abundances. The same tags were also sequenced from the transfected MPRA plasmid pool to facilitate normalization to plasmid copy numbers.

2013-03-15 | E-GEOD-33367 | biostudies-arrayexpress

Characterization of maturational enhancer activity by massively parallel reporter assay [amplicon-Seq]

Project description:The activity of enhancers with dynamic P300 binding or mutagenized nuclear receptor motifs was assessed by massively parallel reporter assay during CM maturation.

2023-01-19 | GSE196346 | GEO

Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay

2012-02-26 | GSE31982 | GEO

Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay

Project description:We apply a massively parallel reporter assay (MPRA) that relies on mRNA and plasmid tag sequencing (Tag-Seq) to compare the regulatory activities of more than 27,000 distinct variants of two inducible enhancers in human cells: a synthetic cAMP-regulated enhancer and the virus-inducible interferon beta enhancer. The resulting data define accurate maps of functional transcription factor binding sites in both enhancers at single-nucleotide resolution and can be used the to train quantitative sequence-activity models (QSAMs). Reporter Tag-Seq from HEK293 cells transfected with each of six MPRA plasmid pools, with and without stimulation (forskolin or Sendai virus). The reporter mRNAs contain unique 10 nucleotide tags that facilitates quantitation of their abundances. The same tags were also sequenced from each ransfected plasmid pool to facilitate normalization to plasmid copy numbers. The reporter constructs were designed according to two different mutagenesis strategies: 'single-hit scanning' and 'multi-hit sampling'. The specific variants are included in the processed data files.

2012-02-26 | E-GEOD-31982 | biostudies-arrayexpress

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