Plotgardener: cultivating precise multi-panel figures in R

Kramer, Nicole E.; Davis, Eric S.; Wenger, Craig D.; Deoudes, Erika M.; Parker, Sarah M; Love, Michael I.; Phanstiel, Douglas H.

doi:10.1093/bioinformatics/btac057

Cited by 64 publications

(35 citation statements)

References 26 publications

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“…SNP-gene pairs obtained this way were filtered for protein-coding genes with HUGO Gene Nomenclature Committee (HGNC) symbols, resulting in a total 272 genes (MPRAHi-C genes). To visualize the loci of MPRAHi-C genes (variants, genes, Hi-C loops), plotgardener Bioconductor package was used (Kramer et al, 2022).…”

Section: Assigning Genes To Mpra-positive Variants Using Hi-c Datamentioning

confidence: 99%

Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants

McAfee

Lee

et al. 2022

Preprint

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Genome-wide association studies (GWAS) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium (LD) makes it challenging to discern causal variants. Computational finemapping prioritized thousands of credible variants, ∼98% of which lie within poorly characterized non-coding regions. To functionally validate their regulatory effects, we performed a massively parallel reporter assay (MPRA) on 5,173 finemapped schizophrenia GWAS variants in primary human neural progenitors (HNPs). We identified 439 variants with allelic regulatory effects (MPRA-positive variants), with 71% of GWAS loci containing at least one MPRA-positive variant. Transcription factor binding had modest predictive power for predicting the allelic activity of MPRA-positive variants, while GWAS association, finemap posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit eQTL signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. MPRA-positive variants differed from eQTLs, as they were more frequently located in distal neuronal enhancers. Therefore, we leveraged neuronal 3D chromatin architecture to identify 272 genes that physically interact with MPRA-positive variants. These genes annotated by chromatin interactome displayed higher mutational constraints and regulatory complexity than genes annotated by eQTLs, recapitulating a recent finding that eQTL- and GWAS-detected variants map to genes with different properties. Finally, we propose a model in which allelic activity of multiple variants within a GWAS locus can be aggregated to predict gene expression by taking chromatin contact frequency and accessibility into account. In conclusion, we demonstrate that MPRA can effectively identify functional regulatory variants and delineate previously unknown regulatory principles of schizophrenia.

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Section: Assigning Genes To Mpra-positive Variants Using Hi-c Datamentioning

confidence: 99%

Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants

McAfee

Lee

et al. 2022

Preprint

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“…Reference data from 1000 Genomes Phase 1 version 2 EUR panel were used with GREGOR to control for LD proxies (1Mb, r 2 > 0.7) 74 . Results were imported into R (v4.1.0) 75 and visualized with ggplot2 76 and plotgardener 77 .…”

Section: Methodsmentioning

confidence: 99%

3D Chromatin Structure in Chondrocytes Identifies Putative Osteoarthritis Risk Genes

Thulson

Davis

D’Costa

et al. 2022

Preprint

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Genome-wide association studies (GWAS) have identified over 100 loci associated with osteoarthrtis (OA) risk, but the majority of OA risk variants are non-coding, making it difficult to identify the impacted genes for further study and therapeutic development. To address this need, we used a multi-omic approach and genome editing to identify and functionally characterize potential OA risk genes. Computational analysis of GWAS and ChIP-seq data revealed that chondrocyte regulatory loci are enriched for OA risk variants. We constructed a chondrocyte specific regulatory network by mapping 3D chromatin structure and active enhancers in human chondrocytes. We then intersected these data with our previously collected RNA-seq dataset of chondrocytes responding to fibronectin fragment (FN-f), a known OA trigger. Integration of the three genomic datasets with recently reported OA GWAS variants revealed a refined set of putative causal OA variants and their potential target genes. One of the novel putative target genes identified was SOCS2, which was connected to a putative causal variant by a 170 Kb loop and is differentially regulated in response to FN-f. CRISPR-Cas9-mediated deletion of SOCS2 in primary human chondrocytes from three independent donors led to heightened expression of inflammatory markers after FN-f treatment. These data suggest that SOCS2 plays a role in resolving inflammation in response to cartilage matrix damage and provides a possible mechanistic explanation for its influence on OA risk. In total, we identified 56 unique putative OA risk genes for further research and potential therapeutic development.

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“…The signs of the output eigenvectors indicate the compartment, but the signs are arbitrary in each set of eigenvectors calculated for each chromosome and condition. Therefore, for regions of interest, eigenvectors were plotted alongside ATAC-seq narrow peaks using the plotgardener R package to determine whether they corresponded to compartment A or B (Kramer et al, 2022).…”

Section: Author Contributionsmentioning

confidence: 99%

Role of theEGR2promoter antisense RNA in modulating chromatin accessibility and spatial genome organization

Moreno

Karambizi

Hwang

et al. 2022

Preprint

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The EGR2 promoter antisense RNA (AS-RNA) recruits chromatin remodeling complexes to inhibit EGR2 transcription following peripheral nerve injury. Here we show that the EGR2-AS-RNA modulates chromatin accessibility and serves as scaffold for two distinct histone modification complexes. It binds to EZH2 and WDR5 and enables coordinate targeting of H3K27me3 and H3K4me3 to promoters of EGR2and C-JUN. Expression of the AS-RNA results in reorganization of the global chromatin landscape and quantitative changes in loop formation and in contact frequency at domain boundaries exhibiting enrichment for AP-1 genes. In addition, the EGR2-AS-RNA induces changes in hierarchical TADs and increases transcriptional activity on an inter-TAD loop between a super-enhancer regulatory hub and the promoter of mTOR. Our results show that the EGR2-AS-RNA may serve as regulator of coordinate chromatin remodeling and spatial genome organization to regulate cellular plasticity-associated transcription in Schwann cells.

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Plotgardener: cultivating precise multi-panel figures in R

Cited by 64 publications

References 26 publications

Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants

Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants

3D Chromatin Structure in Chondrocytes Identifies Putative Osteoarthritis Risk Genes

Role of theEGR2promoter antisense RNA in modulating chromatin accessibility and spatial genome organization

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