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:10.1101/2021.09.08.459338

Cited by 6 publications

(4 citation statements)

References 27 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 (MPRA Hi-C genes). To visualize the loci of MPRA Hi-C genes (variants, genes, Hi-C loops), plotgardener Bioconductor package was used (Kramer et al, 2022). When loops were plotted, we only visualized the midpoint of each loop’s end for simplicity.…”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

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

McAfee

Lee

et al. 2022

Preprint

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“…We used plotgardener to visualize Hi-C datasets (e.g. contact maps, insulation scores, loops) ( 75 ).…”

Section: Methodsmentioning

confidence: 99%

HIV integration in the human brain is linked to microglial activation and 3D genome remodeling

Plaza-Jennings

Valada

O'Shea

et al. 2022

Preprint

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Exploration of genome organization and function in the HIV infected brain is critical to aid in the development of treatments for HIV-associated neurocognitive disorder (HAND) and HIV cure strategies. Here, we generated a resource comprised of single nuclei transcriptomics, complemented by cell-type-specific Hi-C chromosomal conformation (‘3D genome’) and viral integration site sequencing (IS-seq) in frontal brain tissues from individuals with HIV encephalitis (HIVE), HIV-infected people without encephalitis (HIV+), and HIV uninfected (HIV-) controls. We observed profound 3D genomic reorganization of open/repressive (A/B) compartment structures encompassing 6.4% of the HIVE microglial genome that was associated with transcriptomic reprogramming, including down-regulation of homeostasis and synapse-related functions and robust activation of interferon signaling and cell migratory pathways. HIV RNA was detected in 0.003% of all nuclei in HIVE brain, predominantly in the most activated microglia where it ranked as the second most highly expressed transcript. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 insertion events in glial nuclei that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Brain and peripheral myeloid cell integration revealed a preference overall for transcription-permissive chromatin, but robust differences in the frequency of recurrent insertions, intergenic integration, and enrichment for pre-integration complex-associated factors at integration sites. Our resource highlights critical differences in the genomic patterns of HIV infection in brain versus blood and points to a dynamic interrelationship between inflammation-associated 3D genome remodeling and successful integration in brain.

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“…Integrated visualizations of single cell ATAC tracks, peak-to-gene linkages, and cis -co-accessible sites were made using the Plotgardener 75 package (v1.2.0). ATAC signal tracks were normalized to the number of reads in TSS regions to account for differences in sequencing depth and sample quality.…”

Section: Methodsmentioning

confidence: 99%

Three-dimensional chromatin re-organization during muscle stem cell aging

Yang

Larouche

Sabin

et al. 2022

Preprint

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Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the world's population continues to increase. A critical contributor to sarcopenia is the loss in the number and function of muscle stem cells, which maintain tissue homeostasis and regenerate damage. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.

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Plotgardener: Cultivating precise multi-panel figures in R

Cited by 6 publications

References 27 publications

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

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

HIV integration in the human brain is linked to microglial activation and 3D genome remodeling

Three-dimensional chromatin re-organization during muscle stem cell aging

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