A promoter interaction map for cardiovascular disease genetics

Montefiori, Lindsey E.; Sobreira, Débora R.; Sakabe, Noboru Jo; Aneas, Ivy; Joslin, Amelia C; Hansen, Grace; Bozek, Grazyna; Moskowitz, Ivan P.; McNally, Elizabeth M.; Nóbrega, Marcelo A.

doi:10.7554/elife.35788

Cited by 119 publications

(82 citation statements)

References 86 publications

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“…Both mRNA and protein expression levels of PGC-1α were downregulated in differentiate CMs upon TKI exposure and, conversely, upregulated by overexpression of GATA4 (Figure 7D and Supplemental Figure 5E). Moreover, further integration of the current GATA4 ChIP-seq data with promoter-capture Hi-C data previously reported in analogous day 20 CMs 45 , we confirmed a direct interaction between the GATA4-binding site with the PPARGC1A promoter anchor in CMs, consistent with long-range enhancer-promoter regulation through DNA looping (Figure 7E). Given the important roles of PGC-1α in regulating mitochondrial biogenesis and functions, altogether, this demonstrates that GATA4 binds to a PPARGC1A -enhancer and directly influences the expression of PGC-1α, thereby controlling mitochondrial biogenesis and function at early stages.…”

Section: Resultssupporting

confidence: 87%

“…( E ) Visualization of long-range PPARGC1A promoter interactions in iPSC-derived cardiomyocytes confirms direct interaction between GATA4-binding site and PPARGC1A anchor region. Red loop specifies individual long-range interaction called between the GATA4 binding site coordinates and the associated anchor used to capture PPARGC1A promoter interactions in cardiomyocytes 45 .…”

Section: Resultsmentioning

confidence: 99%

“…The annotations of the peaks were achieved using annotatePeaks.pl of the Homer software (version 4.10) 92 . PPARGC1A-centric promoter loops were selected from promoter-capture Hi-C loops called in iPSC-derived cardiomyocytes 45 . Processed loop calls were downloaded from ArrayExpress accession number E-MTAB-6014, and three replicate cardiomyocyte loop calls (capt-CHiCAGO_interactions-CM) were visualized using the Sushi R/Bioconductor package for genomic data visualization 94 .…”

Section: Methodsmentioning

confidence: 99%

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Tyrosine kinase inhibitors induce mitochondrial dysfunction during cardiomyocyte differentiation through alteration of GATA4-mediated networks

Liu

et al. 2020

Preprint

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SUMMARYMaternal drug exposure during pregnancy increases the risks of developmental cardiotoxicity, leading to congenital heart defects (CHDs). In this study, we used human stem cells as an in-vitro system to interrogate the mechanisms underlying drug-induced toxicity during cardiomyocyte differentiation, including anticancer tyrosine kinase inhibitor (TKI) drugs (imatinib, sunitinib, and vandetanib). H1-ESCs were treated with these drugs at sublethal levels during cardiomyocyte differentiation. We found that early exposure to TKIs during differentiation induced obvious toxic effects in differentiated cardiomyocytes, including disarranged sarcomere structure, interrupted Ca2+-handling, and impaired mitochondrial function. As sunitinib exposure showed the most significant developmental cardiotoxicity of all TKIs, we further examine its effect with in-vivo experiments. Maternal sunitinib exposure caused fetal death, bioaccumulation, and histopathologic changes in the neonatal mice. Integrative analysis of both transcriptomic and chromatin accessibility landscapes revealed that TKI-exposure altered GATA4-mediated regulatory network, which included key mitochondrial genes. Overexpression of GATA4 with CRISPR-activation restored morphologies, contraction, and mitochondria function in cardiomyocytes upon TKI exposure early during differentiation. Altogether, our study identified a novel crosstalk mechanism between GATA4 activity and mitochondrial function during cardiomyocyte differentiation, and revealed potential therapeutic approaches for reducing TKI-induced developmental cardiotoxicity for human health.HighlightsEarly-stage exposure to TKIs induced cardiotoxicity and mitochondrial dysfunctionGATA4 transcriptional activity is inhibited by TKIsNetwork analysis reveals interactions between GATA4 and mitochondrial genesGATA4-overexpression rescues cardiomyocytes and mitochondria from TKI exposure

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Tyrosine kinase inhibitors induce mitochondrial dysfunction during cardiomyocyte differentiation through alteration of GATA4-mediated networks

Liu

et al. 2020

Preprint

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“…In many cases, however, the target gene for a regulatory element is not the nearest gene 35 and therefore, information about distal chromatin interactions can be useful in prioritizing candidate gene targets of variants identified in GWAS. To this end, we generated a promoter capture Hi-C map (pcHi-C) of a decidualized cell line, thus enriching for the identification of long-range chromatin interactions between promoters and distant regulatory elements [36][37][38] . We identified a total of 161,337 interactions, of which 53,211 were between promoters and distal regions of accessible chromatin assayed by ATAC-seq and ChIP-seq, suggestive of their regulatory role.…”

Section: Chromatin Interactions Aid In the Identification Of Target Gmentioning

confidence: 99%

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

Sakabe

Aneas

Knoblauch

et al. 2020

Preprint

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While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary deciduaderived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancyrelevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

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“…To measure co-accessible enrichments for TFs and chromatin looping, pgl files were created by pairing together EZH2 and Suz12 peaks within 500bp of one another, and pgltools 50 was used to convert calls from CTCF ChIA-PET 34 in GM12878 and pHiC in iPSCs 33 to the pgl format. Next, pgltools intersect1D was used to find accessible sites at opposing anchors of loops, or at Ezh2 Suz12 pairs, and p-values were obtained from the co-accessibility analysis for enrichments.…”

Section: Co-accessibility Enrichment At Co-binding Tfs and Chromatin mentioning

confidence: 99%

Chromatin co-accessibility is highly structured, spans entire chromosomes, and mediates long range regulatory genetic effects

Ww¹,

D’Antonio‐Chronowska²,

Benaglio³

et al. 2019

Preprint

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Chromatin accessibility identifies active regions of the genome, often at transcription factor (TF) binding sites, enhancers, and promoters, and contains regulatory genetic variation. Functionally related accessible sites have been reported to be co-accessible; however, the prevalence and range of co-accessibility is unknown. We perform ATAC-seq in induced pluripotent stem cells from 134 individuals and integrate it with RNA-seq, WGS, and ChIP-seq, providing the first longrange chromosome-length analysis of co-accessibility. We show that co-accessibility is highly connected, with sites having a median of 24 co-accessible partners up to 250Mb away. We also show that co-accessibility can de novo identify known and novel co-expressed genes, and coregulatory TFs and chromatin states. We perform a cis and trans-caQTL, a trans-eQTL, and examine allelic effects of co-accessibility, identifying tens of thousands of trans-caQTLs, and showing that trans genetic effects can be propagated through co-accessibility to gene expression for cell-type and disease relevant genes.Here, we perform ATAC-seq in 152 induced pluripotent stem cells (iPSCs) from 134 individuals from iPSCORE 20-23 , and integrate this data with available WGS and RNA-seq for the same individuals. We call over 1 million accessible chromatin sites and utilize population-level information to identify co-accessible sites by testing for correlation in accessibility between all sites chromosome-wide. We show co-accessibility is highly connected, with sites being coaccessible with an average of 24 other sites, and can span long distances (up to hundreds of megabases). We then use these significant relationships to create co-accessibility networks, and show that neighbors in these networks are enriched for TF co-binding partners, functionally related TFs, spatially colocalized loci (ie loci in a chromatin loop), and co-expressed genes up to 100Mb apart, and can also be used to infer novel TF functionality. Next, we examine the genetic architecture of co-accessibility by measuring allele specific effects (ASE) and performing one of the largest caQTLs studies to date. We show that genetic effects spread through coaccessibility, with highly connected sites being more likely to have a cis-caQTL or exhibit ASE; additionally, strong ASE explains 52% of co-accessible weaker ASE. Finally, we leverage these networks to identify more than 92,000 trans-caQTLs greater than 1.5Mb from their target, 9 of which are also trans-eQTLs for cell type and disease relevant genes. Overall, our data reveals that chromatin co-accessibility is highly connected, spans the length of entire chromosomes, can de novo identify co-regulatory TFs, is a mechanism underlying trans genetic effects, and can give insight into trans-eQTL mechanisms. Results Samples, ATAC-seq data generation, and ATAC peak characterizationTo measure chromatin co-accessibility, accessible sites were identified from ATAC-seq performed on 152 iPSC lines. These lines were generated from 134 individuals ( Supplementary Table 1...

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A promoter interaction map for cardiovascular disease genetics

Cited by 119 publications

References 86 publications

Tyrosine kinase inhibitors induce mitochondrial dysfunction during cardiomyocyte differentiation through alteration of GATA4-mediated networks

Tyrosine kinase inhibitors induce mitochondrial dysfunction during cardiomyocyte differentiation through alteration of GATA4-mediated networks

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

Chromatin co-accessibility is highly structured, spans entire chromosomes, and mediates long range regulatory genetic effects

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