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Series GSE155882 Query DataSets for GSE155882
Status Public on Apr 08, 2021
Title A Transcriptional Switch Governs Fibroblast Activation in Heart Disease
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Other
Summary In diseased organs, stress-activated signaling cascades alter chromatin, triggering maladaptive cell state transitions. Fibroblast activation is a common tissue stress response that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains obscure. Pharmacologic BET inhibition alleviates cardiac dysfunction, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here, we leverage single-cell epigenomic interrogation of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch underlying fibroblast activation. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed novel DNA elements whose accessibility dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer regulating the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program, and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction, and also demonstrate its upregulation upon activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide new trans- and cis- targets for treating fibrotic disease.
 
Overall design 2 replicates for each sample were run for both single cell RNA and ATAC seq (2x Sham, 2x TAC, 2x TAC JQ1, 2xTAC JQ1 withdrawn).
2 replicates for each sample were run for PRO seq (2x Unstimulated, 2x TGFb, 2x TGFb + siRNA Ctrl, 2x TGFb + siRNA Meox1).
1 replicate for each sample was ran for 4C (1x Unstimulated, 1x TGFb).
2 replicates for MEOX1 ChIPseq.
3 replicates for each sample for bulkRNAseq (3x Sham, 3x TAC, 3x TAC JQ1).
8 PROseq samples (2x Unstimulated, 2x TGFb, 2x TGFb + siRNA Ctrl, 2x TGFb + siRNA Meox1).
6 MEOX1 ChIPseq samples (3x for Unstim and 3x for TGFb-treated conditions).
4 H3K27ac ChIPseq samples (3x for Unstim and 3x for TGFb-treated conditions).
 
Contributor(s) Alexanian M, Przytycki PF
Citation(s) 34163071
Submission date Aug 07, 2020
Last update date Jul 09, 2021
Contact name Pawel Przytycki
E-mail(s) pawel.przytycki@gladstone.ucsf.edu
Organization name Gladstone Institutes
Department GIDB
Lab Katie Pollard
Street address 1650 Owens Street
City San Francisco
State/province California
ZIP/Postal code 94158
Country USA
 
Platforms (3)
GPL19057 Illumina NextSeq 500 (Mus musculus)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (56)
GSM4715037 Sham scATAC rep 1
GSM4715038 Sham scATAC rep 2
GSM4715039 TAC scATAC rep 1
Relations
BioProject PRJNA655922
SRA SRP276680

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE155882_BulkRNAseq_CM_DE_Sham_vs_TAC.csv.gz 471.4 Kb (ftp)(http) CSV
GSE155882_BulkRNAseq_CM_DE_TAC_vs_TACJQ1.csv.gz 469.3 Kb (ftp)(http) CSV
GSE155882_EDGER.Rawcounts_Sham_TAC_TACJQ1.csv.gz 3.2 Mb (ftp)(http) CSV
GSE155882_H3K27ac_TGFb_Rep1_over_input.bw 514.1 Mb (ftp)(http) BW
GSE155882_H3K27ac_TGFb_Rep2_over_input.bw 499.1 Mb (ftp)(http) BW
GSE155882_H3K27ac_TGFb_Rep_intersect.bed.gz 172.1 Kb (ftp)(http) BED
GSE155882_H3K27ac_Unstim_Rep1_over_input.bw 500.5 Mb (ftp)(http) BW
GSE155882_H3K27ac_Unstim_Rep2_over_input.bw 529.6 Mb (ftp)(http) BW
GSE155882_H3K27ac_Unstim_Rep_intersect.bed.gz 153.9 Kb (ftp)(http) BED
GSE155882_MEOX1-HA_TGFb_Rep1_2_3_combined_over_input.bw 272.4 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_TGFb_Rep1_over_input.bw 519.6 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_TGFb_Rep2_over_input.bw 517.0 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_TGFb_Rep3_over_input.bw 532.7 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_TGFb_Rep_intersect.bed.gz 46.7 Kb (ftp)(http) BED
GSE155882_MEOX1-HA_Unstim_Rep1_2_3_combined_over_input.bw 261.4 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_Unstim_Rep1_over_input.bw 490.2 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_Unstim_Rep2_over_input.bw 508.2 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_Unstim_Rep3_over_input.bw 518.6 Mb (ftp)(http) BW
GSE155882_MEOX1-HA_Unstim_Rep_intersect.bed.gz 45.9 Kb (ftp)(http) BED
GSE155882_PROseq_aCFs_merge_TGFb.mTDneg.ucsc.bigWig 87.0 Mb (ftp)(http) BIGWIG
GSE155882_PROseq_aCFs_merge_TGFb.mTDpos.ucsc.bigWig 88.1 Mb (ftp)(http) BIGWIG
GSE155882_PROseq_aCFs_merge_UNT.mTDneg.ucsc.bigWig 85.5 Mb (ftp)(http) BIGWIG
GSE155882_PROseq_aCFs_merge_UNT.mTDpos.ucsc.bigWig 87.4 Mb (ftp)(http) BIGWIG
GSE155882_PROseq_aCFs_merge_siCTRL.mTDneg.ucsc.bigWig 74.4 Mb (ftp)(http) BIGWIG
GSE155882_PROseq_aCFs_merge_siCTRL.mTDpos.ucsc.bigWig 76.3 Mb (ftp)(http) BIGWIG
GSE155882_PROseq_aCFs_merge_siMEOX.mTDneg.ucsc.bigWig 89.1 Mb (ftp)(http) BIGWIG
GSE155882_PROseq_aCFs_merge_siMEOX.mTDpos.ucsc.bigWig 91.1 Mb (ftp)(http) BIGWIG
GSE155882_RAW.tar 4.1 Gb (http)(custom) TAR (of BED, BIGWIG, MTX, TSV, WIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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