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| Status |
Public on Nov 08, 2021 |
| Title |
H3K4 di-methylation controls smooth muscle cell lineage identity and vascular homeostasis [CUT&Tag_H3K4me2_FLAG] |
| Organism |
Rattus norvegicus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Epigenetic control of lineage-specific gene expression is essential for cell differentiation, acquisition of specialized functions, and tissue homeostasis. Here, we uncovered a unique epigenetic pathway critical for governing lineage identity in cells presenting milieu-dependent phenotypic modulation in adult organisms, by using vascular smooth muscle cells (SMC) as a model of highly specialized and differentiated cell type retaining phenotypic plasticity. We found that the histone modification H3K4me2 is essential for the maintenance of vascular SMC lineage identity and functions by performing H3K4me2 demethylation selectively on a SMC lineage-specific subset of genes. Removal of H3K4me2 on the myocardin-regulated genes led to a marked loss of contractility and alteration in SMC adaptive response capacities during vascular remodeling. Rather than presenting intrinsic gene activation properties, H3K4me2 serves as a stable preferential hub for the dynamic recruitment of the DNA methylcytosine dioxygenase Ten-Eleven Translocation 2 (TET2). Besides the SMC contractile apparatus, the H3K4me2/TET2 complex controls the expression of miR-145, a central microRNA promoting SMC differentiation and participation in vascular remodeling. Finally, H3K4me2 editing induced a profound loss of SMC lineage identity and gain of plasticity, characterized by the redistribution of H3K4me2 on genes associated with stemness and developmental programs and the greater ability of H3K4me2 edited SMC to transdifferentiate into other lineages. These studies identified H3K4me2 as a central epigenetic mechanism controlling lineage identity and cell-specific specialized functions. Our findings may have broad implications for the understanding of mechanisms controlling multiple plastic cell type behaviors and functions in various pathophysiological processes.
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| Overall design |
Compare H3K4me2 distribution in control, Myocd-LSD1 and Myocd-LSD1NF SMC by CUT &Tag seq targeting H3K4me2. FLAG-tagged Mycod-LSD1 binding sites were assessed by CUT&Tag-seq targeting FLAG in Mycod-LSD1 SMC.
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| Contributor(s) |
Liu M, Espinosa-Diez C, Mahan S, Du M, Nguyen AT, Hahn S, Straub AC, Chakraborty R, Martin KA, Owens GK, Gomez D |
| Citation(s) |
34582749, 35465051 |
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| Submission date |
Jun 30, 2021 |
| Last update date |
Apr 27, 2022 |
| Contact name |
Delphine Gomez |
| E-mail(s) |
gomezd@pitt.edu
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| Phone |
412-383-3269
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| Organization name |
University of Pittsburgh
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| Department |
Medicine, division of Cardiology
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| Lab |
Delphine Gomez Lab
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| Street address |
200 Lothrop Street
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| City |
Pittsburgh |
| State/province |
PA |
| ZIP/Postal code |
15261 |
| Country |
USA |
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| Platforms (1) |
| GPL19052 |
Illumina MiSeq (Rattus norvegicus) |
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| Samples (13)
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| This SubSeries is part of SuperSeries: |
| GSE179220 |
H3K4 di-methylation controls smooth muscle cell lineage identity and vascular homeostasis |
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| Relations |
| BioProject |
PRJNA742884 |
| SRA |
SRP326544 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE179217_Chipseeker_Ctrl_H3K4me2.xlsx |
6.0 Mb |
(ftp)(http) |
XLSX |
| GSE179217_Chipseeker_FLAG.xlsx |
3.8 Mb |
(ftp)(http) |
XLSX |
| GSE179217_Chipseeker_Myocd-LSD1_H3K4me2.xlsx |
6.0 Mb |
(ftp)(http) |
XLSX |
| GSE179217_Diffbind_Myocd-LSD1_Myocd-LSD1NF.xlsx |
396.5 Kb |
(ftp)(http) |
XLSX |
| GSE179217_RAW.tar |
259.1 Mb |
(http)(custom) |
TAR (of BIGWIG) |
| GSE179217_chipseeker_Myocd-LSD1NF_H3K4me2.xlsx |
6.0 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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