H3K4 di-methylation governs smooth muscle lineage identity and promotes vascular homeostasis by restraining plasticity.
Dev Cell
; 56(19): 2765-2782.e10, 2021 10 11.
Article
in En
| MEDLINE
| ID: mdl-34582749
ABSTRACT
Epigenetic mechanisms contribute to the regulation of cell differentiation and function. Vascular smooth muscle cells (SMCs) are specialized contractile cells that retain phenotypic plasticity even after differentiation. Here, by performing selective demethylation of histone H3 lysine 4 di-methylation (H3K4me2) at SMC-specific genes, we uncovered that H3K4me2 governs SMC lineage identity. Removal of H3K4me2 via selective editing in cultured vascular SMCs and in murine arterial vasculature led to loss of differentiation and reduced contractility due to impaired recruitment of the DNA methylcytosine dioxygenase TET2. H3K4me2 editing altered SMC adaptative capacities during vascular remodeling due to loss of miR-145 expression. Finally, H3K4me2 editing induced a profound alteration of SMC lineage identity by redistributing H3K4me2 toward genes associated with stemness and developmental programs, thus exacerbating plasticity. Our studies identify the H3K4me2-TET2-miR145 axis as a central epigenetic memory mechanism controlling cell identity and function, whose alteration could contribute to various pathophysiological processes.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Adaptation, Physiological
/
Gene Expression Regulation
/
Muscle, Smooth, Vascular
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Dev Cell
Journal subject:
EMBRIOLOGIA
Year:
2021
Document type:
Article
Affiliation country:
United States