Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells.
Chiara CencioniFrancesco SpallottaMatteo SavoiaCarsten KuenneStefan GuentherAgnese ReSusanne WingertMaike RehageDuran SürünMauro SiragusaJacob G SmithFrank SchnütgenHarald von MelchnerMichael A RiegerFabio MartelliAntonella RiccioIngrid FlemingThomas BraunAndreas M ZeiherAntonella FarsettiCarlo GaetanoPublished in: Nature communications (2018)
Nitric oxide (NO) synthesis is a late event during differentiation of mouse embryonic stem cells (mESC) and occurs after release from serum and leukemia inhibitory factor (LIF). Here we show that after release from pluripotency, a subpopulation of mESC, kept in the naive state by 2i/LIF, expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes NO. This eNOS/NO-positive subpopulation (ESNO+) expresses mesendodermal markers and is more efficient in the generation of cardiovascular precursors than eNOS/NO-negative cells. Mechanistically, production of endogenous NO triggers rapid Hdac2 S-nitrosylation, which reduces association of Hdac2 with the transcriptional repression factor Zeb1, allowing mesendodermal gene expression. In conclusion, our results suggest that the interaction between Zeb1, Hdac2, and eNOS is required for early mesendodermal differentiation of naive mESC.
Keyphrases
- nitric oxide synthase
- embryonic stem cells
- nitric oxide
- gene expression
- histone deacetylase
- epithelial mesenchymal transition
- long non coding rna
- hiv infected
- endothelial cells
- hydrogen peroxide
- induced apoptosis
- dna methylation
- bone marrow
- genome wide
- acute myeloid leukemia
- oxidative stress
- cell cycle arrest
- signaling pathway
- transcription factor
- cell death
- heat shock
- antiretroviral therapy