Smad-interacting protein-1 and microRNA 200 family define a nitric oxide-dependent molecular circuitry involved in embryonic stem cell mesendoderm differentiation

Simona Nanni, J Rosati, F Spallotta, A Grasselli, A Antonini, S Vincenti, C Presutti, C Colussi, C D'Angelo, A Biroccio, A Farsetti, Mc Capogrossi, B Illi, C. Gaetano

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Abstract

Smad-interacting protein-1 (Sip1/ZEB2) is a transcriptional repressor of the telomerase reverse transcriptase catalytic subunit (Tert) and has recently been identified as a key regulator of embryonic cell fate with a phenotypic effect similar, in our opinion, to that reported for nitric oxide (NO). Remarkably, SIP1/ZEB2 is a known target of the microRNA 200 (miR-200) family. In this light, we postulated that Sip1/ZEB2 and the miR-200 family could play a role during the NO-dependent differentiation of mES. METHODS AND RESULTS: The results of the present study show that Sip1/ZEB2 expression is downregulated during the NO-dependent expression of mesendoderm and early cardiovascular precursor markers, including Flk1 and CXCR4 in mES. Coincidently, members of the miR-200 family, namely miR-429, -200a, -200b, and -200c, were transcriptionally induced in parallel to mouse Tert. This regulation occurred at the level of chromatin. Remarkably, miR-429/miR-200a overexpression or Sip1/ZEB2 knockdown by short hairpin RNA interference elicited a gene expression pattern similar to that of NO regardless of the presence of leukemia inhibitory factor. CONCLUSIONS: These results are the first demonstrating that the miR-200 family and Sip1/ZEB2 transcription factor are regulated by NO, indicating an unprecedented molecular circuitry important for telomerase regulation and early differentiation of mES.
Lingua originaleEnglish
pagine (da-a)898-907
Numero di pagine10
RivistaArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Stato di pubblicazionePubblicato - 2011

Keywords

  • differentiation
  • microRNA

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