TY - JOUR
T1 - Esrrb Is a Direct Nanog Target Gene that Can Substitute for Nanog Function in Pluripotent Cells
AU - Festuccia, Nicola
AU - Osorno, Rodrigo
AU - Halbritter, Florian
AU - Karwacki-Neisius, Violetta
AU - Navarro, Pablo
AU - Colby, Douglas
AU - Wong, Frederick
AU - Yates, Adam
AU - Tomlinson, Simon R
AU - Chambers, Ian
N1 - Copyright © 2012 Elsevier Inc. All rights reserved.
PY - 2012/10
Y1 - 2012/10
N2 - Embryonic stem cell (ESC) self-renewal efficiency is determined by the level of Nanog expression. However, the mechanisms by which Nanog functions remain unclear, and in particular, direct Nanog target genes are uncharacterized. Here we investigate ESCs expressing different Nanog levels and Nanog(-/-) cells with distinct functionally inducible Nanog proteins to identify Nanog-responsive genes. Surprisingly, these constitute a minor fraction of genes that Nanog binds. Prominent among Nanog-reponsive genes is Estrogen-related receptor b (Esrrb). Nanog binds directly to Esrrb, enhances binding of RNAPolII, and stimulates Esrrb transcription. Overexpression of Esrrb in ESCs maintains cytokine-independent self-renewal and pluripotency. Remarkably, this activity is retained in Nanog(-/-) ESCs. Moreover, Esrrb can reprogram Nanog(-/-) EpiSCs and can rescue stalled reprogramming in Nanog(-/-) pre-iPSCs. Finally, Esrrb deletion abolishes the defining ability of Nanog to confer LIF-independent ESC self-renewal. These findings are consistent with the functional placement of Esrrb downstream of Nanog.
AB - Embryonic stem cell (ESC) self-renewal efficiency is determined by the level of Nanog expression. However, the mechanisms by which Nanog functions remain unclear, and in particular, direct Nanog target genes are uncharacterized. Here we investigate ESCs expressing different Nanog levels and Nanog(-/-) cells with distinct functionally inducible Nanog proteins to identify Nanog-responsive genes. Surprisingly, these constitute a minor fraction of genes that Nanog binds. Prominent among Nanog-reponsive genes is Estrogen-related receptor b (Esrrb). Nanog binds directly to Esrrb, enhances binding of RNAPolII, and stimulates Esrrb transcription. Overexpression of Esrrb in ESCs maintains cytokine-independent self-renewal and pluripotency. Remarkably, this activity is retained in Nanog(-/-) ESCs. Moreover, Esrrb can reprogram Nanog(-/-) EpiSCs and can rescue stalled reprogramming in Nanog(-/-) pre-iPSCs. Finally, Esrrb deletion abolishes the defining ability of Nanog to confer LIF-independent ESC self-renewal. These findings are consistent with the functional placement of Esrrb downstream of Nanog.
U2 - 10.1016/j.stem.2012.08.002
DO - 10.1016/j.stem.2012.08.002
M3 - Article
C2 - 23040477
SN - 1875-9777
VL - 11
SP - 477
EP - 490
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 4
ER -