Gro/TLE enables embryonic stem cell differentiation by repressing pluripotent gene expression
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Gro/TLE enables embryonic stem cell differentiation by repressing pluripotent gene expression. / Laing, Adam F; Lowell, Sally; Brickman, Joshua M.
In: Developmental Biology, Vol. 397, No. 1, 01.01.2015, p. 56-66.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Gro/TLE enables embryonic stem cell differentiation by repressing pluripotent gene expression
AU - Laing, Adam F
AU - Lowell, Sally
AU - Brickman, Joshua M
N1 - Copyright © 2014 Elsevier Inc. All rights reserved.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Gro/TLE proteins (TLE1-4) are a family of transcriptional corepressors acting downstream of multiple signalling pathways. Several TLEs are expressed in a dynamic manner throughout embryonic development and at high levels in embryonic stem cells (ESCs). Here we find that Gro/TLE is not required in ESC for sustaining pluripotency and suppressing differentiation genes, but rather is important for the shutting down of the pluripotency network in differentiation. Consistent with this view, we found that one of the Gro/TLE family, TLE4 is expressed heterogeneously in ESCs in a population that corresponds to a Nanog low subset of ESC culture. TLE4 expression is also increased in response to LIF withdrawal and Fgf/Mek/Erk stimulation. To explore the role of Gro/TLE in more detail we generated an allelic series of knockout ESCs of two TLE genes expressed most dynamically in early differentiation, TLE3 and TLE4. Genetic reduction in TLE dose resulted in an increase in the expression of pluripotency markers and inhibition of ESC differentiation towards both epiblast and endoderm lineages. Overexpression of a drug inducible TLE4 could both rescue TLE3/TLE4 compound phenotypes and induce early expression of endoderm (Hhex-Venus) and neural (Sox1-GFP) reporter genes. Taken together, our results suggest that TLE activity is essential for early differentiation where it acts to suppress the pluripotency network, allowing for the initiation of lineage specific gene expression programs.
AB - Gro/TLE proteins (TLE1-4) are a family of transcriptional corepressors acting downstream of multiple signalling pathways. Several TLEs are expressed in a dynamic manner throughout embryonic development and at high levels in embryonic stem cells (ESCs). Here we find that Gro/TLE is not required in ESC for sustaining pluripotency and suppressing differentiation genes, but rather is important for the shutting down of the pluripotency network in differentiation. Consistent with this view, we found that one of the Gro/TLE family, TLE4 is expressed heterogeneously in ESCs in a population that corresponds to a Nanog low subset of ESC culture. TLE4 expression is also increased in response to LIF withdrawal and Fgf/Mek/Erk stimulation. To explore the role of Gro/TLE in more detail we generated an allelic series of knockout ESCs of two TLE genes expressed most dynamically in early differentiation, TLE3 and TLE4. Genetic reduction in TLE dose resulted in an increase in the expression of pluripotency markers and inhibition of ESC differentiation towards both epiblast and endoderm lineages. Overexpression of a drug inducible TLE4 could both rescue TLE3/TLE4 compound phenotypes and induce early expression of endoderm (Hhex-Venus) and neural (Sox1-GFP) reporter genes. Taken together, our results suggest that TLE activity is essential for early differentiation where it acts to suppress the pluripotency network, allowing for the initiation of lineage specific gene expression programs.
U2 - 10.1016/j.ydbio.2014.10.007
DO - 10.1016/j.ydbio.2014.10.007
M3 - Journal article
C2 - 25446531
VL - 397
SP - 56
EP - 66
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 1
ER -
ID: 129742655