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Stem Cell Res. 2014 Jan;12(1):296-308. doi: 10.1016/j.scr.2013.11.007. Epub 2013 Nov 16.
Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells.
Abstract
The
aryl hydrocarbon receptor (AHR) is a transcription factor and
environmental sensor that regulates expression of genes involved in
drug-metabolism and cell cycle regulation.
Chromatin immunoprecipitation (ChIP) analyses, Ahr ablation in mice and studies with orthologous genes in invertebrates suggest that AHR may also play a significant role in embryonic development.
To address this hypothesis, we studied the regulation of Ahr expression in mouse embryonic stem cells (ESC) and their differentiated progeny. In ES cells, interactions between OCT3/4, NANOG, SOX2 and Polycomb Group (PcG) proteins at the Ahr promoter repress AHR expression, which can also be repressed by ectopic expression of reprogramming factors in hepatoma cells.
In ES cells, unproductive RNA polymerase II (RNAPII) binds at the Ahr transcription start site (TSS) and drives the synthesis of short abortive transcripts. Activation of Ahr expression during differentiation follows from reversal of repressive marks in Ahr promoter chromatin, release of pluripotency factors and PcG proteins, binding of Sp factors, establishment of histone marks of open chromatin, and engagement of active RNAPII to drive full-length RNA transcript elongation.
Our results suggest that reversible Ahr repression in ES cells holds the gene poised for expression and allows for a quick switch to activation during embryonic development.
Chromatin immunoprecipitation (ChIP) analyses, Ahr ablation in mice and studies with orthologous genes in invertebrates suggest that AHR may also play a significant role in embryonic development.
To address this hypothesis, we studied the regulation of Ahr expression in mouse embryonic stem cells (ESC) and their differentiated progeny. In ES cells, interactions between OCT3/4, NANOG, SOX2 and Polycomb Group (PcG) proteins at the Ahr promoter repress AHR expression, which can also be repressed by ectopic expression of reprogramming factors in hepatoma cells.
In ES cells, unproductive RNA polymerase II (RNAPII) binds at the Ahr transcription start site (TSS) and drives the synthesis of short abortive transcripts. Activation of Ahr expression during differentiation follows from reversal of repressive marks in Ahr promoter chromatin, release of pluripotency factors and PcG proteins, binding of Sp factors, establishment of histone marks of open chromatin, and engagement of active RNAPII to drive full-length RNA transcript elongation.
Our results suggest that reversible Ahr repression in ES cells holds the gene poised for expression and allows for a quick switch to activation during embryonic development.
Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.
KEYWORDS:
AHR, aryl hydrocarbon receptor; ( transkriptiotekijä ja miljöösensori)ARNT; Ah receptor nuclear translocator;
AhRE,AHR response element;
CTD, carboxyl-terminal repeat domain;
ChIP, chromatin immunoprecipitation;
EB, embryoid bodies;
EMT, epithelial-to-mesenchymal transition;
ESC, embryonic stem cells;
EZH2, enhancer of zeste homolog 2;
H3K27ac; acetylated lysine-27 of histone H3;
H3K27me3/2/1, tri/di/mono-methylated lysine-27 of histone H3;
H3K36me3; tri-methylated lysine-36 of histone H3;
H3K4me3/2/, ;tri/di/mono-methylated lysine-4 of histone H3;
H3K9ac, acetylated lysine-9 of histone H3;
H3K9me3/2/1, tri/di/mono-methylated lysine-9 of histone H3
H3ac, acetylated histone H3;
HMT, histone methyltransferase;
ICMm inner-cell-mass;
KDM6A/B, lysine demethylase 6A and 6B;
KO, knock out;
MET, mesenchymal-to-epithelial transition;
MLL, myeloid/lymphoid or mix-lineage leukemia;
OCT3/4,
SOX2,
KLF4,
MYC;
OSKM;
PRC1/2, Polycomb repressive complexes 1 and 2;
PcG; Polycomb Group proteins;
RING1B, ring finger protein 1B;
RNAPII, RNA polymerase II;
RNAPII (S5p(+)S2p(+)), RNA polymerase II hyperphosphorylated in CTD serine-5 and serine-2;
RNAPII (S5p(+)S2p(−)), RNA polymerase II phosphorylated in CTD serine-5 but not serine-2;
SUZ12, suppressor of zeste 12 homolog;
TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin;
TES. transcription end site;
TSS, transcription start site;
TxG, Trithorax Group proteins;
bHLH/PAS, basic helix–loop–helix/Per-ARNT-Sim;
iPSC, induced pluripotent stem cells;
Kommentti: Otin tämäna rtikkelin sitaatina, näiden termisanojen takia, ksoka Suomen keliakiatutkimus on tällä tasolla asian syvillä juurilla ja näitä termejä käytetään. Jätetään tämä asia hautumaan. ja seurataan mitä tuloksia Tempereelta ilmenee.
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