TY - JOUR
T1 - OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency
AU - Bernard, Laure D
AU - Dubois, Agnès
AU - Heurtier, Victor
AU - Fischer, Véronique
AU - Gonzalez, Inma
AU - Chervova, Almira
AU - Tachtsidi, Alexandra
AU - Gil, Noa
AU - Owens, Nick
AU - Bates, Lawrence E
AU - Vandormael-Pournin, Sandrine
AU - Silva, José C R
AU - Ulitsky, Igor
AU - Cohen-Tannoudji, Michel
AU - Navarro, Pablo
N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2022/7/22
Y1 - 2022/7/22
N2 - Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. How global H3K9 methylation levels are coupled with the loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of Suv39h1as, an antisense long non-coding RNA to Suv39h1. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, affecting all heterochromatic regions, particularly peri-centromeric major satellites and retrotransposons. This increase in heterochromatinization efficiency leads to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the genetic control of pluripotency with the global efficiency of H3K9 methylation associated with a major cell fate restriction, the irreversible loss of pluripotency.
AB - Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. How global H3K9 methylation levels are coupled with the loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of Suv39h1as, an antisense long non-coding RNA to Suv39h1. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, affecting all heterochromatic regions, particularly peri-centromeric major satellites and retrotransposons. This increase in heterochromatinization efficiency leads to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the genetic control of pluripotency with the global efficiency of H3K9 methylation associated with a major cell fate restriction, the irreversible loss of pluripotency.
KW - Animals
KW - Chromatin
KW - Histone Code
KW - Histones/genetics
KW - Methylation
KW - Methyltransferases/genetics
KW - Mice
KW - Octamer Transcription Factor-3/metabolism
KW - RNA, Long Noncoding/genetics
KW - Repressor Proteins/genetics
U2 - 10.1093/nar/gkac550
DO - 10.1093/nar/gkac550
M3 - Article
C2 - 35762231
SN - 0305-1048
VL - 50
SP - 7367
EP - 7379
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 13
ER -