TY - JOUR
T1 - Genome-wide studies reveal that H3K4me3 modification in bivalent genes is dynamically regulated during the pluripotent cell cycle and stabilized upon differentiation
AU - Grandy, Rodrigo A.
AU - Whitfield, Troy W.
AU - Wu, Hai
AU - Fitzgerald, Mark P.
AU - VanOudenhove, Jennifer J.
AU - Zaidi, Sayyed K.
AU - Montecino, Martin A.
AU - Lian, Jane B.
AU - van Wijnen, André J.
AU - Stein, Janet L.
AU - Stein, Gary S.
N1 - Funding Information:
HHS | NIH | National Cancer Institute (NCI) provided funding to Gary S. Stein under grant number R01 CA139322. HHS | NIH | National Institute on Aging (NIA) provided funding to Gary S. Stein under grant number RC1 AG035886. Fondo Nacional en Areas Prioritarias (FONDAP; Chile) provided funding to Martin A. Montecino under grant number 15090007.
Publisher Copyright:
© 2016, American Society for Microbiology. All Rights Reserved.
PY - 2016
Y1 - 2016
N2 - Stem cell phenotypes are reflected by posttranslational histone modifications, and this chromatin-related memory must be mitotically inherited to maintain cell identity through proliferative expansion. In human embryonic stem cells (hESCs), bivalent genes with both activating (H3K4me3) and repressive (H3K27me3) histone modifications are essential to sustain pluripotency. Yet, the molecular mechanisms by which this epigenetic landscape is transferred to progeny cells remain to be established. By mapping genomic enrichment of H3K4me3/H3K27me3 in pure populations of hESCs in G2, mitotic, and G1 phases of the cell cycle, we found striking variations in the levels of H3K4me3 through the G2-M-G1 transition. Analysis of a representative set of bivalent genes revealed that chromatin modifiers involved in H3K4 methylation/demethylation are recruited to bivalent gene promoters in a cell cycle-dependent fashion. Interestingly, bivalent genes enriched with H3K4me3 exclusively during mitosis undergo the strongest upregulation after induction of differentiation. Furthermore, the histone modification signature of genes that remain bivalent in differentiated cells resolves into a cell cycle-independent pattern after lineage commitment. These results establish a new dimension of chromatin regulation important in the maintenance of pluripotency.
AB - Stem cell phenotypes are reflected by posttranslational histone modifications, and this chromatin-related memory must be mitotically inherited to maintain cell identity through proliferative expansion. In human embryonic stem cells (hESCs), bivalent genes with both activating (H3K4me3) and repressive (H3K27me3) histone modifications are essential to sustain pluripotency. Yet, the molecular mechanisms by which this epigenetic landscape is transferred to progeny cells remain to be established. By mapping genomic enrichment of H3K4me3/H3K27me3 in pure populations of hESCs in G2, mitotic, and G1 phases of the cell cycle, we found striking variations in the levels of H3K4me3 through the G2-M-G1 transition. Analysis of a representative set of bivalent genes revealed that chromatin modifiers involved in H3K4 methylation/demethylation are recruited to bivalent gene promoters in a cell cycle-dependent fashion. Interestingly, bivalent genes enriched with H3K4me3 exclusively during mitosis undergo the strongest upregulation after induction of differentiation. Furthermore, the histone modification signature of genes that remain bivalent in differentiated cells resolves into a cell cycle-independent pattern after lineage commitment. These results establish a new dimension of chromatin regulation important in the maintenance of pluripotency.
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U2 - 10.1128/MCB.00877-15
DO - 10.1128/MCB.00877-15
M3 - Article
C2 - 26644406
AN - SCOPUS:84957875072
VL - 36
SP - 615
EP - 627
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 4
ER -