Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to define a pluripotency gene regulatory network

AbstractThe pluripotency gene regulatory network of porcine-induced pluripotent stem cells (piPSCs), especially in epigenetics, remains elusive. To determine this biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs.SummaryErasure of H3K9 methylation in porcine pluripotent stem cells depends on the complex of transcription factors OCT4/SOX2 and histone demethylase KDM3A/KDM3B.

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Faculty Opinions recommendation of Ground rules of the pluripotency gene regulatory network.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727162803.793550339 ◽

2018 ◽

Author(s):

Jing-Dong Jackie Han

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Pluripotency Gene ◽

Gene Regulatory

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Ground rules of the pluripotency gene regulatory network

Nature Reviews Genetics ◽

10.1038/nrg.2016.156 ◽

2017 ◽

Vol 18 (3) ◽

pp. 180-191 ◽

Cited By ~ 60

Author(s):

Mo Li ◽

Juan Carlos Izpisua Belmonte

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Pluripotency Gene ◽

Gene Regulatory

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Genetic signatures of evolution of the pluripotency gene regulating network across mammals

10.1101/2020.04.16.043943 ◽

2020 ◽

Author(s):

Yoshinori Endo ◽

Ken-ichiro Kamei ◽

Miho Inoue-Murayama

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Mammalian Species ◽

Rapid Evolution ◽

Network Evolution ◽

Downstream Targets ◽

The Core ◽

Regulatory Circuit ◽

Pluripotency Gene ◽

Gene Regulatory

AbstractMammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics, but we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we applied a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We found evolutionary conservation in JAK-STAT and PI3K-Akt signaling pathways, suggesting equivalent capabilities in self-renewal and proliferation of mammalian PSCs. On the other hand, we discovered rapid evolution of the downstream targets of the core regulatory circuit, providing insights into variations of characteristics. Our data indicate that the variations in the PSCs characteristics may be due to positive selections in the downstream targets of the core regulatory circuit. We further reveal that positively selected genes can be associated with species unique adaptation that is not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs.

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Evolution of the mammalian embryonic pluripotency gene regulatory network

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1010708107 ◽

2010 ◽

Vol 107 (46) ◽

pp. 19955-19960 ◽

Cited By ~ 24

Author(s):

B. Fernandez-Tresguerres ◽

S. Canon ◽

T. Rayon ◽

B. Pernaute ◽

M. Crespo ◽

...

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Pluripotency Gene ◽

Gene Regulatory

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Genetic Signatures of Evolution of the Pluripotency Gene Regulating Network across Mammals

Genome Biology and Evolution ◽

10.1093/gbe/evaa169 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1806-1818

Author(s):

Yoshinori Endo ◽

Ken-ichiro Kamei ◽

Miho Inoue-Murayama

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Mammalian Species ◽

Rapid Evolution ◽

Regulatory Elements ◽

Network Evolution ◽

Pluripotency Gene ◽

Fundamental Biological Process ◽

Gene Regulatory ◽

Taxonomic Groups

Abstract Mammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics among species, but to date we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we carried out a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We report that mammalian genes in the pluripotency regulatory network show a remarkably high degree of evolutionary stasis, suggesting the conservation of fundamental biological process of mammalian PSCs across species. Nevertheless, despite the overall conservation of the regulatory network, we discovered rapid evolution of the downstream targets of the core regulatory elements and specific amino acid residues that have undergone positive selection. Our data indicate development of lineage-specific pluripotency regulating networks that may explain observed variations in some characteristics of mammalian PSCs. We further revealed that positively selected genes could be associated with species’ unique adaptive characteristics that were not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs.

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