Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway

Jiang, Wei; Wang, Jinzhao; Zhang, Yi

doi:10.1038/cr.2012.119

Cited by 127 publications

(114 citation statements)

References 24 publications

(30 reference statements)

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“…As mentioned above, during Activin/Nodal-induced ME differentiation, Smad2 recruits JMJD3 onto the promoters of the Nodal and Brachyury genes to remove H3K27me3 and thereby activate their transcription [53; 141]. In response to Wnt signaling, JMJD3 and UTX remove H3K27me3 in the promoter region of Wnt3 and induce its expression [139]. Wnt3 is…”

Section: Crosstalk Between Extrinsic Signals and Epigenetic Regulationsmentioning

confidence: 99%

Signaling Control of Differentiation of Embryonic Stem Cells toward Mesendoderm

Wang

Chen

2016

Journal of Molecular Biology

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Section: Crosstalk Between Extrinsic Signals and Epigenetic Regulationsmentioning

confidence: 99%

Signaling Control of Differentiation of Embryonic Stem Cells toward Mesendoderm

Wang

Chen

2016

Journal of Molecular Biology

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“…For example, KDM6B is a histone H3 lysine demethylase with an important gene regulatory role in development and physiology. It has been reported not only to interact with ␤-catenin and contribute to ␤-catenin-dependent promoter activation but also to upregulate Wnt3 expression and cause activation of Wnt signaling (64,65). PPP3R1 is calcineurin subunit B type 1, an important component of the Wnt/Ca 2ϩ pathway with Ca 2ϩ /calmodulin binding activity.…”

Section: Discussionmentioning

confidence: 99%

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

et al. 2016

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Ehrlichia chaffeensis invades and survives in phagocytes by modulating host cell processes and evading innate defenses, but the mechanisms are not fully defined. Recently we have determined that E. chaffeensis tandem repeat proteins (TRPs) are type 1 secreted effectors involved in functionally diverse interactions with host targets, including components of the evolutionarily conserved Wnt signaling pathways. In this study, we demonstrated that induction of host canonical and noncanonical Wnt pathways by E. chaffeensis TRP effectors stimulates phagocytosis and promotes intracellular survival. After E. chaffeensis infection, canonical and noncanonical Wnt signalings were significantly stimulated during early stages of infection (1 to 3 h) which coincided with dephosphorylation and nuclear translocation of ␤-catenin, a major canonical Wnt signal transducer, and NFATC1, a noncanonical Wnt transcription factor. In total, the expression of ϳ44% of Wnt signaling target genes was altered during infec- Ehrlichia chaffeensis is an obligately intracellular bacterium responsible for the emerging life-threatening human zoonosis human monocytotropic ehrlichiosis (HME) (1). E. chaffeensis selectively infects mononuclear phagocytes and resides in early-endosome-like membrane-bound vacuoles (1). The mechanisms by which E. chaffeensis enters host cells, establishes persistent infection, and avoids host defenses are not completely understood but occur through functionally relevant host-pathogen interactions involving secreted ehrlichial tandem repeat protein (TRP) effectors that are posttranslationally modified by ubiquitin (Ub) and the small ubiquitin-like modifier (SUMO) (2-5). E. chaffeensis TRPs interact with a diverse group of human proteins associated with major cellular processes, including transcription, translation, protein trafficking, cell signaling, cytoskeleton organization, and apoptosis, indicating that they play a role in manipulating these important cellular processes to facilitate infection (6-8).E. chaffeensis TRPs were first recognized as antigens that elicit strong protective antibody responses during infection that are directed at continuous species-specific epitopes in tandem repeat regions (9-12). Subsequently, our understanding of the functional role of TRPs as effectors in pathobiology has been advanced through studies that have defined specific TRP-host protein and DNA interactions (4, 13). Notably, E. chaffeensis TRP120 and TRP32 interact with numerous host proteins and genes associated with the canonical and noncanonical Wnt signaling pathways. One of TRP32-interacting targets, deleted-in-azoospermia-associated protein 2 (DAZAP2), is a highly conserved protein that modulates gene transcription driven by Wnt/␤-catenin signaling effector T-cell factors (TCFs), and knockdown of host DAZAP2 by small interfering RNA (siRNA) reduced the E. chaffeensis load in infected cells (7,14). Several other TRP120-interacting host proteins, such as AT-rich interactive domain 1B (ARID1B), lysine (K)-specific demethylase...

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“…The activin/Nodal signaling mediators Smad2/3 have been shown to recruit JMJD3 to the promoters of the T and Nodal genes in mouse ESCs, leading to removal of the repressive H3K27me3 mark and thereby initiating ME differentiation (19). JMJD3/UTX can also remove H3K27me3 from the WNT3 gene and activate its expression, which, in turn, stimulates ␤-catenin-mediated gene expression and promotes definitive endoderm differentiation (20). In response to TGF-␤/Nodal signals, the PHD-Bromo-containing protein TRIM33 facilitates the binding of Smad2/3 to trimethylated histone H3 Lys-9 and acetylated histone H3 Lys-18 on the promoters of the ME regulators Gsc and MixL1, thus leading to displacement of the chromatin-compacting factor HP1␥ and gene activation in mouse ESCs (21).…”

Section: Differentiation Of Human Embryonic Stem Cells (Hescs)mentioning

confidence: 99%

Activin/Smad2-induced Histone H3 Lys-27 Trimethylation (H3K27me3) Reduction Is Crucial to Initiate Mesendoderm Differentiation of Human Embryonic Stem Cells

Wang

Yun

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangDifferentiation of human embryonic stem cells into mesendoderm (ME) is directed by extrinsic signals and intrinsic epigenetic modifications. However, the dynamics of these epigenetic modifications and the mechanisms by which extrinsic signals regulate the epigenetic modifications during the initiation of ME differentiation remain elusive. In this study, we report that levels of histone H3 Lys-27 trimethylation (H3K27me3) decrease during ME initiation, which is essential for subsequent differentiation induced by the combined effects of activin and Wnt signaling. Furthermore, we demonstrate that activin mediates the H3K27me3 decrease via the Smad2-mediated reduction of EZH2 protein level. Our results suggest a two-step process of ME initiation: first, epigenetic priming via removal of H3K27me3 marks and, second, transcription activation. Our findings demonstrate a critical role of H3K27me3 priming and a direct interaction between extrinsic signals and epigenetic modifications during ME initiation.

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Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway

Cited by 127 publications

References 24 publications

Signaling Control of Differentiation of Embryonic Stem Cells toward Mesendoderm

Signaling Control of Differentiation of Embryonic Stem Cells toward Mesendoderm

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

Activin/Smad2-induced Histone H3 Lys-27 Trimethylation (H3K27me3) Reduction Is Crucial to Initiate Mesendoderm Differentiation of Human Embryonic Stem Cells

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