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JMJD3: a critical epigenetic regulator in stem cell fate

Cell Communication and Signaling volume 19, Article number: 72 (2021) Cite this article

Abstract

The Jumonji domain-containing protein-3 (JMJD3) is a histone demethylase that regulates the trimethylation of histone H3 on lysine 27 (H3K27me3). H3K27me3 is an important epigenetic event associated with transcriptional silencing. JMJD3 has been studied extensively in immune diseases, cancer, and tumor development. There is a comprehensive epigenetic transformation during the transition of embryonic stem cells (ESCs) into specialized cells or the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Recent studies have illustrated that JMJD3 plays a major role in cell fate determination of pluripotent and multipotent stem cells (MSCs). JMJD3 has been found to enhance self-renewal ability and reduce the differentiation capacity of ESCs and MSCs. In this review, we will focus on the recent advances of JMJD3 function in stem cell fate.

Video Abstract

Background

In the human genome, the sequence of DNA and epigenetic mechanisms such as DNA methylation, histone modification (methylation, phosphorylation, acetylation, adenylation, ADP ribosylation, and ubiquitination), and chromatin remodeling are thought to alter gene expression [1, 2]. It has been discovered that the aberrant expression of histone methylation leads to demethylation and abnormal histone methylation, which contributes to migration, invasion, and carcinogenesis, during cancer development [3, 4]. The trimethylation of histone H3 at lysine-27 (H3K27me3) is an epigenetic modification that contributes to epigenetic silencing and influences the development of normal and abnormal cells [5–7]. The accumulation of H3K27me3 is essential for the recruitment of transcription factors (TFs) to DNA [8, 9]. The Jumonji domain-containing protein-3 (JMJD3, also known as KDM6B) is a histone demethylase that regulates H3K27me3-mediated gene repression and removes H3K27me3 [10, 11]. JMJD3 has been studied extensively in immune diseases, cancer, and tumor development [12–16]. Recent studies have illustrated that JMJD3 plays an important role in cell fate determination of pluripotent and multipotent stem cells [11, 17, 18]. Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have the ability to divide and give rise to all cells of the tissues of the body under specific conditions [19, 20]. Human PSCs are very useful in the field of disease modeling, drug screening, and cell-based regenerative medicine for many diseases [21–23]. Human ESCs can be derived from the inner cell mass (ICM) of the human blastocyst [24]. Human iPSCs are generated by introducing exogenous factors (OCT4, SOX2, KLF4, and c-MYC) into somatic cells [25]. Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity to differentiate into various cell types such as adipocytes, osteocytes, neurocytes, hepatocytes, and chondrocytes [26, 27]. MSCs can be obtained from bone marrow (BM), dental pulp (DP), adipose tissues (AT), and umbilical cord blood (UCB) [28, 29]. Several recent studies have shown that JMJD3 plays an important role during the transition of ESCs and MSCs into specialized cells or the reprogramming of somatic cells to iPSCs [11, 30]. JMJD3 has been found to enhance self-renewal ability and reduce the differentiation capacity of pluripotent and multipotent stem cells [12, 31, 32]. In this review, we will focus on the recent advances of JMJD3 function in stem cell fate.

Structure and function of JMJD3

There are at least 6 families of histone demethylases. KDM4B (JMJD2B) and KDM6B (JMJD3) are two important histone demethylases [35–37]. Human JMJD3 or KDM6B (lysine-specific demethylase 6B) gene is located at 17p13.1 and encodes a polypeptide that contains 1682 amino acids with an average molecular weight of 176,632 Da [10, 38]. JMJD3 belongs to a subfamily of the UTX/UTY JmjC-domain protein [12]. UTX1 (KDM6A) and JMJD3 are the KDM6 family members that demethylate H3K27me3 [39, 40]. JMJD3 contains a Jumonji C (JmjC) domain (demethylates histones) and a C-terminal segment that is embedded with a GATA-like (GATAL) domain [41, 42]. The KDM6A protein has a catalytic JmjC domain at the C terminus and six tetratricopeptide repeat (TPR) domains at the N terminus [43] (Fig. 1).

Fig. 1
figure 1

The molecular mechanisms of JMJD3-mediated transcription of target genes. The Jumonji domain-containing protein-3 (JMJD3) belongs to a subfamily of the UTX/UTY JmjC-domain protein. UTX1 (KDM6A) and JMJD3 (KDM6B) are the KDM6 family members. JMJD3 is a histone demethylase that regulates H3K27me3-mediated gene repression and removes H3K27me3. JMJD3 has a JmjC domain (demethylates histones) and a C-terminal segment that is embedded with a GATA-like (GATAL) domain. The KDM6A protein has a catalytic JmjC domain at the C terminus and six tetratricopeptide repeat (TPR) domains at the N terminus. JMJD3 in a demethylase-dependent or independent manner can regulate gene transcription. Polycomb repressive complex 2 (PRC2, including EZH2, SUZ12, and EED) is a transcriptional repressor that interacts with PRC1 and adds methyl groups to histone H3K27. JMJD3, which opposes the enzymatic activity of the PRC2, regulates the expression of specific genes. JMJD3 as a transcription factor can interact with co-activators and regulate the transcription of target genes

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JMJD3 catalyzes the transition from a repressive status (H3K27me3) to active status (H3K27me1) [44]. JMJD3 in a demethylase-dependent or independent manner can regulate gene transcription [45]. Polycomb repressive complex 2 (PRC2, composed of the enzyme EZH2, SUZ12, and EED) is a transcriptional repressor that interacts with PRC1 and adds methyl groups to histone H3K27 [46, 47]. JMJD3, which opposes the enzymatic activity of the PRC2, regulates the expression of specific genes [48, 49]. JMJD3 as a transcription factor (independent of demethylase activity) can interact with co-activators and regulate the transcription of target genes [45]. JMJD3 by impacting RNA polymerase II (Pol II) promotes transcriptional elongation and gene expression [50]. The molecular mechanisms of JMJD3-mediated transcription of target genes are shown in Fig. 1.

It has been reported that JMJD3 participates in the regulation of cell cycle arrest, apoptosis, tumorigenesis, immune diseases, and cell differentiation by targeting distinct transcription factors and epigenetic proteins [51–54]. JMJD3 by reducing H3K27me3 enrichment negatively regulates the transcription of Sestrin2 (SESN2) and induces cardiomyocyte apoptosis [55]. JMJD3 also negatively mediates inflammatory response, blood-spinal cord barrier (BSCB) disruption, and apoptosis after spinal cord injury (SCI) [56]. JMJD3 is positively correlated with tumor diameter, differentiation, and microvascular infiltration [10, 57, 58]. Therefore, JMJD3 is involved in cellular plasticity and inhibits abnormal tissue growth by regulating unlimited cell proliferation [59].

JMJD3 function in embryonic stem cells

JMJD3 plays a critical role in undifferentiated ESCs and ESC-derived cell gene expressions [60]. GSK-J4 by suppressing the enzymatic activity of JMJD3 triggers cell cycle arrest, DNA damage, and cell death in ESCs-derived cells but not in undifferentiated ESCs [60].

The expression profile of JMJD3 suggests that it may contribute to the regulation of ectoderm, mesoderm, and endoderm differentiation in murine and human ESCs [11, 17, 18] (Fig. 2).

  • Differentiation of ESCs into ectoderm lineage

Fig. 2
figure 2

JMJD3 function in pluripotent stem cells. JMJD3 plays a critical role in the differentiation of ESCs and iPSCs. The expression profile of JMJD3 suggests that it may contribute to the regulation of ectoderm, mesoderm, and endoderm differentiation in murine and human ESCs. JMJD3 as an epigenetic barrier is thought to increase during the reprogramming of differentiated cells into iPSCs

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During differentiation of ESC to the neuronal lineage, JMJD3 can modulate the expression of key markers of neurogenesis (Pax6, Nestin, and Sox1) and enhance neural commitment [61].

Vitamin C is a critical micronutrient that improves the rate of ESC proliferation and the efficiency of iPSC formation [62]. In mouse ESC differentiation, vitamin C can impact JMJD3 and induce a pluripotent state [63], but during the differentiation of dopamine neurons in the fetal midbrain, vitamin C upregulates JMJD3 and decreases the H3K27m3 of dopamine phenotypic to facilitate dopamine neuron differentiation [64].

  • Differentiation of ESCs into mesoderm lineage

JMJD3 also displays an important role in cardiac differentiation [65]. JMJD3 may be involved in the determination of the cardiomyogenic lineage from mouse ESCs and enhanced the expression levels of Jmjd3, Jmjd2a, and Jhdm1d [66]. The transcription factor insulin gene enhancer-binding protein 1 (ISL1) plays a key role in cardiac lineage differentiation [67]. It has been found that ISL1 cooperates with JMJD3 to alter the cardiac epigenome and regulate cardiac differentiation of ESCs [65]. JMJD3 by regulating the Wnt/β-catenin signaling pathway at early and DKK1 (WNT antagonist gene) at a late stage, facilitates differentiation of human ESCs toward mesendoderm and definitive endoderm [32, 68]. Ectopic expression of the JMJD3 has recently been uncovered to facilitate the conversion of hESCs and hiPSCs into skeletal muscle cells and hepatic cells [69].

  • Differentiation of ESCs into endoderm lineage

NODAL is the central transcription factor of TGF-β signaling and a target for repression by Polycomb proteins and accumulation of H3K27me3 [70]. SMAD2/3 proteins that transduce signals from TGF-β signaling are capable of recruiting JMJD3 to remove the H3K27me3 repressive mark on the NODAL promoter and facilitate human ESCs differentiation into endoderm [71].

The role of JMJD3 in reprogramming

JMJD3 as an epigenetic barrier is thought to be increased during the reprogramming of differentiated cells into iPSCs [72] (Fig. 2). It was recently reported that JMJD3 interacts with KLF4 and decreases H3K27me3 in pluripotency genes [34]. A recent study has shown that the Jmjd3-PHF20 axis plays a key role in the reprogramming of somatic cells [33]. PHF20 (plant homeodomain finger protein 20 or glioma-expressed antigen 2) is a critical epigenetic regulator that enhances reprogramming and stemness through activation of Oct4 and Sox2 [73]. JMJD3 by recruiting an E3 ligase Trim26 causes the ubiquitination and degradation of PHF20 [33, 74]. JMJD3 through its H3K27me2/3 demethylase activity enhances the expression of Ink4a/Arf and P21. Thus, a decrease in PHF20 leads to reduce endogenous Oct4 expression, cell proliferation, and the outcome of reprogramming [33]. JMJD3 by removing the H3K27me3 mark from the hepatic transcription factors (HTFs) promoter is participated in the reprogramming of bone marrow progenitor cells (BMPCs) to hepatic cells. In contrast, GSK-J4 can effectively repress the activity of JMJD3 and the loss of the H3K27me3 chromatin mark in BMPCs [75].

JMJD3 function in multipotent stem cells

  • Neural stem cells

It has been reported that JMJD3 interacts with the activated SMAD3 and enhances the differentiation of neural stem cells (NSCs) [76]. JMJD3 is required to interact with neural promoters, regulate neurogenic gene expression, and activate neurogenesis from the adult subventricular zone (SVZ)-derived NSCs [77]. Following differentiation of NSCs to neurons, SMRT (NCoR2, nuclear receptor co-repressor 2) inhibits JMJD3 and maintains the NSCs state [78]. STAT3 as an important component of the LIF signaling pathway is necessary for stem cell self-renewal [79, 80]. STAT3 binds to the JMJD3 promoter, prevents the demethylase activity of JMJD3, and suppresses the activity of differentiation-specific genes [81–83]. It has been shown that inhibition of STAT3 in glioblastoma stem cells (GBM-SC) can promote the levels of histone H3K27 demethylation and the expression of neural-specific genes, such as FGF21, GDF15, and Myt1 [52]. The p53 tumor suppressor has a key role in mouse neurogenesis [84, 85]. In response to differentiation inducers, the recruitment of JMJD3 to p53 responsive elements is increased [86]. During mouse NSCs differentiation, JMJD3 is thought to act as a tumor suppressor and increase the expression of the INK4a/ARF (or CDKN2a) locus, and then stabilize the nuclear distribution of P53 [87].

  • Osteogenic stem cells

JMJD3 by removing H3K27me3 plays an important role in the osteogenic commitment of MSCs [88]. JMJD3 appears to induce osteoblast differentiation by stimulating transcription factors Runx2 and Osterix and control the expressions of bone-related genes [44, 89]. Ras-association domain family 5 (RASSF5) or novel Ras effector 1 (NORE1) is a pro-apoptotic protein that regulates a variety of key biological processes [90, 91]. JMJD3 was reported to reduce the expression of RASSF5 and suppress tumor necrosis factor-alpha (TNF-α)-induced osteoblast apoptosis [92].

MicroRNA‐99a by targeting JMJD3 is involved in osteogenic differentiation of bone MSCs [93, 94]. In contrast, MIR146A is a negative regulator of JMJD3 and RUNX2 that reduces MSCs capacity to differentiate into osteoblasts [95]. The PLZF transcription factor was previously shown to play an essential role in the osteogenic fate of human MSCs. At the pre-osteoblast stage of differentiation (osteoblast commitment of progenitor cells), JMJD3 enhances the expression of PLZF and controls osteoblast differentiation in MSCs [96]. Nuclear factor–activated T cells c1 (NFATc1) is a key transcription factor that induces osteoclast differentiation in response to receptor activator of nuclear factor‐κB ligand (RANKL) [66]. JMJD3 has been shown to remove the inhibitory H3K27me3 marker on the Nfatc1 gene and regulate RANKL-mediated osteoclast differentiation [97]. The inhibition of JMJD3 activity by GSK-J4 could be used as a non-invasive treatment for preventing the prefusion of cranial sutures in a patient with excessive osteogenic differentiation of MSCs [98].

  • Dental pulp-derived MSCs

JMJD3 by removing H3K27me3 from the promoters of osteogenic genes improves the odontogenic differentiation in dental pulp-derived MSCs [44, 99]. Ethanol (EtOH) can suppress JMJD3 and alter DNA methylation. EtOH-induced DNA methylation influences odontogenic differentiation and reduces mineralization [100]. Insulin‐like growth factor binding protein 5 (IGFBP5) is a multifunctional protein with anti‐inflammatory potential that promotes osteogenic differentiation in dental pulp‐derived MSCs [101, 102]. A recent study showed JMJD3 through the removal of H3K27me3 at the promoter of IGFBP5 mediated periodontal tissue regeneration [101].

  • Hematopoietic stem cells

JMJD3 is necessary for the self-renewal properties of hematopoietic stem cells (HSCs) [103].

Unlike KDM6A, which is frequently mutated in hematopoietic disorders, JMJD3 is necessary for HSC self-renewal in response to stress conditions [104, 105]. The adaptor-related protein complex 1 (AP-1) transcription factors such as Fos and JunB are crucial for interleukin (IL)-17-producing T helper (Th17) cell development [106]. JMJD3 was found to modulate the MAPK pathway, suppress the expression of AP-1, and support leukemia initiation and maintenance [107]. Hence, targeted inhibition of JMJD3 led to increaseing HSCs differentiation [74].

These studies suggest that JMJD3 might be a feasible and effective target for cell fate regulation of multipotent stem cells.

Conclusion

In this review, we summarize the roles of JMJD3 in pluripotency, reprogramming, and differentiation. JMJD3 has been found in several biological processes, including cell proliferation, differentiation, invasion, apoptosis, signaling regulatory pathways. Direct manipulation of epigenomes may be a suitable method for generating desired cell types from pluripotent or multipotent stem cells. Although JMJD3 via epigenetic modifications targets several signaling pathways, off-target effects could lead to minimize the applications of this enzyme in cancer. For example, JMJD3 by promoting cyclin D1 transcription is involved in the development of cancer cells [108]. Also, JMJD3 can impact other histone modifiers and alter chromatin structure, activate the expression of oncogenes, and trigger the development of many types of human diseases [108]. Thus, further studies are required to determine the downstream targets of JMJD3 in pluripotent and multipotent stem cells.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AP-1:

Adaptor related protein complex 1

AT:

Adipose tissues

BM:

Bone marrow

BSCB:

Blood-spinal cord barrier

DP:

Dental pulp

ESCs:

Embryonic stem cells

HSCs:

Hematopoietic stem cells

HTFs:

Hepatic transcription factors

H3K27me3:

Trimethylation of histone H3 on lysine 27

ICM:

Inner cell mass

IGFBP5:

Insulin‐like growth factor binding protein 5

IPSCs:

Induced pluripotent stem cells

JMJD3:

Jumonji domain-containing protein-3

KDM6B:

Lysine-specific demethylase 6B

LSD1:

Lysine-specific demethylase 1

MSCs:

Mesenchymal stem cells

NCoR2:

Nuclear receptor co-repressor 2

NORE1:

Novel Ras effector 1

NFATc1:

Nuclear factor–activated T cells c1

PHF20:

Plant homeodomain finger protein 20

Pol II:

Polymerase II

PRC2:

Polycomb repressive complex 2

PSCs:

Pluripotent stem cells

RASSF5:

Ras-association domain family 5

SCI:

Spinal cord injury

SESN2:

Sestrin2

SVZ:

Subventricular zone

T-ALL:

T-cell acute lymphoblastic leukemia

TFs:

Transcription factors

TNF-α:

Tumor necrosis factor-alpha

UCB:

Umbilical cord blood

References

  1. Gibney E, Nolan C. Epigenetics and gene expression. Heredity. 2010;105:4–13.

    Article  CAS  PubMed  Google Scholar 

  2. Miller JL, Grant PA. The role of DNA methylation and histone modifications in transcriptional regulation in humans. Subcell Biochem. 2013;61:289–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen Y, Ren B, Yang J, Wang H, Yang G, Xu R, You L, Zhao Y. The role of histone methylation in the development of digestive cancers: a potential direction for cancer management. Signal Transduct Target Ther. 2020;5:143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Song Y, Wu F, Wu J. Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives. J Hematol Oncol. 2016;9:49–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Wiles ET, Selker EU. H3K27 methylation: a promiscuous repressive chromatin mark. Curr Opin Genet Dev. 2017;43:31–7.

    Article  CAS  PubMed  Google Scholar 

  6. Akter A, Takahashi S, Deng W, Shea DJ, Itabashi E, Shimizu M, Miyaji N, Osabe K, Nishida N, Suzuki Y, Helliwell CA, Seki M, Peacock WJ, Dennis ES, Fujimoto R. The histone modification H3 lysine 27 tri-methylation has conserved gene regulatory roles in the triplicated genome of Brassica rapa L. DNA Res. 2019;26:433–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sen GL, Webster DE, Barragan DI, Chang HY, Khavari PA. Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev. 2008;22:1865–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Petruk S, Cai J, Sussman R, Sun G, Kovermann SK, Mariani SA, Calabretta B, McMahon SB, Brock HW, Iacovitti L, Mazo A. Delayed accumulation of H3K27me3 on nascent DNA is essential for recruitment of transcription factors at early stages of stem cell differentiation. Mol Cell. 2017;66:247-257.e245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Canovas S, Cibelli JB, Ross PJ. Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development. Proc Natl Acad Sci. 2012;109:2400–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yin X, Yang S, Zhang M, Yue Y. The role and prospect of JMJD3 in stem cells and cancer. Biomed Pharmacother. 2019;118:109384.

    Article  CAS  PubMed  Google Scholar 

  11. Srinageshwar B, Maiti P, Dunbar GL, Rossignol J. Role of epigenetics in stem cell proliferation and differentiation: implications for treating neurodegenerative diseases. Int J Mol Sci. 2016;17:199.

    Article  PubMed Central  CAS  Google Scholar 

  12. Burchfield JS, Li Q, Wang HY, Wang R-F. JMJD3 as an epigenetic regulator in development and disease. Int J Biochem Cell Biol. 2015;67:148–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Burgold T, Voituron N, Caganova M, Tripathi Prem P, Menuet C, Tusi Betsabeh K, Spreafico F, Bévengut M, Gestreau C, Buontempo S, Simeone A, Kruidenier L, Natoli G, Casola S, Hilaire G, Testa G. The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival. Cell Rep. 2012;2:1244–58.

    Article  CAS  PubMed  Google Scholar 

  14. Yu X-X, Qiu W-L, Yang L, Li L-C, Zhang Y-W, Xu C-R. Dynamics of chromatin marks and the role of JMJD3 during pancreatic endocrine cell fate commitment. Development. 2018;145:dev163162.

    Article  PubMed  CAS  Google Scholar 

  15. Iida A, Iwagawa T, Kuribayashi H, Satoh S, Mochizuki Y, Baba Y, Nakauchi H, Furukawa T, Koseki H, Murakami A, Watanabe S. Histone demethylase Jmjd3 is required for the development of subsets of retinal bipolar cells. Proc Natl Acad Sci U S A. 2014;111:3751–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bergmann C, Brandt A, Merlevede B, Hallenberger L, Dees C, Wohlfahrt T, Pötter S, Zhang Y, Chen C-W, Mallano T, Liang R, Kagwiria R, Kreuter A, Pantelaki I, Bozec A, Abraham D, Rieker R, Ramming A, Distler O, Schett G, Distler JHW. The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis. 2018;77:150–8.

    Article  CAS  PubMed  Google Scholar 

  17. Shan Y, Zhang Y, Zhao Y, Wang T, Zhang J, Yao J, Ma N, Liang Z, Huang W, Huang K, Zhang T, Su Z, Chen Q, Zhu Y, Wu C, Zhou T, Sun W, Wei Y, Zhang C, Li C, Su S, Liao B, Zhong M, Zhong X, Nie J, Pei D, Pan G. JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells. Nat Commun. 2020;11:382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Han JW, Yoon Y-S. Epigenetic landscape of pluripotent stem cells. Antioxid Redox Signal. 2012;17:205–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Farzaneh M, Derakhshan Z, Hallajzadeh J, Sarani NH, Nejabatdoust A, Khoshnam SE. Suppression of TGF-β and ERK signaling pathways as a new strategy to provide rodent and non-rodent pluripotent stem cells. Curr Stem Cell Res Ther. 2019;14:466–73.

    Article  CAS  PubMed  Google Scholar 

  20. Kolagar TA, Farzaneh M, Nikkar N, Khoshnam SE. Human pluripotent stem cells in neurodegenerative diseases: potentials, advances and limitations. Curr Stem Cell Res Ther. 2020;15:102–10.

    Article  CAS  PubMed  Google Scholar 

  21. Pan B, Fan G. Stem cell-based treatment of kidney diseases. Exp Biol Med. 2020;1535370220915901.

  22. Paredes‐Redondo A, Lin YY. Human induced pluripotent stem cells: challenges and opportunities in developing new therapies for muscular dystrophies. eLS 2019;1–10.

  23. Bai X. Stem cell-based disease modeling and cell therapy. Multidisciplinary Digital Publishing Institute; 2020.

    Book  Google Scholar 

  24. Boroviak T, Loos R, Bertone P, Smith A, Nichols J. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat Cell Biol. 2014;16:516–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao N, Sheng M, Wang X, Li Y, Farzaneh M. Differentiation of human induced pluripotent stem cells into male germ cells. Curr Stem Cell Res Ther. 2020;17:1–8.

    Google Scholar 

  26. Farzaneh M, Khoshnam S, Mozdziak P. Concise review: avian multipotent stem cells as a novel tool for investigating cell-based therapies. J Dairy Vet Anim Res. 2017;5:00125.

    Article  Google Scholar 

  27. Javan MR, Khosrojerdi A, Moazzeni SM. New insights into implementation of mesenchymal stem cells in cancer therapy: prospects for anti-angiogenesis treatment. Front Oncol. 2019;9:840.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep. 2015;35:e00191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Lu M, Guo J, Wu B, Zhou Y, Wu M, Farzaneh M, Khoshnam SE. Mesenchymal stem cell-mediated mitochondrial transfer: a therapeutic approach for ischemic stroke. Transl Stroke Res. 2020;12(2):212–29.

    Article  PubMed  Google Scholar 

  30. Liang G, Zhang Y. Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Res. 2013;23:49–69.

    Article  CAS  PubMed  Google Scholar 

  31. Rodas-Junco BA, Canul-Chan M, Rojas-Herrera RA, De-la-Peña C, Nic-Can GI. Stem cells from dental pulp: what epigenetics can do with your tooth. Front Physiol. 2017;8:999–999.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ohtani K, Zhao C, Dobreva G, Manavski Y, Kluge B, Braun T, Rieger MA, Zeiher AM, Dimmeler S. Jmjd3 controls mesodermal and cardiovascular differentiation of embryonic stem cells. Circ Res. 2013;113:856–62.

    Article  CAS  PubMed  Google Scholar 

  33. Zhao W, Li Q, Ayers S, Gu Y, Shi Z, Zhu Q, Chen Y, Wang HY, Wang R-F. Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination. Cell. 2013;152:1037–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huang Y, Zhang H, Wang L, Tang C, Qin X, Wu X, Pan M, Tang Y, Yang Z, Babarinde IA, Lin R, Ji G, Lai Y, Xu X, Su J, Wen X, Satoh T, Ahmed T, Malik V, Ward C, Volpe G, Guo L, Chen J, Sun L, Li Y, Huang X, Bao X, Gao F, Liu B, Zheng H, Jauch R, Lai L, Pan G, Chen J, Testa G, Akira S, Hu J, Pei D, Hutchins AP, Esteban MA, Qin B. JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency. Nat Commun. 2020;11:5061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wilson C, Krieg AJ. KDM4B: a nail for every hammer? Genes (Basel). 2019;10:134.

    Article  CAS  Google Scholar 

  36. D’Oto A, Tian Q-W, Davidoff AM, Yang J. Histone demethylases and their roles in cancer epigenetics. J Med Oncol Ther. 2016;1:34.

    PubMed  PubMed Central  Google Scholar 

  37. Labbé RM, Holowatyj A, Yang Z-Q. Histone lysine demethylase (KDM) subfamily 4: structures, functions and therapeutic potential. Am J Transl Res. 2014;6:1.

    Google Scholar 

  38. Stolerman ES, Francisco E, Stallworth JL, Jones JR, Monaghan KG, Keller-Ramey J, Person R, Wentzensen IM, McWalter K, Keren B. Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features. Am J Med Genet A. 2019;179:1276–86.

    CAS  PubMed  Google Scholar 

  39. Cuyàs E, Verdura S, Llorach-Pares L, Fernández-Arroyo S, Luciano-Mateo F, Cabré N, Stursa J, Werner L, Martin-Castillo B, Viollet B. Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging Cell. 2018;17:e12772.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Copur Ö, Müller J. Histone demethylase activity of Utx is essential for viability and regulation of HOX gene expression in drosophila. Genetics. 2018;208:633–7.

    Article  CAS  PubMed  Google Scholar 

  41. Klose RJ, Kallin EM, Zhang Y. JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 2006;7:715–27.

    Article  CAS  PubMed  Google Scholar 

  42. Gang Xiao Z, Shen J, Zhang L, Li LF, Xing Li M, Hu W, Jie Li Z, Hin Cho C. The roles of histone demethylase UTX and JMJD3 (KDM6B) in cancers: current progress and future perspectives. Curr Med Chem. 2016;23:3687–96.

    Article  CAS  Google Scholar 

  43. Tran N, Broun A, Ge K. Lysine Demethylase KDM6A in Differentiation, Development, and Cancer. Mol Cell Biol. 2020;40:e00341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang D, Yu B, Sun H, Qiu L. The roles of histone demethylase Jmjd3 in osteoblast differentiation and apoptosis. J Clin Med. 2017;6:24.

    Article  PubMed Central  CAS  Google Scholar 

  45. Zhang X, Liu L, Yuan X, Wei Y, Wei X. JMJD3 in the regulation of human diseases. Protein Cell. 2019;10(12):864–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kasinath V, Poepsel S, Nogales E. Recent structural insights into Polycomb repressive complex 2 regulation and substrate binding. Biochemistry. 2018;58:346–54.

    Article  PubMed  CAS  Google Scholar 

  47. Jiao H, Xie Y, Li Z. Current understanding of plant Polycomb group proteins and the repressive histone H3 Lysine 27 trimethylation. Biochem Soc Trans. 2020;48:1697–706.

    Article  CAS  PubMed  Google Scholar 

  48. Iwagawa T, Honda H, Watanabe S. Jmjd3 plays pivotal roles in the proper development of early-born retinal lineages: amacrine, horizontal, and retinal ganglion cells. Invest Ophthalmol Vis Sci. 2020;61:43–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Argaud D, Boulanger M-C, Chignon A, Mkannez G, Mathieu P. Enhancer-mediated enrichment of interacting JMJD3–DDX21 to ENPP2 locus prevents R-loop formation and promotes transcription. Nucleic Acids Res. 2019;47:8424–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen S, Ma J, Wu F, Xiong L-J, Ma H, Xu W, Lv R, Li X, Villen J, Gygi SP. The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation. Genes Dev. 2012;26:1364–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xun J, Wang D, Shen L, Gong J, Gao R, Du L, Chang A, Song X, Xiang R, Tan X. JMJD3 suppresses stem cell-like characteristics in breast cancer cells by downregulation of Oct4 independently of its demethylase activity. Oncotarget. 2017;8:21918.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sherry-Lynes MM, Sengupta S, Kulkarni S, Cochran BH. Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3. PLoS ONE. 2017;12:e0174775.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Qin M, Han F, Wu J, Gao F-x, Li Y, Yan D-x, He X-m, Long Y, Tang X-p. Ren D-l, KDM6B promotes ESCC cell proliferation and metastasis by facilitating C/EBPβ transcription. 2020.

  54. Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K. Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun. 2014;5:1–15.

    Article  Google Scholar 

  55. Wang P, Lan R, Guo Z, Cai S, Wang J, Wang Q, Li Z, Li Z, Wang Q, Li J. Histone demethylase JMJD3 mediated doxorubicin-induced cardiomyopathy by suppressing SESN2 expression. Front Cell Dev Biol. 2020;8:1037.

    Google Scholar 

  56. Park CS, Lee JY, Choi HY, Lee K, Heo Y, Ju BG, Choo H-YP, Yune TY. Gallic acid attenuates blood-spinal cord barrier disruption by inhibiting Jmjd3 expression and activation after spinal cord injury. Neurobiol Dis. 2020;145:105077.

    Article  CAS  PubMed  Google Scholar 

  57. Li S, Jiang L, He Q, Wei W, Wang Y, Zhang X, Liu J, Chen K, Chen J, Xie D. The prognostic significance of JMJD3 in primary sarcomatoid carcinoma of the lung, a rare subtype of lung cancer. Onco Targets Ther. 2019;12:9385–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yu S-H, Zhu K-Y, Chen J, Liu X-Z, Xu P-F, Zhang W, Yan L, Guo H-Z, Zhu J. JMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML. Nat Commun. 2018;9:1–15.

    Article  CAS  Google Scholar 

  59. Zhang X, Liu L, Yuan X, Wei Y, Wei X. JMJD3 in the regulation of human diseases. Protein Cell. 2019;10:864–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hofstetter C, Kampka JM, Huppertz S, Weber H, Schlosser A, Müller AM, Becker M. Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage. J Cell Sci. 2016;129:788–803.

    CAS  PubMed  Google Scholar 

  61. Burgold T, Spreafico F, De Santa F, Totaro MG, Prosperini E, Natoli G, Testa G. The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment. PLoS ONE. 2008;3:e3034.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Lee Chong T, Ahearn EL, Cimmino L. Reprogramming the epigenome with vitamin C. Front Cell Dev Biol. 2019;7:128–128.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gao Y, Han Z, Li Q, Wu Y, Shi X, Ai Z, Du J, Li W, Guo Z, Zhang Y. Vitamin C induces a pluripotent state in mouse embryonic stem cells by modulating micro RNA expression. FEBS J. 2015;282:685–99.

    Article  CAS  PubMed  Google Scholar 

  64. He XB, Kim M, Kim SY, Yi SH, Rhee YH, Kim T, Lee EH, Park CH, Dixit S, Harrison FE. Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET 1-and JMJD 3-dependent epigenetic control manner. Stem Cells. 2015;33:1320–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang Y, Li Y, Guo C, Lu Q, Wang W, Jia Z, Chen P, Ma K, Reinberg D, Zhou C. ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells. Nucleic Acids Res. 2016;44:6741–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kim JH, Kim N. Regulation of NFATc1 in osteoclast differentiation. J Bone Metab. 2014;21:233–41.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Ziegler N, Bader E, Epanchintsev A, Margerie D, Kannt A, Schmoll D. AMPKβ1 and AMPKβ2 define an isoform-specific gene signature in human pluripotent stem cells, differentially mediating cardiac lineage specification. J Biol Chem. 2020;295:17659–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jiang W, Wang J, Zhang Y. Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway. Cell Res. 2013;23:122–30.

    Article  CAS  PubMed  Google Scholar 

  69. Akiyama T, Wakabayashi S, Soma A, Sato S, Nakatake Y, Oda M, Murakami M, Sakota M, Chikazawa-Nohtomi N, Ko SB. Transient ectopic expression of the histone demethylase JMJD3 accelerates the differentiation of human pluripotent stem cells. Development. 2016;143:3674–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dahle Ø, Kumar A, Kuehn MR. Nodal signaling recruits the histone demethylase Jmjd3 to counteract polycomb-mediated repression at target genes. Science signaling. 2010;3:ra48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Kim SW, Yoon S-J, Chuong E, Oyolu C, Wills AE, Gupta R, Baker J. Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs. Dev Biol. 2011;357:492–504.

    Article  CAS  PubMed  Google Scholar 

  72. Akiyama T, Wakabayashi S, Soma A, Sato S, Nakatake Y, Oda M, Murakami M, Sakota M, Chikazawa-Nohtomi N, Ko SBH, Ko MSH. Transient ectopic expression of the histone demethylase JMJD3 accelerates the differentiation of human pluripotent stem cells. Development. 2016;143:3674–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Long W, Zhao W, Ning B, Huang J, Chu J, Li L, Ma Q, Xing C, Wang HY, Liu Q, Wang R-F. PHF20 collaborates with PARP1 to promote stemness and aggressiveness of neuroblastoma cells through activation of SOX2 and OCT4. J Mol Cell Biol. 2018;10:147–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Niemitz E. Jmjd3, PHF20 and reprogramming. Nat Genet. 2013;45:477–477.

    Article  CAS  Google Scholar 

  75. Kochat V, Equbal Z, Baligar P, Kumar V, Srivastava M, Mukhopadhyay A. JMJD3 aids in reprogramming of bone marrow progenitor cells to hepatic phenotype through epigenetic activation of hepatic transcription factors. PLoS ONE. 2017;12:e00173977.

    Article  CAS  Google Scholar 

  76. Estarás C, Akizu N, García A, Beltrán S, de la Cruz X, Martínez-Balbás MA. Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program. Development. 2012;139:2681–91.

    Article  PubMed  CAS  Google Scholar 

  77. Park DH, Hong SJ, Salinas RD, Liu SJ, Sun SW, Sgualdino J, Testa G, Matzuk MM, Iwamori N, Lim DA. Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis. Cell Rep. 2014;8:1290–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim H-J, Glass CK, Hermanson O, Rosenfeld MG. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature. 2007;450:415–9.

    Article  CAS  PubMed  Google Scholar 

  79. Ye S, Zhang D, Cheng F, Wilson D, Mackay J, He K, Ban Q, Lv F, Huang S, Liu D. Wnt/β-catenin and LIF–Stat3 signaling pathways converge on Sp5 to promote mouse embryonic stem cell self-renewal. J Cell Sci. 2016;129:269–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhang Y, Wang D, Xu J, Wang Y, Ma F, Li Z, Liu N. Stat3 activation is critical for pluripotency maintenance. J Cell Physiol. 2019;234:1044–51.

    Article  CAS  PubMed  Google Scholar 

  81. Przanowski P, Dabrowski M, Ellert-Miklaszewska A, Kloss M, Mieczkowski J, Kaza B, Ronowicz A, Hu F, Piotrowski A, Kettenmann H. The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia. J Mol Med. 2014;92:239–54.

    Article  CAS  PubMed  Google Scholar 

  82. Yoon S, Wu X, Armstrong B, Habib N, Rossi JJ. An RNA aptamer targeting the receptor tyrosine kinase PDGFRα induces anti-tumor effects through STAT3 and p53 in Glioblastoma. Mol Therapy-Nucleic Acids. 2019;14:131–41.

    Article  CAS  Google Scholar 

  83. Qi H, Yang Z, Dai C, Wang R, Ke X, Zhang S, Xiang X, Chen K, Li C, Luo J, Shao J, Shen J. STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis. Oncogenesis. 2020;9:15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mendrysa SM, Ghassemifar S, Malek R. p53 in the CNS: perspectives on development, stem cells, and cancer. Genes Cancer. 2011;2:431–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Niklison-Chirou MV, Agostini M, Amelio I, Melino G. Regulation of adult neurogenesis in mammalian brain. Int J Mol Sci. 2020;21:4869.

    Article  CAS  PubMed Central  Google Scholar 

  86. Williams K, Christensen J, Rappsilber J, Nielsen AL, Johansen JV, Helin K. The histone lysine demethylase JMJD3/KDM6B is recruited to p53 bound promoters and enhancer elements in a p53 dependent manner. PLoS ONE. 2014;9:e96545.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Sola S, Xavier JM, Santos DM, Aranha MM, Morgado AL, Jepsen K, Rodrigues CM. p53 interaction with JMJD3 results in its nuclear distribution during mouse neural stem cell differentiation. PLoS ONE. 2011;6:e18421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ye L, Fan Z, Yu B, Chang J, Al Hezaimi K, Zhou X, Park N-H, Wang C-Y. Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell Stem Cell. 2012;11:50–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yang D, Okamura H, Nakashima Y, Haneji T. Histone demethylase Jmjd3 regulates osteoblast differentiation via transcription factors Runx2 and osterix. J Biol Chem. 2013;288:33530–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Park J, Kang SI, Lee S-Y, Zhang XF, Kim MS, Beers LF, Lim D-S, Avruch J, Kim H-S, Lee SB. Tumor suppressor ras association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis. J Biol Chem. 2010;285:35029–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. van der Weyden L, Adams DJ. The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta. 2007;1776:58–85.

    PubMed  PubMed Central  Google Scholar 

  92. Sun H-Y, Yang D, Mi J, Yu Y-Q, Qiu L-H. Histone demethylase Jmjd3 modulates osteoblast apoptosis induced by tumor necrosis factor-alpha through directly targeting RASSF5. Connect Tissue Res. 2020;61:517–25.

    Article  PubMed  Google Scholar 

  93. Tang Y, Zhang L, Tu T, Li Y, Murray D, Tu Q, Chen JJ. MicroRNA-99a is a novel regulator of KDM6B-mediated osteogenic differentiation of BMSCs. J Cell Mol Med. 2018;22:2162–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Moura SR, Bras JP, Freitas J, Osório H, Barbosa MA, Santos SG, Almeida MI. miR-99a in bone homeostasis: regulating osteogenic lineage commitment and osteoclast differentiation. Bone. 2020;134:115303.

    Article  CAS  PubMed  Google Scholar 

  95. Huszar JM, Payne CJ. MIR146A inhibits JMJD3 expression and osteogenic differentiation in human mesenchymal stem cells. FEBS Lett. 2014;588:1850–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Singh SA, Lerdrup M, Gomes A-LR, van de Werken HJ, Johansen JV, Andersson R, Sandelin A, Helin K, Hansen K. PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells. Elife. 2019;8:40364.

    Article  CAS  Google Scholar 

  97. Yasui T, Hirose J, Tsutsumi S, Nakamura K, Aburatani H, Tanaka S. Epigenetic regulation of osteoclast differentiation: possible involvement of Jmjd3 in the histone demethylation of Nfatc1. J Bone Miner Res. 2011;26:2665–71.

    Article  CAS  PubMed  Google Scholar 

  98. Pribadi C, Camp E, Cakouros D, Anderson P, Glackin C, Gronthos S. Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre–Chotzen syndrome. Stem Cell Res Ther. 2020;11:529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Xu J, Yu B, Hong C, Wang C-Y. KDM6B epigenetically regulates odontogenic differentiation of dental mesenchymal stem cells. Int J Oral Sci. 2013;5:200–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hoang M, Kim JJ, Kim Y, Tong E, Trammell B, Liu Y, Shi S, Lee C-R, Hong C, Wang C-Y. Alcohol-induced suppression of KDM6B dysregulates the mineralization potential in dental pulp stem cells. Stem cell research. 2016;17:111–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Liu D, Wang Y, Jia Z, Wang L, Wang J, Yang D, Song J, Wang S, Fan Z. Demethylation of IGFBP5 by histone demethylase KDM6B promotes mesenchymal stem cell-mediated periodontal tissue regeneration by enhancing osteogenic differentiation and anti-inflammation potentials. Stem Cells. 2015;33:2523–36.

    Article  CAS  PubMed  Google Scholar 

  102. Wang Y, Jia Z, Diao S, Lin X, Lian X, Wang L, Dong R, Liu D, Fan Z. IGFBP5 enhances osteogenic differentiation potential of periodontal ligament stem cells and Wharton’s jelly umbilical cord stem cells, via the JNK and MEK/Erk signalling pathways. Cell Prolif. 2016;49:618–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sui B-D, Zheng C-X, Li M, Jin Y, Hu C-H. Epigenetic regulation of mesenchymal stem cell homeostasis. Trends Cell Biol. 2020;30:97–116.

    Article  CAS  PubMed  Google Scholar 

  104. Mallaney C. Kdm6b is required for self-renewal of normal and leukemic mouse stem cells under proliferative stress. 2018.

  105. Wei Y, Zheng H, Jia Y, Bao N, Jiang S, Colla S, Bueso-Ramos CE, Khoury JD, Bohannan ZS, Garcia-Manero G. Overexpression of KDM6B, an epigenetic and innate immune regulator, results in hematopoietic alterations of mice including changes in hematopoietic stem cells. American Society of Hematology Washington; 2016.

    Book  Google Scholar 

  106. Yamazaki S, Tanaka Y, Araki H, Kohda A, Sanematsu F, Arasaki T, Duan X, Miura F, Katagiri T, Shindo R, Nakano H, Ito T, Fukui Y, Endo S, Sumimoto H. The AP-1 transcription factor JunB is required for Th17 cell differentiation. Sci Rep. 2017;7:17402.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Ohguchi H, Harada T, Sagawa M, Kikuchi S, Tai YT, Richardson PG, Hideshima T, Anderson KC. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia. 2017;31:2661–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cao Z, Shi X, Tian F, Fang Y, Wu JB, Mrdenovic S, Nian X, Ji J, Xu H, Kong C, Xu Y, Chen X, Huang Y, Wei X, Yu Y, Yang B, Chung LWK, Wang F. KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer. Cell Death Dis. 2021;12:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The study was supported by the National Natural Science Foundation of China (Grant No. 31260634) and the Science and Technology Program of Jishou University (Grant No. DNGC2010).

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  1. School of Medicine, Jishou University, Jishou, 416000, China

    Yuanjie Ding, Yuanchun Yao, Xingmu Gong, Qi Zhuo, Jinhua Chen & Miao Tian

  2. Key Laboratory of Hunan Forest Products and Chemical Industry Engineering, Jishou University, Zhangjiajie, 427000, China

    Yuanjie Ding

  3. Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Maryam Farzaneh

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YD and YY have made substantial contributions to the writing of the manuscript. XG has made a substantial contribution to the design of the Figures and writing of the manuscript. QZ and JC contributed to the revision of the manuscript. MT and MF has made a substantial contribution to the final revision of the manuscript. All authors have approved the submitted version of the article and have agreed to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work. All authors read and approved the final manuscript.

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Ding, Y., Yao, Y., Gong, X. et al. JMJD3: a critical epigenetic regulator in stem cell fate. Cell Commun Signal 19, 72 (2021). https://doi.org/10.1186/s12964-021-00753-8

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  • DOI: https://doi.org/10.1186/s12964-021-00753-8

Keywords

  • Pluripotent stem cells
  • JMJD3
  • Pluripotency
  • Reprogramming
  • Differentiation

Cell Communication and Signaling

ISSN: 1478-811X