Epigenetic
regulation
of hypoxia-responsive gene
expression: focusing on chromatin and DNA modifications
Ya-Ping Tsai1 and Kou-Juey Wu1,2,3,
1Institute of Biochemistry & Molecular Biology, 2Head and Neck Cancer Research
Program, Cancer Research Center, and 3VYM Genome Research Center, National
Yang-Ming University, Taipei 112, Taiwan
Running title: Epigenetic regulation of gene expression under hypoxia
Correspondence should be addressed to:
Kou-Juey Wu, Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No.155, Li-Nong St., Sec.2, Peitou, Taipei 112, Taiwan; Email: [email protected]; Tel: 886-228267328; Fax: 886-228264843
Keywords: hypoxia, epigenetic regulation, epithelial-mesenchymal transition, chromatin modifier, transcriptional co-regulator
Abstract
Mammalian cells constantly encounter hypoxia, which is a stress condition occurring during development and physiological processes. In order to adapt to this inevitable condition, cells develop various mechanisms to cope with this stress and survive. In addition to the activation/stabilization of transcriptional regulators (hypoxia-inducible factors (HIFs)), other epigenetic mechanisms of gene regulation are utilized. These mechanisms are mediated by various players including transcriptional co-regulators, chromatin-modifying complexes, histone modification enzymes, and changes in DNA methylation status. Recent progress in all the fields mentioned above has greatly improved the knowledge of how gene regulation contributes to the hypoxic response. This review should shed light on the molecular epigenetic mechanisms of hypoxia-induced gene regulation and help understand the processes adapted by cells to cope with hypoxia.
Introduction
Insufficient oxygen availability, or hypoxia, is a microenvironmental factor that plays a critical role in various biological processes including development, metabolism, inflammation, tumor progression, and cancer stemness.1-5 Hypoxia
induces stabilization of hypoxia-inducible factors (HIFs; HIF-1 and HIF-2) that heterodimerize with a ubiquitous partner, HIF-1or aryl hydrocarbon receptor nuclear translocator (ARNT, to regulate downstream target gene expression, leading to hypoxia-induced phenotypes.1,2 Since these events involve gene regulation,
transcriptional control of hypoxia-regulated target gene expression constitutes one of the major mechanisms operating under hypoxia. Regulation of target genes by HIFs will allow the cells to channel cellular activities toward a status so the cells can survive under hypoxic stress.1,2
Histone modification, DNA methylation, nucleosome remodeling, and RNA-mediated targeting represent the major mechanisms of epigenetic regulation.6 These
epigenetic mechanisms account for DNA-independent regulation of gene expression. Chromatin modifications are mediated by chromatin remodelers that include histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), histone lysine demethylases (KDMs), and other histone-modifying
enzymes.7-9 All these enzymes were recently identified and demonstrated to be critical
for various biological processes for the past one and half decades.7-9 Together with
other epigenetic mechanisms, recent advances in the knowledge of these mechanisms expand our understanding of gene expression regulation through multiple levels.
Chromatin alterations including histone acetylation/deacetylation, histone methylation, etc constantly occur under hypoxia, although the detailed changes in chromatin structure remain largely unknown.10 The function of these chromatin
reprogramming allows cells to adapt to hypoxic stress.10 Hypoxia causes widespread
repression of transcription that is HIF-1 independent.11 Hypoxia also induces a novel
signature of chromatin modifications including an increase in histone 3 lysine 4 trimethylation (H3K4me3) levels and a decrease in histone 3 lysine 27 trimethylation (H3K27me3) levels at the promoters of hypoxia-responsive genes.11 The observation
of gene repression is in contrast to the activation of many target genes regulated by HIFs.1,2 Since the mechanism of widespread transcriptional repression is unknown,
only the epigenetic controls that include the participation of transcriptional co-regulators, chromatin-modifying complexes, and DNA methylation/demethylation in the regulation of hypoxia-responsive gene expression will be discussed. The involvement of these players represents the majority of epigenetic mechanisms operating under hypoxia that were reported in the literature.6-9 The discussion will not
include non-coding RNAs and nucleosome remodeling. We hope that through examining their critical roles this review will provide an illuminating guide to the further exploration of epigenetic mechanisms regulating hypoxic response.
Physiology of hypoxic response and hypoxia-inducible factors (HIFs)
Oxygen deprivation causes significant stress in mammalian cells.1,2 Under
hypoxia, cells perform a few adaptive processes to cope with the stress.1,2 Among
these adaptive processes, stabilization/activation of HIFs is important to trigger different pathways so the cells can adapt and survive. HIFs regulate the expression of various downstream target genes and other genes regulated by these downstream targets.1,2 Many downstream target genes regulated by HIF-1 were identified. These
target genes are related to the aspects of tumor growth (e.g. c-Myc),3 angiogenesis
(e.g. vascular endothelial growth factor (VEGF)),12 energy metabolism (e.g. glucose
transporter type 1 (Glut-1), pyruvate dehydrogenase kinase, isozyme 1 (PDK1), and cytochrome C oxidase),13-16 stemness (e.g. Oct3/4 and Nanog),17,18 tumor progression
and metastasis (e.g. Twist1).5,19,20 Although the hypoxia response elements (HREs)
that respond to HIFs in various gene promoters are identified (e.g. VEGF, Glut-1, and Twist1), modulation of HIFs-regulated gene expression by distinct epigenetic changes remain largely unknown.
Tumor metabolism is important for cells to adapt to hypoxic stress. There is a rapid increase in the knowledge gained from recent researches in hypoxia-regulated metabolic shift. One important aspect is that HIF-1activates genes encoding glucose
transporters (e.g. Glut-1) and glycolytic enzymes, which take up glucose and convert it to lactate.21 The other two critical molecules that are activated by HIF-1 are PDK1
which shunts pyruvate away from mitochondria, and Bcl2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) which triggers selective mitochondrial autophagy.21 The
metabolic shift could allow maintenance of redox homeostasis and survival under hypoxia.1,13-16,21
For metastasis, stabilization/activation of HIF-1 transcriptional complex induced by intratumoral hypoxia is one of the most important mechanisms promoting tumor aggressiveness, causing metastasis and patient mortality.20 Epithelial-mesenchymal
transition (EMT) is one of the highly controlled key processes that occur in development and aberrations of this process drive carcinoma cell invasion and metastasis.22,23 EMT is manifested by the ability of epithelial cells to acquire
fibroblastoid properties and show reduced intercellular adhesion and increased invasiveness/motility.22,23 Signature phenotypic changes of EMT include the loss of
E-cadherin-mediated cell-cell adhesion (downregulation of E-cadherin, catenins, etc) and activation of mesenchymal markers (upregulation of vimentin, N-cadherin, fibronectin, smooth muscle actin, etc), and induction of cell motility.20,22,23 The
molecules regulating EMT include transcriptional regulators such as Snail, Twist1, ZEB1, SIP1, and E47, which are demonstrated to mediate the phenotypes of EMT.20,24
These EMT regulators are induced by hypoxia, although not all of them are direct HIF-1 target genes.20
HIF-2 is another key player to mediate hypoxic response.1,2 Although HIF-2
was shown to promote tumor progression through largely overlapping functions with HIF-1 and its expression correlates with poor prognosis in many cancer types, it may behave differently from HIF-1 due to their non-overlapping regulation of unique sets of target genes.25 In addition, their differential interaction with
oncoproteins (e.g. c-Myc) or tumor suppressors (e.g. p53) showed that HIF-1 and 2 may play diverse roles under different context. For example, HIF-2expressing cells (e.g. renal cell carcinoma cells with loss of von Hippel-Lindau (VHL) gene) exhibit enhanced c-Myc activity to drive cell cycle progression, whereas HIF-1 expressing cells produce cell cycle arrest by inhibiting c-Myc in many cell types.25 The difference between HIF-2 and HIF-1 can be found in an excellent
review.25
Transcriptional co-regulators involved in the hypoxic response
Various transcriptional co-regulators are involved in hypoxia-regulated gene expression. The histone acetyltransferases CREB binding protein (CBP)/p300 were the first co-activators that facilitate the activation of target genes by HIF-1in HEK
293 and Hep3B cells.26,27 The domains in HIF-1 and CBP/p300 that interact with
each other are mapped.28,29 In contrast, HDAC activity is essential for 70% of
HIF-1-responsive genes from mice experiments,30 suggesting that both gene activation and
repression mechanisms are required for hypoxia-induced gene expression. p300/CBP-associated factor (PCAF) is also a co-activator of 1 and PCAF acetylates HIF-1 to regulate the expression of BH3 interacting domain death agonist (BID) and
VEGF but not erythropoietin in U2OS cells.31 Peroxisome proliferator-activated
receptor , coactivator 1 (PGC-1 can regulate hypoxia-inducible genes and serves as a co-activator of HIF-1 in cultured muscle cells.32,33 Recently, pyruvate kinase M2
(PKM2), a kinase linked to glucose metabolism, was shown to be directly induced by HIF-1and also interacts directly with HIF-1in mouse embryonic fibroblasts (MEFs) and HeLa cells.34 PKM2 facilitates the binding of HIF-1 to HRE and
recruitment of p300 to enhance the HIF-1 transcriptional activity. PKM2 also interacts with prolyl hydroxylase 3 (PHD3) that enhances the binding and activity of PKM2 through proline hydroxylation (a.a. 403 and 408) of PKM2. These results indicate that PKM2 functions together with PHD3 to result in a positive feedback loop that amplifies HIF-1 transcriptional activity and accelerate metabolic reprogramming to facilitate tumor metabolism and tumor progression.34
HIF-1levels andtranscriptionalactivity in 293T and HCT116 cells.35 MCM7 interacts
with the PAS domain of HIF-1 to increase the PHD-dependent ubiquitination and degradation of HIF-1and MCM3 interacts with the C-terminal transactivation domain of HIF-1 to inhibit its transcriptional activity. In addition, quiescence leads to downregulation of MCM proteins and HIF-1 upregulation, whereas hypoxia leads to MCM proteins downregulation, indicating the inverse relationship between hypoxia and MCM proteins.35 These results indicate the homeostatic regulation of cellular
proliferation by balancing the levels of HIF-1vs. MCM proteins and also provide functional interactions between key proteins that regulate cell proliferation and oxygen homeostasis. Finally, four-and-a-half LIM (FHL) proteins were shown to inhibit the transcriptional activity of HIF-1in Hep3B cells.36 FHL2 binds to HIF-1
directly and FHL3 interferes with the binding of CBP/p300 to HIF-1, both contributing to repression of HIF-1 transcriptional activity. The expression of FHL proteins increases under hypoxia, indicating a negative feedback loop.36 All the results
described above indicate that various proteins can serve as HIF-1 co-regulators to regulate the transcriptional activity of HIF-1.
Chromatin-modifying complexes involved in the hypoxia-inducible
gene expression
Chromatin-modifying complexes are enzymatic complexes that utilize ATP to alter DNA-protein contacts and chromatin structure by moving or removing nucleosomes.6,7,37 The SWI/SNF chromatin-modifying complex associates with
HIF-1 to regulate hypoxia-responsive genes in U2OS cells.38 Modulation of the SWI/SNF
levels changes the transcriptional activity of HIF-1 to activate its downstream targets. It is interesting that HIF-1 is a direct target of the SWI/SNF complex, indicating a positive feedback loop. BRG1 (also called SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4)), a component of the SWI/SNF complex, was found at the HIF-1promoter using knockout mice experiments.39 Hematopoietic and endothelial
conditional BRG1 null mice show defects in erythropoiesis and vascular development.39 Recent results showed that ISWI (also called SWI/SNF related, matrix
associated, actin dependent regulator of chromatin, subfamily a, member 5 (SMARCA5)) is involved in cellular response to hypoxia in U2OS cells.40 ISWI
depletion enhances HIF-1 activity and alters the expression of a subset of HIF-1 target genes. ISWI is required for full expression of factor inhibiting HIF-1 (FIH) mRNA and protein levels. ISWI depletion reduces autophagy and increases apoptosis under hypoxia, indicating a novel role of ISWI as a survival factor under hypoxia.40
histone deacetylase (NuRD) complex, associates with HIF-1 to increase its transcriptional activity and the levels of VEGF in MCF-7 and MDA-MB-231 cells.41,42
These results demonstrate the role of various chromatin-modifying complexes in the regulation of different aspects of hypoxic response.
Proteins mediating histone modifications involved in hypoxia
Histone modifications can dictate gene expression outcome.7 These
modifications include acetylation, methylation, phosphorylation, ubiquitination, etc.7
Specific amino acids on various histones can be modified (i.e. commonly mentioned as histone codes) that lead to changes in gene expression outcome. Histone acetylation usually indicates gene activation, whereas histone deacetylation indicates gene repression. Methylation of the specific amino acids of histone may have different outcome. For example, histone 3 lysine 9 methylations (H3K9me2, me3) and H3K27me3 usually indicate gene repression, whereas histone 3 lysine 4 methylations (H3K4me, me2, me3) indicate gene activation. The activation or repression dictated by these histone codes are reflected through recognition of these codes by specific chromatin-reader complexes that will induce changes in gene expression.7
Under this scenario, hypoxia-induced Jumonji-domain-containing proteins (JMJD1A, JMJD2B, JMJD2C) decrease histone methylation and regulate the
expression of adrenomedullin, growth and differentiation factor 15 (GDF15), endothelin 1 (EDN1), and heme oxygenase 1 (HMOX1) in various types of cells.43,44
Suv39h1 and Suv39h2 are activated by hypoxia to repress the activation of surfactant protein A (SP-A) that is originally activated by cAMP in fetal lung epithelial cells.45
Protein arginine methyltransferase 2 (PRMT2) is increased in mice exposed to hypoxia.46 In human corneal epithelial cells, de-SUMOylation of CCCTC binding
factor (CTCF, an epigenetic factor) is induced by hypoxia.47 Interaction between
HIF-1 and KDM3A mediates the expression of Glut3 gene in HUVEC cells.48
Induction of euchromatic histone-lysine N-methyltransferase 2 (G9a) by hypoxia increases the H3K9me2 level and results in the repression of different hypoxia-regulated genes such as mutL homolog 1, colon cancer, nonpolyposis type 2 (Mlh1), dihydrofolate reductase (Dhfr), runt-related transcription factor 3 (RUNX3), neprilysin, and breast cancer 1, early onset (BRCA1) in several mammalian cell lines.49-52 G9a also methylates a non-histone chromatin modifier, Reptin in HEK293,
embryonic stem (ES) and MEF cells.53 Reptin is related to the INO80 ATPase
complex in yeast and is a subunit of the lysine acetyltransferase 5 (Tip60) co-activator complex in mammals. G9a specifically methylates Reptin at K67 under hypoxic condition. Microarray analysis subsequently showed that 24.6% of hypoxia-responsive genes are regulated by Reptin. Whether these genes are directly regulated
by Reptin remains to be determined. Among these genes, VEGF, BNIP3, PGK1 are directly regulated by methylated Reptin; whereas insulin-like growth factor binding protein 3 (IGFBP3), KDM3A, and CBP/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain2 (CITED2) are not. Reptin binds to the promoters of VEGF, BNIP3, and PGK1 to negatively regulate their expression through recruitment of HDAC1.53 The outcome is the negative regulation of tumor
growth and invasion property by methylated Reptin under hypoxia. In contrast, G9a methylates Pontin, a chromatin-remodeling factor that has both ATPase and DNA helicase activities, under hypoxia in HEK293, MCF7, and HeLa cells. G9a potentiates HIF-1-mediated gene activation by recruiting p300 to a subset of HIF-1 target promoters including v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1), KDM4B, and IGFBP3.54 23.5% of hypoxia-responsive genes are regulated by Pontin.
Positive regulation of these genes through methylated Pontin contributes to tumor growth and metastasis induced by hypoxia. Various sirtuins (SIRTs; NAD+-dependent deacetylases) are implicated in hypoxia-regulated gene expression. Sirutin1 is induced by hypoxia/HIF-1in Hep3B and HT1080 cells.55 SIRT3 destablizes or
suppresses HIF-1 to inhibit reprogramming of cancer cell metabolism or mitochondria ROS production in MEF, 143B, and HCT116 cells.56,57 SIRT6 regulates
The histone methyltransferase mixed lineage leukemia 1 (MLL1) is induced by hypoxia to enhance glioma stem cell tumorigenic potential.59 Finally, a histone
variant, H2AX, is shown to be required for hypoxia-induced neovascularization in HUVEC cells and mice.60 These results provide a sophisticated view of regulation of
hypoxia-responsive gene expressionthrough various histone modifications mediated by histone modifiers or histone variants.
Chromatin modifiers and chromatin changes mediating
hypoxia-induced EMT
Although various histone modifications on specific histone residues were reported under hypoxia,10,11 specific histone modifications mediated by hypoxia to
regulate hypoxia-induced EMT remain elusive. Recent results showed that HDAC3 induced by hypoxia/HIF-1 appears to fulfill the role of regulating EMT marker gene expression in head and neck and breast cancer cells.61 Knockdown of HDAC3
abolishes hypoxia-induced EMT. HDAC3 directly deacetylates acetylated histone 3 lysine 4 (H3K4Ac) at the promoters of EMT marker genes. H3K4Ac may be a histone mark specifically for EMT marker genes. However, it will be difficult to reconcile the role of HDAC3 in the activation of mesenchymal gene expression since HDAC3 is considered a co-repressor.62 Further screening of histone mark changes showed that
HDAC3 activity increased the levels of H3K4me2 and H3K4me3.61 WD repeat
domain 5 (WDR5), a component of the histone methyltransferase (HMT) MLL complex,63 is induced by hypoxia and also interacts with HDAC3 under hypoxia.61
Interaction between HDAC3 and WDR5 increases HMT activity under hypoxia. HDAC3 possibly augments the HMT activity through conformational changes, protein modifications, or increase in the stability of the HMT complex. The exact molecular mechanism still remains to be explored.
A bivalent domain of increased H3K4me2/me3 and H3K27me3 levels was observed on the epithelial gene promoters and it may be important for gene expression events later on in the mesenchymal-epithelial transition (MET). Bivalent domains on the promoters of EMT marker genes would maintain the repression status of such genes and also keep them poised for activation at a later stage, which can be observed at developmental genes in ES cells.64,65 However, an alternative model may
exist that actively transcribed genes are enriched for H3K4me3 and histone acetylation (including H3K4Ac and H3K27Ac). Under hypoxia, HDAC3 is recruited to the epithelial gene promoters to deacetylate local histones that will become available for further modifications. Subsequent binding of enhancer of zeste homolog 2 (EZH2), a polycomb group silencer and lysine methyltransferase, would cause H3K27 trimethylation. Together with the persistence and/or increase of H3K4me3, a
bivalent domain is thereby established.
DNA methylation status under hypoxia
DNA cytosine methylation and various histone modifications can depend on each other to cause gene repression.66 The crosstalk between these two mechanisms
may be due to the interaction between DNA methyltransferases (DNMTs) and SET-domain containing histone methyltransferases (e.g. G9a, EZH2, etc). For example, G9a-containing complex can recruit DNMT3A and DNMT3B to mediate de novo DNA methylation at the promoter of Oct3/4 gene.66 Methylcytosine-binding protein 2
(MeCP2 or MBD2) recruits HDAC to mediate gene repression and the presence of DNA methylation directs H3K9me2 through the interaction between DNMT1 and G9a.66 Change of DNA methylation status induced by hypoxia was reported in human
colorectal and melanoma cell lines.67 Specifically, hypoxia induces genomic DNA
demethylation through the direct activation of Methionine adenosyltransferase 2A (MAT2A) that maintains the homeostasis of S-adenosylmethionine (SAM), a critical marker of genomic methylation status, in human hepatoma cell lines.68 HIF-1 and
MTA2A expression also correlate with tumor size and staging of liver cancers. Tumor-associated CpG demethylation results in increased HIF-1 binding to the HRE and augments HIF-1-mediated effects on tumor progression in the HCT116 colon
cancer cell line.69 Down regulation of DNMT1 and DNMT3A was also reported,
which contributes to DNA hypomethylation under hypoxia in human colorectal cancer (HCT116, 379.2) cell lines.70 In contrast, hypoxia induces promoter CpG
methylation of PKC gene to decrease its expression in fetal rat hearts and rat embryonic ventricular myocyte cell lines H9c2.71 However, more epigenetic
mechanisms mediating changes of DNA methylation status under hypoxia still remain to be explored.
Epigenetic regulation of hypoxia response in tumor biology
Since it is well demonstrated that hypoxia promotes tumor progression and metastasis,3-5,20 there is no doubt that some of the hypoxia-regulated target genes and
epigenetic modifiers can play a significant role. It is not surprising that the target genes regulated by hypoxia mediate tumor progression through an epigenetic mechanism (the detailed information is described in a recent review).72 The best
examples are HDAC3, WDR5, JMJD family members, MLL, etc. Because hypoxia induces EMT that is one of the major mechanisms to trigger tumor progression, epigenetic regulation of hypoxia-induced EMT is a major topic under intensive investigation.61 The functional significance of epigenetic regulation in hypoxic
chromatin modifiers should coordinate HIF-1 or other transcription factors to regulate the expression of target genes that mediate tumor progression and metastasis.
Conclusion and future perspective
In addition to the involvement of HIFs in hypoxia-responsive gene expression, transcriptional co-regulators and chromatin modifiers that occupy the promoters of hypoxia-responsive genes also play important roles to achieve appropriate gene regulation. Table 1 summarizes all the chromatin modifiers described in this review. A summary figure is also presented (Figure 1). Figure 2 summarizes the specific epigenetic factors regulating their downstream targets to mediate various aspects of hypoxic response. Specific histone codes (e.g. H3K4Ac) are also associated with various chromatin modifiers (e.g. HDAC3, WDR5) to determine gene expression status. Consequently, identifying the novel genes regulated by the specific histone code and chromatin modifier will be the next step to further delineate the regulatory mechanisms of hypoxia-responsive gene expression. Changes of DNA methylation status will also be an important aspect that is regulated by hypoxia to mediate gene expression. All these approaches will open up novel and insightful findings in the field of hypoxia biology. It is equally important to delineate the interacting mechanism between HIFs and chromatin modifiers (e.g., CBP/p300, G9a, etc) to have the whole picture of hypoxia-regulated gene expression mediated by these two different categories of players.
Overall, the take-home message is that chromatin modifications mediated by chromatin modifiers are essential for the regulation of hypoxia-responsive gene expression. Unknown epigenetic mechanisms to facilitate or coordinate hypoxia response will be the major focus of future experimental endeavors. This review will provide a guide to further delineate these mechanisms and point to the target-tailored therapy using the different epigenetic targets identified under various mechanisms.
Acknowledgments
We apologize to the authors whose work could not be cited due to the space constraint of reference citation. We declare no competing financial interests. This work was supported in part to K.J.W. by National Science Council Frontier grant 2321-B-010-002), National Research Program for Biopharmaceuticals (NSC101-2325-B-010-004), a grant from Ministry of Education, Aim for the Top University Plan (101AC-T505, 102AC-TC13), center of excellence for cancer research at Taipei Veterans General Hospital (DOH101-TD-C-111-007), Taichung Veterans General Hospital (TCVGH-YM1000301, TCVGH-YM1010301), and National Health Research Institutes (NHRI-EX101-9931BI, NHRI-EX102-10230SI).
List of abbreviations:
HIF-1: hypoxia inducible factor-1; ARNT: aryl hydrocarbon receptor nuclear translocator; HAT: histone acetyltransferase; HDAC: histone deacetylase; HMT: histone methyltransferase; KDM: histone lysine demethylase; H3K4me2: H3K4 dimethylation; H3K4me3: H3K4 trimethylation ; H3K27me3: H3K27 trimethylation; VEGF: vascular endothelial growth factor; Glut-1: glucose transporter type 1; PDK1: pyruvate dehydrogenase kinase, isozyme 1; HRE: hypoxia response element; BNIP3: Bcl2/adenovirus E1B 19kDa interacting protein 3; EMT: epithelial-mesenchymal transition; VHL: von Hippel-Lindau gene; CBP: CREB binding protein; PCAF: p300/CBP-associated factor; BID: BH3 interacting domain death agonist; PGC-1: Peroxisome proliferator-activated receptor , coactivator 1 MEF: mouse embryonic fibroblasts; PHD3: prolyl hydroxylase 3; PKM2: pyruvate kinase 2; MCM proteins: minichromosome maintenance proteins; BRG1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4); ISWI: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 5 (SMARCA5); FIH: factor inhibiting HIF-1; MTA1: Metastasis associated 1; NuRD: Nucleosome remodeling and histone deacetylase; H3K9me2: histone 3 lysine 9 dimethylation; H3K9me3: histone 3 lysine 9 trimethylation; JMJD proteins: Jumonji-domain-containing proteins; GDF15: growth
and differentiation factor 15; EDN1: endothelin 1; HMOX1: heme oxygenase 1; PRMT2: Protein arginine methyltransferase 2; G9a: euchromatic histone-lysine N-methyltransferase 2; Mlh1: mutL homolog 1, colon cancer, nonpolyposis type 2; Dhfr: dihydrofolate reductase; RUNX3: runt-related transcription factor 3; BRCA1: breast cancer 1, early onset; ES: embryonic stem; Tip60: lysine acetyltransferase 5; IGFBP3: insulin-like growth factor binding protein 3; CITED2: CBP/p300-interacting transactivtor, with Glu/Asp-rich carboxy-terminal domain2; Ets1: v-ets erythroblastosis virus E26 oncogene homolog 1; SIRT: sirtuin; MLL1: mixed lineage leukemia 1; H3K4Ac: H3K4 acetylation; HSP90: heat shock protein 90; WDR5: WD repeat domain 5; MET: mesenchymal-epithelial transition; EZH2: enhancer of zeste homolog 2; DNMT: DNA methyltransferase; MeCP2: Methylcytosine-binding protein 2 (MBD2); MAT2A: Methionine adenosyltransferase 2A; SAM: S-adenosylmethionine.
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Figure legend:
Figure 1. A model to depict the hypoxia-regulated gene expression through
modulation of various epigenetic components including co-regulators, histone acetyltransferases/histone deacetylases (HATs/HDACs), histone methyltransferases/lysine demethylases (HMTs/KDMs), chromatin remodeling complexes, and DNA methyltransferases (DNMTs). Me: methylation, Ac; acetylation. Arrows indicate the regulations of various epigenetic components by hypoxia. Double-sided arrows indicate the interactions between different epigenetic components. Empty arrowheads indicate enzymatic actions to add or remove acetyl or methyl group. Solid arrowhead indicates the overall readout of gene expression after epigenetic regulation.
Figure 2. A model to depict the flow from hypoxia-regulated epigenetic
components to their regulation of downstream targets followed by the final readout of different hypoxia-induced phenotypes including cell cycle/growth control, metabolism shift, EMT/metastasis, tumor progression, and angiogenesis/vascular development. Due to the limitation of space, only the representative targets are presented. The intersecting arrows between targets and phenotypes indicate the sophisticated regulation of the same phenotype by
different group of genes and the contribution of the same group of genes to different phenotypes.
