Chromatin and oxygen sensing in the context of JmjC histone demethylases
Open accessAbstract
Responding appropriately to changes in oxygen availability is essential for multicellular organism survival. Molecularly, cells have evolved intricate gene expression programmes to handle this stressful condition. Although it is appreciated that gene expression is co-ordinated by changes in transcription and translation in hypoxia, much less is known about how chromatin changes allow for transcription to take place. The missing link between co-ordinating chromatin structure and the hypoxia-induced transcriptional programme could be in the form of a class of dioxygenases called JmjC (Jumonji C) enzymes, the majority of which are histone demethylases. In the present review, we will focus on the function of JmjC histone demethylases, and how these could act as oxygen sensors for chromatin in hypoxia. The current knowledge concerning the role of JmjC histone demethylases in the process of organism development and human disease will also be reviewed.
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Hypoxia can potentially impact DNA and histone methylation because the demethylase enzymes are dioxygenases and require oxygen and 2-oxoglutarate for their activity.
“Hypoxia can potentially impact on DNA and histone methylation since the demethylase enzymes are dioxygenases, and so require oxygen and 2-oxoglutarate for their activity (501).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [501]
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“In vitro studies have revealed that while some JmjC have quite particular selectivity for histone residues, such as KDM3A that is specific to mono- and di-methylation on histone H3 lysine 9 (H3K9); others have a broader range of targets [7].”
BackgroundThe EGLN-HIF O 2 -Sensing System: Multiple Inputs and Feedbacks
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InfluentialHypoxia and Inflammation in Cancer, Focus on HIF and NF-κB
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“These enzymes, of which there are over 30 discovered in humans, mainly control histone methylation, and they are often deregulated in many cancers (reviewed in [57]).”
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“The best-studied histone modification in response to hypoxia is lysine 27 methylation on histone H3 (H3K27me) via the Jumonji C (JmjC) family of histone demethylases (Shmakova et al. 2014).”
BackgroundOxygen-sensing mechanisms across eukaryotic kingdoms and their roles in complex multicellularity
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“Although recent reports confirmed the hypoxia sensitivity of members of this protein family in human cells, with consequences for differentiation in several cell line model systems (45, 46, 48, 130), this has not yet been explored in plants.”
BackgroundSalminen, A., Kauppinen, A., & Kaarniranta, K. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1978-z · Cited by 99 · see citing works
“The functional differences between KDMs can be attributed to the fact that the proteins of distinct KDM subgroups have unique binding domains, which target enzymes to specific complexes [9, 47, 96, 98].”
BackgroundHistone lysine demethylases and their functions in cancer
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“For example, KDM2A is hypoxia-inducible at the transcriptional level as HIF-1α is required for the recruitment of RNA polymerase II to the KDM2A promoter.55 Further KDMs induced by hypoxia, some in a HIF-dependent manner, include KDM3A, KDM4B/C, KDM5C and KDM6A.156,157 Ubiquitination by SCF ubiquitin ligase complex co…”
BackgroundHypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases
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“PHDs are clearly more sensitive hypoxic sensors than Jumonji-type histone demethylases.”
BackgroundInfluentialOxygen‐sensing mechanisms in cells
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An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption
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A transient ischemic environment induces reversible compaction of chromatin
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“Consequently, hypoxia can limit the activity of a subset of JmjC histone demethylases, resulting in global increases in the methylation of histone H3K4, H3K9, H3K27 and H3K36 and in chromatin condensation [13].”
OH, the Places You’ll Go! Hydroxylation, Gene Expression, and Cancer
Ploumakis, A., & Coleman, M. L. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.026 · Cited by 74 · see citing works
“Interestingly, a role for KDMs in the hypoxia response is supported by their general 736 Molecular Cell 58, June 4, 2015 ª2015 Elsevier Inc. transcriptional regulation by HIF (reviewed in Shmakova et al., 2014).”
BackgroundJumonji histone demethylases as emerging therapeutic targets
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Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A
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“chromatin-binding hydroxylases 125,126 and histone methylases 127–129 , which can alter the epigenome and transcriptional landscape of individual cells, and by implication, their function.”
Regulation of hypoxia-inducible gene expression after HIF activation
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Hypoxia and Chromatin: A Focus on Transcriptional Repression Mechanisms
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“Furthermore, increased H3K9me3 in U2OS cells overexpressing KDM4A was reduced in a stepwise fashion when exposed to 5%, 1%, and 0.1% oxygen [62].”
BackgroundInfluentialSelf-citationChung, Y. J., Luo, A., Park, K. C., Loonat, A. A., Lakhal‐Littleton, S., Robbins, P. A., & Swietach, P. (2019) · JCI Insight · doi:10.1172/jci.insight.125618 · Cited by 56 · see citing works
“The demethylase KDM4A (12, 13), previously implicated in HF (16), acts specifically on di- and trimethylated H3K36 and H3K9 (13), which were found to be enriched in the hearts of iron-deficient animals (Figure 1I and Supplemental Figure 1; supplemental material available online with this”
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“JmjC (Jumonji C) is a demethylase-related domain [26,27] and JmjN (Jumonji N) is always located adjacent to JmjC to form one functional unit [28,29].”
BackgroundDynamic regulation of epigenetic demethylation by oxygen availability and cellular redox
Lamadema, N., Burr, S., & Brewer, A. C. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.12.009 · Cited by 48 · see citing works
“they have not been identified as direct HIF targets, suggesting the contribution of additional mechanism(s) [58, 114, 115].”
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Gene transcription and chromatin regulation in hypoxia
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Self-citationSearching for molecular hypoxia sensors among oxygen-dependent enzymes
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ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate
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Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia
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“Furthermore, many JmjC histone demethylases are HIF target genes that are upregulated in hypoxia (reviewed in [215]), this is thought in part to be a compensatory mechanism to counteract reduced demethylase activity, acting as a hypoxia feedback loop similar to what is seen with transcriptional upregulation of PHD2/3…”
BackgroundSelf-citationKDM2 Family Members are Regulated by HIF-1 in Hypoxia
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“Given that the KDM2 family targets important histone methylation marks such histone H3 lysine 4 trimethylation (H3K4me3) and H3K36me/me2 [13], regulation of KDM2 abundance will impinge into the levels of these histone marks.”
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“KDM4B (JMJD2B) and KDM6B are both members of the JmjC protein domain family and are regulated by HIF1A, require oxygen as a cofactor, and act as oxygen sensors for chromatin in hypoxia [101, 102].”
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“Furthermore, enhanced KDM4 activity or increased levels of KDM4B and/or KDM4C caused by intermittent hypoxia may also impact tumors, as the KDM4 group is associated with various cancers (37).”
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“Notably, hypoxia has been shown to trigger epigenetic change in a HIF1 α -dependent or HIF1 α -independent manner [57, 58].”
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“KDM subfamilies 3-6 themselves are HIF1α target genes [72, 76-82], however”
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“Hypoxia is a powerful inducer of the molecular machinery underlying epigenetic events (23) by upregulating the expression of several JmjC domain proteins while attenuating their activity.”
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“Indeed recent assessment of their low affinity for oxygen and consequent inactivation under hypoxia, associated with the widespread increase in histone methylation observed in vivo in such condition, confirmed this role (Chakraborty et al., 2002; Shmakova et al., 2014; Hancock et al., 2017; Batie et al., 2019; Chakrab…”
BackgroundFunctional crosstalk between chromatin and hypoxia signalling
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Mitochondrial respiration reduces exposure of the nucleus to oxygen
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“Among the post-translational modifications of histones, lysine (K) methylation in particular has been shown to be sensitive to the cellular levels of O2 (28).”
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“Given that JARID1B plays a critical role in neural growth and differentiation [34,52,56], perturbed expression of this protein during neural development provides a molecular mechanism whereby early-life brain iron depletion alters the regulation of synaptic plasticity genes that lasts beyond the period of ID [14,19–21…”
BackgroundJmjC histone demethylases act as chromatin oxygen sensors
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“some of the JmjC KDMs are proposed to be involved in the hypoxic response (26,27).”
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PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation
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“Each subfamily is specialised to preferentially achieve particular chromatin outcomes: assembly, access or editing, and has been shown to contribute to gene expression changes in response to hypoxic stress [3,4] The levels and activity of SWI/SNF chromatin remodelling complexes are important for controlling gene expre…”
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Oxygen‐regulated post‐translation modifications as master signalling pathway in cells
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“There are 32 identified JmjC domain-containing proteins in humans, which are divided based on target selectivity and sequence homology into subfamilies (lysine specific demethylase (KDM)2-KDM8), and 23 of them display demethylase activity in cells (Shmakova et al , 2014).”
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Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents
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“In a further example, the Jumonji-domain dioxygenases, a histone demethylase sub-group, are important factors that are upregulated during hypoxia [24] and in tumors, for example, colorectal cancer [25].”
BackgroundRecent Advances in Comprehending the Signaling Pathways Involved in the Progression of Breast Cancer
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“Jumonji C (JmjC) domain-containing proteins, many of which are 2-OG dioxygenases are enzymes working as protein demethylases and are often deregulated in many cancers [78].”
BackgroundEpigenetic regulation of the hypoxic response
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“Jumonji C (JmjC)-domain containing demethylases The enzymatic activity of JmjC-domain containing demethylases can be reduced by low oxygen levels because JmjC-domain demethylases require oxygen and 2-oxoglutarate for their activity [22,23].”
BackgroundPhysiological function of the dynamic oxygen signaling pathway at the maternal-fetal interface
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The Role of 2-Oxoglutarate-Dependent Oxygenases in Hypoxia Sensing
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The Essential Role of Epigenetic Modifications in Neurodegenerative Diseases with Dyskinesia
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Obesity Disrupts H3K4me3 ‐Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages
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“In particular, hypoxia induces histone hypermethylation and upregulates gene expression through increased histone 3-lysine 4 trimethylation (H3K4me3) [18].”
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“This matters for MRS because JmjC enzymes are Fe(II)-, O 2 -, and 2-oxoglutarate-depend-ent oxygenases, with activity sensitive to oxygen concentration and the α -ketoglutarate/succinate/fumarate/2-hydroxyglutarate metabolite landscape [211], [23], [212].”
Histone demethylase inhibitors and their potential in cancer treatment
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Transcription | Regulation of Gene Transcription by Hypoxia-Inducible Factor 1α
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Expression pattern of histone lysine‑specific demethylase 6B in gastric cancer
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“KMD6B is a member of the histone demethylase family of proteins containing the JmjC domain and requires Fe2+ and α‐ketoglutarate as co‐factors (23).”
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A patent review of KDM4 histone demethylase inhibitors (2014-present)
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- Authors
- Shmakova, A., Batie, M., Druker, J., & Rocha, S.
- Affiliations
- University of Dundee (GB)
- Centre for Gene Regulation and Expression, MSI/WTB/JBC Complex, Dow Street, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
- Corresponding author
- Shmakova, Alena
- Batie, Michael
- Druker, Jimena
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2014-08-22
- Volume
- 462
- Issue
- 3
- Pages
- 385-395
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC4147966
- OpenAlex
- W2167617091
- Cited by
- 99
- References
- 146
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 15 · 2020: 14 · 2019: 8 · 2018: 7 · 2017: 10 · 2016: 10 · 2015: 8 · 2014: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (C99667/A12918, 097945, 097945/B/11/Z)
- Cancer Research UK (C99667/A12918, 097945/B/11/Z, A12918, 12918)
- Tenovus
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- oxygen sensing, hypoxia, chromatin structure, histone demethylation, dioxygenase, transcriptional regulation, gene expression, development (biology), human disease
- MeSH terms
- Chromatin, Histones, Humans, Oxygen, Transcription, Genetic, Cell Hypoxia, Jumonji Domain-Containing Histone Demethylases
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