Hypoxia induces rapid changes to histone methylation and reprograms chromatin

Oxygen is essential for the life of most multicellular organisms. Cells possess enzymes called molecular dioxygenases that depend on oxygen for activity. A subclass of molecular dioxygenases is the histone demethylase enzymes, which are characterized by the presence of a Jumanji-C (JmjC) domain. Hypoxia can alter chromatin, but whether this is a direct effect on JmjC-histone demethylases or due to other mechanisms is unknown. Here, we report that hypoxia induces a rapid and hypoxia-inducible factor–independent induction of histone methylation in a range of human cultured cells. Genomic locations of histone-3 lysine-4 trimethylation (H3K4me3) and H3K36me3 after a brief exposure of cultured cells to hypoxia predict the cell’s transcriptional response several hours later. We show that inactivation of one of the JmjC-containing enzymes, lysine demethylase 5A (KDM5A), mimics hypoxia-induced cellular responses. These results demonstrate that oxygen sensing by chromatin occurs via JmjC-histone demethylase inhibition.

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Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate

Science ◽

10.1126/science.aaw1026 ◽

2019 ◽

Vol 363 (6432) ◽

pp. 1217-1222 ◽

Cited By ~ 100

Author(s):

Abhishek A. Chakraborty ◽

Tuomas Laukka ◽

Matti Myllykoski ◽

Alison E. Ringel ◽

Matthew A. Booker ◽

...

Keyword(s):

Cell Fate ◽

Histone Methylation ◽

Mammalian Cells ◽

Control Cell ◽

Hypoxia Inducible Factor ◽

Histone Demethylase ◽

Histone Demethylases ◽

Independent Manner ◽

H3k27 Methylation ◽

Oxygen Sensitive

Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG–independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.

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Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1α

Biochemical Journal ◽

10.1042/bj20081238 ◽

2008 ◽

Vol 416 (3) ◽

pp. 387-394 ◽

Cited By ~ 209

Author(s):

Patrick J. Pollard ◽

Christoph Loenarz ◽

David R. Mole ◽

Michael A. McDonough ◽

Jonathan M. Gleadle ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Cell Lines ◽

Epigenetic Regulation ◽

Histone Methylation ◽

Chromatin Immunoprecipitation ◽

Methylation Status ◽

Hypoxia Inducible Factor ◽

Transcriptional Response ◽

Histone Demethylases

The transcription factor HIF (hypoxia-inducible factor) mediates a highly pleiotrophic response to hypoxia. Many recent studies have focused on defining the extent of this transcriptional response. In the present study we have analysed regulation by hypoxia among transcripts encoding human Fe(II)- and 2-oxoglutarate-dependent oxygenases. Our results show that many of these genes are regulated by hypoxia and define two groups of histone demethylases as new classes of hypoxia-regulated genes. Patterns of induction were consistent across a range of cell lines with JMJD1A (where JMJD is Jumonji-domain containing) and JMJD2B demonstrating robust, and JMJD2C more modest, up-regulation by hypoxia. Functional genetic and chromatin immunoprecipitation studies demonstrated the importance of HIF-1α in mediating these responses. Given the importance of histone methylation status in defining patterns of gene expression under different physiological and pathophysiological conditions, these findings predict a role for the HIF system in epigenetic regulation.

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The Saccharomyces cerevisiae Histone Demethylase Jhd1 Fine-Tunes the Distribution of H3K36me2

Molecular and Cellular Biology ◽

10.1128/mcb.00127-07 ◽

2007 ◽

Vol 27 (13) ◽

pp. 5055-5065 ◽

Cited By ~ 26

Author(s):

Jia Fang ◽

Gregory J. Hogan ◽

Gaoyang Liang ◽

Jason D. Lieb ◽

Yi Zhang

Keyword(s):

Saccharomyces Cerevisiae ◽

Histone Methylation ◽

Histone Demethylase ◽

Lysine Methylation ◽

Chromatin Dynamics ◽

Histone Lysine Methylation ◽

Jmjc Domain ◽

Steady State Levels ◽

Microarray Studies

ABSTRACT Histone methylation plays important roles in the regulation of chromatin dynamics and transcription. Steady-state levels of histone lysine methylation are regulated by a balance between enzymes that catalyze either the addition or removal of methyl groups. Using an activity-based biochemical approach, we recently uncovered the JmjC domain as an evolutionarily conserved signature motif for histone demethylases. Furthermore, we demonstrated that Jhd1, a JmjC domain-containing protein in Saccharomyces cerevisiae, is an H3K36-specific demethylase. Here we report further characterization of Jhd1. Similar to its mammalian homolog, Jhd1-catalyzed histone demethylation requires iron and α-ketoglutarate as cofactors. Mutation and deletion studies indicate that the JmjC domain and adjacent sequences are critical for Jhd1 enzymatic activity, while the N-terminal PHD domain is dispensable. Overexpression of JHD1 results in a global reduction of H3K36 methylation in vivo. Finally, chromatin immunoprecipitation-coupled microarray studies reveal subtle changes in the distribution of H3K36me2 upon overexpression or deletion of JHD1. Our studies establish Jhd1 as a histone demethylase in budding yeast and suggest that Jhd1 functions to maintain the fidelity of histone methylation patterns along transcription units.

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Histone H3K4 demethylases are essential in development and differentiationThis paper is one of a selection of papers published in this Special Issue, entitled 28th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o07-057 ◽

2007 ◽

Vol 85 (4) ◽

pp. 435-443 ◽

Cited By ~ 55

Author(s):

Elizaveta V. Benevolenskaya

Keyword(s):

Cell Fate ◽

Histone Methylation ◽

Peer Review Process ◽

Active Regions ◽

Model Organisms ◽

Global Changes ◽

Histone Demethylases ◽

Trithorax Group ◽

Demethylase Activity ◽

Jmjc Domain

Lysine histone methylation is one of the most robust epigenetic marks and is essential for the regulation of multiple cellular processes. The methylation of Lys4 of histone H3 seems to be of particular significance. It is associated with active regions of the genome, and in Drosophila it is catalyzed by trithorax-group proteins that have become paradigms of developmental regulators at the level of chromatin. Like other histone methylation events, H3K4 methylation was considered irreversible until the identification of a large number of histone demethylases indicated that demethylation events play an important role in histone modification dynamics. However, the described demethylases had no strictly assigned biological functions and the identity of the histone demethylases that would contribute to the epigenetic changes specifying certain biological processes was unknown. Recently, several groups presented evidence that a family of 4 JmjC domain proteins results in the global changes of histone demethylation, and in elegant studies using model organisms, they demonstrated the importance of this family of histone demethylases in cell fate determination. All 4 proteins possess the demethylase activity specific to H3K4 and belong to the poorly described JARID1 protein family.

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The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

Biomolecules ◽

10.3390/biom11121911 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1911

Author(s):

Hans Felix Staehle ◽

Heike Luise Pahl ◽

Jonas Samuel Jutzi

Keyword(s):

Histone Methylation ◽

Chromatin Accessibility ◽

Methyl Groups ◽

Histone Demethylases ◽

Histone Tails ◽

Myeloid Malignancies ◽

Show Evidence ◽

Jmjc Domain ◽

Drug Interventions

Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.

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Hypoxia induces rapid changes to histone methylation reprogramming chromatin for the cellular response

10.1101/513069 ◽

2019 ◽

Author(s):

Michael Batie ◽

Julianty Frost ◽

Mark Frost ◽

James W. Wilson ◽

Pieta Schofield ◽

...

Keyword(s):

Histone Methylation ◽

Cellular Response ◽

Oxygen Sensing ◽

Gene Signature ◽

Oxygen Sensors ◽

Histone Demethylases ◽

Rapid Changes ◽

Transcriptional Changes ◽

Genomic Locations ◽

In Cells

AbstractMolecular dioxygenases include JmjC-containing histone demethylases and PHD enzymes, but only PHDs are considered to be molecular oxygen sensors in cells. Although, it is known that hypoxia can alter chromatin, whether this is a direct effect on histone demethylases or due to hypoxia induced HIF-dependent transcriptional changes is not known. Here, we report that hypoxia induces a rapid and HIF-independent alteration to a variety of histone methylation marks. Genomic locations of H3K4me3 and H3K36me3 following short hypoxia predict the hypoxia gene signature observed several hours later in cells. We show that KDM5A inactivation mimics hypoxic changes to H3K4me3 in its targets and is required for the cellular response to hypoxia. Our results demonstrate a direct link between oxygen sensing and chromatin changes via KDM inhibition.One Sentence SummaryRapid oxygen sensing by chromatin

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Demethylation of Histone H3K36 and H3K9 by Rph1: a Vestige of an H3K9 Methylation System in Saccharomyces cerevisiae?

Molecular and Cellular Biology ◽

10.1128/mcb.02180-06 ◽

2007 ◽

Vol 27 (11) ◽

pp. 3951-3961 ◽

Cited By ~ 50

Author(s):

Robert J. Klose ◽

Kathryn E. Gardner ◽

Gaoyang Liang ◽

Hediye Erdjument-Bromage ◽

Paul Tempst ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Histone Methylation ◽

Budding Yeast ◽

Large Family ◽

Epigenetic Inheritance ◽

Histone Demethylase ◽

H3k9 Methylation ◽

Lysine Methylation ◽

Modification System ◽

Jmjc Domain

ABSTRACT Histone methylation is an important posttranslational modification that contributes to chromatin-based processes including transcriptional regulation, DNA repair, and epigenetic inheritance. In the budding yeast Saccharomyces cerevisiae, histone lysine methylation occurs on histone H3 lysines 4, 36, and 79, and its deposition is coupled mainly to transcription. Until recently, histone methylation was considered to be irreversible, but the identification of histone demethylase enzymes has revealed that this modification can be dynamically regulated. In budding yeast, there are five proteins that contain the JmjC domain, a signature motif found in a large family of histone demethylases spanning many organisms. One JmjC-domain-containing protein in budding yeast, Jhd1, has recently been identified as being a histone demethylase that targets H3K36 modified in the di- and monomethyl state. Here, we identify a second JmjC-domain-containing histone demethylase, Rph1, which can specifically demethylate H3K36 tri- and dimethyl modification states. Surprisingly, Rph1 can remove H3K9 methylation, a histone modification not found in budding yeast chromatin. The capacity of Rph1 to demethylate H3K9 provides the first indication that S. cerevisiae may have once encoded an H3K9 methylation system and suggests that Rph1 is a functional vestige of this modification system.

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Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Molecular and Cellular Biology ◽

10.1128/mcb.00444-09 ◽

2009 ◽

Vol 30 (1) ◽

pp. 344-353 ◽

Cited By ~ 225

Author(s):

Adam J. Krieg ◽

Erinn B. Rankin ◽

Denise Chan ◽

Olga Razorenova ◽

Sully Fernandez ◽

...

Keyword(s):

Gene Expression ◽

Tumor Growth ◽

Histone Methylation ◽

Hypoxia Inducible Factor ◽

Histone Demethylase ◽

Carcinoma Cell Lines ◽

Signal Amplifier ◽

Reduce Tumor Growth ◽

Inducible Genes

ABSTRACT The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylase genes JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIFs indirectly influence gene expression at the level of histone methylation under hypoxia. In this study, we identify a subset of hypoxia-inducible genes that are dependent on JMJD1A in both renal cell and colon carcinoma cell lines. JMJD1A regulates the expression of adrenomedullin (ADM) and growth and differentiation factor 15 (GDF15) under hypoxia by decreasing promoter histone methylation. In addition, we demonstrate that loss of JMJD1A is sufficient to reduce tumor growth in vivo, demonstrating that histone demethylation plays a significant role in modulating growth within the tumor microenvironment. Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth.

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Fanconi Anemia FANCM/FNCM-1 and FANCD2/FCD-2 are required for maintaining histone methylation levels and interact with the histone demethylase LSD1/SPR-5 in C. elegans

10.1101/265876 ◽

2018 ◽

Author(s):

Hyun-Min Kim ◽

Sara E. Beese-Sims ◽

Monica P. Colaiácovo

Keyword(s):

Dna Damage ◽

Fanconi Anemia ◽

Histone Methylation ◽

Dna Damage Repair ◽

Replication Stress ◽

Histone Demethylase ◽

Histone Demethylases ◽

Checkpoint Activation ◽

C Elegans ◽

Damage Repair

ABSTRACTThe histone demethylase LSD1 was originally discovered as removing methyl groups from di- and monomethylated histone H3 lysine 4 (H3K4me2/1), and several studies suggest it plays roles in meiosis as well as epigenetic sterility given that in its absence there is evidence of a progressive accumulation of H3K4me2 through generations. In addition to transgenerational sterility, growing evidence for the importance of histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which histone methylation is involved in DNA damage repair and only a few studies have been focused on the roles of histone demethylases in germline maintenance. Here, we show that the histone demethylase LSD1/CeSPR-5 is interacting with the Fanconi Anemia (FA) protein FANCM/CeFNCM-1 based on biochemical, cytological and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 re-localizes upon hydroxyurea exposure and co-localizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5 suggesting coordination between this histone demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance regardless of the presence of replication stress. Our study reveals a connection between Fanconi Anemia and epigenetic maintenance, therefore providing new mechanistic insight into the regulation of histone methylation in DNA repair.

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Investigations on the oxygen dependence of a 2-oxoglutarate histone demethylase

Biochemical Journal ◽

10.1042/bj20121155 ◽

2012 ◽

Vol 449 (2) ◽

pp. 491-496 ◽

Cited By ~ 42

Author(s):

Elena M. Sánchez-Fernández ◽

Hanna Tarhonskaya ◽

Khalid Al-Qahtani ◽

Richard J. Hopkinson ◽

James S. O. McCullagh ◽

...

Keyword(s):

Steady State ◽

Methylation Status ◽

Kinetic Studies ◽

Histone Demethylase ◽

Histone Demethylases ◽

Graded Response ◽

Histone Lysine Demethylase ◽

Demethylase Activity ◽

Lysine Demethylase ◽

Relevant Range

Histone Nϵ-methyl lysine demethylases are important in epigenetic regulation. KDM4E (histone lysine demethylase 4E) is a representative member of the large Fe(II)/2-oxoglutarate- dependent family of human histone demethylases. In the present study we report kinetic studies on the reaction of KDM4E with O2. Steady-state assays showed that KDM4E has a graded response to O2 over a physiologically relevant range of O2 concentrations. Pre-steady state assays implied that KDM4E reacts slowly with O2 and that there are variations in the reaction kinetics which are dependent on the methylation status of the substrate. The results demonstrate the potential for histone demethylase activity to be regulated by oxygen availability.

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