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.

2007 ◽  
Vol 85 (4) ◽  
pp. 435-443 ◽  
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.

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

Science ◽  
2019 ◽  
Vol 363 (6432) ◽  
pp. 1217-1222 ◽  
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.

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

Biomolecules ◽  
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.

scholarly journals Hypoxia induces rapid changes to histone methylation and reprograms chromatin

Science ◽  
2019 ◽  
Vol 363 (6432) ◽  
pp. 1222-1226 ◽  
Author(s):  
Michael Batie ◽  
Julianty Frost ◽  
Mark Frost ◽  
James W. Wilson ◽  
Pieta Schofield ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Cultured Cells ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Histone Demethylase ◽  
Histone Demethylases ◽  
Jmjc Domain ◽  
Genomic Locations ◽  
Multicellular Organisms ◽  
Lysine Demethylase

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.

scholarly journals The H3K4 Demethylase Lid Associates with and Inhibits Histone Deacetylase Rpd3

2008 ◽  
Vol 29 (6) ◽  
pp. 1401-1410 ◽  
Author(s):  
Nara Lee ◽  
Hediye Erdjument-Bromage ◽  
Paul Tempst ◽  
Richard S. Jones ◽  
Yi Zhang
Keyword(s):  
Histone Deacetylase ◽  
Gene Activation ◽  
Polycomb Group ◽  
Genetic Classification ◽  
Trithorax Group ◽  
Nuclear Extracts ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Active Transcription ◽  
Group Protein

ABSTRACT JmjC domain-containing proteins have been shown to possess histone demethylase activity. One of these proteins is the Drosophila histone H3 lysine 4 demethylase Little imaginal discs (Lid), which has been genetically classified as a Trithorax group protein. However, contrary to the supposed function of Lid in gene activation, the biochemical activity of this protein entails the removal of a histone mark that is correlated with active transcription. To understand the molecular mechanism behind the function of Lid, we have purified a Lid-containing protein complex from Drosophila embryo nuclear extracts. In addition to Lid, the complex contains Rpd3, CG3815/Drosophila Pf1, CG13367, and Mrg15. Rpd3 is a histone deacetylase, and along with Polycomb group proteins, which antagonize the function of Trithorax group proteins, it negatively regulates transcription. By reconstituting the Lid complex, we demonstrated that the demethylase activity of Lid is not affected by its association with other proteins. However, the deacetylase activity of Rpd3 is greatly diminished upon incorporation into the Lid complex. Thus, our finding that Lid antagonizes Rpd3 function provides an explanation for the genetic classification of Lid as a positive transcription regulator.

Pcgf1 regulates early neural tube development through histone methylation in zebrafish

2020 ◽  
Author(s):  
Xinyue Li ◽  
Guangyu Ji ◽  
Juan Zhou ◽  
Jingyi Du ◽  
Xian Li ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neural Tube ◽  
Histone Methylation ◽  
Control Cell ◽  
Neural Induction ◽  
Induction Phase ◽  
Zebrafish Embryos ◽  
Rna Seq ◽  
Self Renewal ◽  
Neural Tube Development

Abstract Objective Early neural tube development in the embryo includes neural induction and self-renewal of neural stem cells (NSCs). The abnormal of neural tube development could lead to neural tube defects. The research on the mechanism of neural induction is the key to reveal the pathogenesis of the abnormal of neural tube. Though studies have confirmed a genetic component, the responsible mechanisms for the abnormal of neural tube are still largely unknown. Polycomb repressive complex 1 (PRC1) plays an important role in regulating early embryonic development, and has been sub-classified into six major complexes based on the presence of a Pcgf subunit. Pcgf1, as one of six Pcgf paralogs, is an important requirement in early embryonic brain development. Here, we intended to investigate the role and mechanism of Pcgf1 in early neural tube development of zebrafish embryos. Material and methods Morpholino (MO) antisense oligonucleotides were used to construct a Pcgf1 loss-of function zebrafish model. We analyzed the phenotype of zebrafish embryos and the expression of related genes in the process of neural induction by in situ hybridization, immunolabelling and RNA-sEq. The regulation of histone modifications on gene was detected by western blot and chromatin immunoprecipitation. Results In this study, we found that zebrafish embryos exhibited small head and reduced or even absence of telencephalon after inhibiting the expression of Pcgf1. Moreover, the neural induction process of zebrafish embryos was abnormal, and the subsequent NSCs self-renewal was inhibited under the inhibition of Pcgf1. RNA-seq and gene ontology (GO) analysis identified that the differentially expressed genes were enriched in many functional categories which related to the development phenotype. Finally, our results showed that Pcgf1 regulated the trimethylation of histone H3K27 in the Ngn1 and Otx2 promoter regions, and the levels of H3K4me3 at the promoters of Pou5f3 and Nanog. Conclusion Together, our data for the first time demonstrate that Pcgf1 plays an essential role in early neural induction phase through histone methylation in neural tube development. Our findings reveal a critical context-specific function for Pcgf1 in directing PRC1 to control cell fate.

scholarly journals Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2027 ◽  
Author(s):  
Rosaria Benedetti ◽  
Carmela Dell’Aversana ◽  
Tommaso De Marchi ◽  
Dante Rotili ◽  
Ning Qing Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histone Methylation ◽  
Ex Vivo ◽  
Acquired Resistance ◽  
Chemical Properties ◽  
Breast Cancers ◽  
Histone Demethylases ◽  
Lysine Specific Demethylase ◽  
Breast Cancer Model

In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer.

scholarly journals The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

Blood ◽  
2019 ◽  
Vol 134 (14) ◽  
pp. 1154-1158 ◽  
Author(s):  
Karl Agger ◽  
Koutarou Nishimura ◽  
Satoru Miyagi ◽  
Jan-Erik Messling ◽  
Kasper Dindler Rasmussen ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Clinical Use ◽  
Histone Demethylases ◽  
Hematopoietic Stem ◽  
Stem Cell Maintenance ◽  
Demethylase Activity ◽  
Cell Maintenance ◽  
Acute Myeloid

Abstract KDM4 and JMJD2 are histone demethylases that are considered promising targets for treatment of MLL translocation–bearing acute myeloid leukemia. Agger and colleagues demonstrate an important role of KDM4 activity in long-term normal hematopoiesis that should be considered when contemplating the clinical use of long-term inhibition of KDM4 demethylase activity.

JmjN interacts with JmjC to ensure selective proteolysis of Gis1 by the proteasome

Microbiology ◽  
2011 ◽  
Vol 157 (9) ◽  
pp. 2694-2701 ◽  
Author(s):  
Zhenzhen Quan ◽  
Stephen G. Oliver ◽  
Nianshu Zhang
Keyword(s):  
Structural Unit ◽  
Transcription Activation ◽  
Histone Demethylase ◽  
Transcription Activity ◽  
The Core ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Β Sheets ◽  
The Stability ◽  
Selective Proteolysis

A group of JmjC domain-containing proteins also harbour JmjN domains. Although the JmjC domain is known to possess histone demethylase activity, the function of the JmjN domain remains largely undetermined. Previously, we have demonstrated that the yeast Gis1 transcription factor, bearing both JmjN and JmjC domains at its N terminus, is subject to proteasome-mediated selective proteolysis to downregulate its transcription activation ability. Here, we reveal that the JmjN and JmjC domains interact with each other through two β-sheets, one in each domain. Removal of either or both β-strands or the entire JmjN domain leads to complete degradation of Gis1, mediated partially by the proteasome. Mutating the core residues essential for histone demethylase activity demonstrated for other JmjC-containing proteins or deleting both Jumonji domains enhances the transcription activity of Gis1, but has no impact on its selective proteolysis by the proteasome. Together, these data suggest that JmjN and JmjC interact physically to form a structural unit that ensures the stability and appropriate transcription activity of Gis1.

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