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

2012 ◽  
Vol 449 (2) ◽  
pp. 491-496 ◽  
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.

scholarly journals A KDM5-Prospero transcriptional axis functions during early neurodevelopment to regulate mushroom body formation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hayden AM Hatch ◽  
Helen M Belalcazar ◽  
Owen J Marshall ◽  
Julie Secombe
Keyword(s):  
Transcription Factor ◽  
Mushroom Body ◽  
Transcriptional Regulators ◽  
Histone Demethylase ◽  
Body Formation ◽  
Demethylase Activity ◽  
Mother Cells ◽  
Lysine Demethylase ◽  
Canonical Histone

Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding their spatiotemporal requirements or neurodevelopmental contributions. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is required within ganglion mother cells and immature neurons for proper axogenesis. Moreover, the mechanism by which KDM5 functions in this context is independent of its canonical histone demethylase activity. Using in vivo transcriptional and binding analyses, we identify a network of genes directly regulated by KDM5 that are critical modulators of neurodevelopment. We find that KDM5 directly regulates the expression of prospero, a transcription factor that we demonstrate is essential for MB morphogenesis. Prospero functions downstream of KDM5 and binds to approximately half of KDM5-regulated genes. Together, our data provide evidence for a KDM5-Prospero transcriptional axis that is essential for proper MB development.

scholarly journals Epigenetic Control and Cancer: The Potential of Histone Demethylases as Therapeutic Targets

2012 ◽  
Vol 5 (9) ◽  
pp. 963-990 ◽  
Author(s):  
Fernando Lizcano ◽  
Jeison Garcia
Keyword(s):  
Molecular Level ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Histone Demethylase ◽  
Point Of View ◽  
Histone Demethylases ◽  
Regulate Gene Expression ◽  
Number Of Factors ◽  
Demethylase Activity ◽  
Current Point

The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal of functional groups to specific histone residues, are of great interest as a promising way to identify markers for cancer diagnosis, classify the disease and determine its prognosis, and these markers could be potential targets for the treatment of this disease in its different forms. This manuscript presents the current point of view regarding members of the recently described family of proteins that exhibit histone demethylase activity; histone demethylases are genetic regulators that play a fundamental role in both the activation and repression of genes and whose expression has been observed to increase in many types of cancer. Some fundamental aspects of their association with the development of cancer and their relevance as potential targets for the development of new therapeutic strategies at the epigenetic level are discussed in the following manuscript.

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 Advances in Histone Demethylase KDM3A as a Cancer Therapeutic Target

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1098 ◽  
Author(s):  
Jung Yoo ◽  
Yu Hyun Jeon ◽  
Ha Young Cho ◽  
Sang Wu Lee ◽  
Go Woon Kim ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Structural Information ◽  
Therapeutic Agents ◽  
Histone Demethylase ◽  
Histone Demethylases ◽  
Selective Inhibitors ◽  
Lxxll Motif ◽  
Demethylase Activity ◽  
Potential Cancer ◽  
Insight Into

Lysine-specific histone demethylase 3 (KDM3) subfamily proteins are H3K9me2/me1 histone demethylases that promote gene expression. The KDM3 subfamily primarily consists of four proteins (KDM3A−D). All four proteins contain the catalytic Jumonji C domain (JmjC) at their C-termini, but whether KDM3C has demethylase activity is under debate. In addition, KDM3 proteins contain a zinc-finger domain for DNA binding and an LXXLL motif for interacting with nuclear receptors. Of the KDM3 proteins, KDM3A is especially deregulated or overexpressed in multiple cancers, making it a potential cancer therapeutic target. However, no KDM3A-selective inhibitors have been identified to date because of the lack of structural information. Uncovering the distinct physiological and pathological functions of KDM3A and their structure will give insight into the development of novel selective inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM3A in cancer. We also discuss existing KDM3A-related inhibitors and review their potential as therapeutic agents for overcoming cancer.

scholarly journals Histone lysine demethylase 4B regulates general and unique gene expression signatures in hypoxic cancer cells

MedComm ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 414-429
Author(s):  
Lei Qiu ◽  
Yang Meng ◽  
Lingli Wang ◽  
Sumedha Gunewardena ◽  
Sicheng Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Unique Gene ◽  
Histone Lysine ◽  
Histone Lysine Demethylase ◽  
Gene Expression Signatures ◽  
Lysine Demethylase

scholarly journals Pluripotency Transcription Factor Oct4 Mediates Stepwise Nucleosome Demethylation and Depletion

2015 ◽  
Vol 35 (6) ◽  
pp. 1014-1025 ◽  
Author(s):  
Arvind Shakya ◽  
Catherine Callister ◽  
Alon Goren ◽  
Nir Yosef ◽  
Neha Garg ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chromatin Immunoprecipitation ◽  
Time Course ◽  
Embryonic Stem ◽  
Assay System ◽  
Histone Demethylation ◽  
Oct4 Expression ◽  
Genome Wide ◽  
Histone Lysine Demethylase ◽  
Lysine Demethylase

The mechanisms whereby the crucial pluripotency transcription factor Oct4 regulates target gene expression are incompletely understood. Using an assay system based on partially differentiated embryonic stem cells, we show that Oct4 opposes the accumulation of local H3K9me2 and subsequent Dnmt3a-mediated DNA methylation. Upon binding DNA, Oct4 recruits the histone lysine demethylase Jmjd1c. Chromatin immunoprecipitation (ChIP) time course experiments identify a stepwise Oct4 mechanism involving Jmjd1c recruitment and H3K9me2 demethylation, transient FACT ( fa cilitates c hromatin t ransactions) complex recruitment, and nucleosome depletion. Genome-wide and targeted ChIP confirms binding of newly synthesized Oct4, together with Jmjd1c and FACT, to the Pou5f1 enhancer and a small number of other Oct4 targets, including the Nanog promoter. Histone demethylation is required for both FACT recruitment and H3 depletion. Jmjd1c is required to induce endogenous Oct4 expression and fully reprogram fibroblasts to pluripotency, indicating that the assay system identifies functional Oct4 cofactors. These findings indicate that Oct4 sequentially recruits activities that catalyze histone demethylation and depletion.

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