KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

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.

Download Full-text

Inhibition of H3K27me3 Histone Demethylase Activity Prevents the Proliferative Regeneration of Zebrafish Lateral Line Neuromasts

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2017.00051 ◽

2017 ◽

Vol 10 ◽

Cited By ~ 10

Author(s):

Beier Bao ◽

Yingzi He ◽

Dongmei Tang ◽

Wenyan Li ◽

Huawei Li

Keyword(s):

Lateral Line ◽

Histone Demethylase ◽

Demethylase Activity

Download Full-text

KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s40182 ◽

2016 ◽

Vol 10 ◽

pp. BCBCR.S40182 ◽

Cited By ~ 2

Author(s):

Jeison Garcia ◽

Fernando Lizcano

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Chromosome Segregation ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Human Cancer ◽

Histone Demethylase ◽

Breast Cancer Cell Lines ◽

Demethylase Activity

The Jumonji-containing domain protein, KDM4C, is a histone demethylase associated with the development of several forms of human cancer. However, its specific function in the viability of tumoral lineages is yet to be determined. This work investigates the importance of KDM4C activity in cell proliferation and chromosome segregation of three triple-negative breast cancer cell lines using a specific demethylase inhibitor. Immunofluorescence assays show that KDM4C is recruited to mitotic chromosomes and that the modulation of its activity increases the number of mitotic segregation errors. However, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell proliferation assays demonstrate that the demethylase activity is required for cell viability. These results suggest that the histone demethylase activity of KDM4C is essential for breast cancer progression given its role in the maintenance of chromosomal stability and cell growth, thus highlighting it as a potential therapeutic target.

Download Full-text

Compromised JMJD6 Histone Demethylase Activity Affects VHL Gene Repression in Preeclampsia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02197 ◽

2018 ◽

Vol 103 (4) ◽

pp. 1545-1557 ◽

Cited By ~ 12

Author(s):

Sruthi Alahari ◽

Martin Post ◽

Alessandro Rolfo ◽

Rosanna Weksberg ◽

Isabella Caniggia

Keyword(s):

Gene Expression ◽

Epigenetic Regulation ◽

Human Placenta ◽

Iron Homeostasis ◽

Late Onset ◽

Normal Pregnancy ◽

Histone Demethylase ◽

Vhl Gene ◽

Morphological Alterations ◽

Demethylase Activity

Abstract Context The von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5% to 7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive. Objective We examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia. Design, Setting, and Participants Placentae were obtained from early-onset preeclampsia (n = 56; <34 weeks of gestation) and late-onset preeclampsia (n = 19; ≥34 weeks of gestation). Placentae from healthy normotensive age-matched preterm control (n = 43) and term control (n = 23) pregnancies were included as controls. Main Outcome Measure(s) We measured the activity of Jumonji domain containing protein 6 (JMJD6), a ferrous iron (Fe2+)– and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL. Results JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592–treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592–treated mice. Conclusions Our study uncovers epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia.

Download Full-text

Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells

Molecular and Clinical Oncology ◽

10.3892/mco.2014.445 ◽

2014 ◽

Vol 3 (1) ◽

pp. 171-178 ◽

Cited By ~ 7

Author(s):

KARINA GALOIAN ◽

AMIR QURESHI ◽

GINA WIDEROFF ◽

H.T. TEMPLE

Keyword(s):

Protein Expression ◽

Histone Demethylase ◽

Human Chondrosarcoma ◽

Tumorigenic Potential ◽

Junction Protein ◽

Demethylase Activity

Download Full-text

The histone demethylase KDM5 is essential for larval growth in Drosophila

10.1101/297804 ◽

2018 ◽

Cited By ~ 1

Author(s):

Coralie Drelon ◽

Helen M. Belalcazar ◽

Julie Secombe

Keyword(s):

Mammalian Cells ◽

Cell Cycle Progression ◽

Biological Activities ◽

Larval Growth ◽

Imaginal Discs ◽

Complete Loss ◽

Histone Demethylase ◽

Ideal System ◽

Demethylase Activity ◽

Regulated Gene Expression

AbstractRegulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of proteins are histone H3 lysine 4 demethylases that can regulate transcription through both demethylase-dependent and independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells. To examine the consequences of complete loss of KDM5, we generated a null allele of Drosophila kdm5, also known as little imaginal discs (lid), and show that it is essential for development. Animals lacking KDM5 die during late pupal development but show a dramatically delayed larval development that coincides with decreased proliferation and increased cell death in imaginal discs. Interestingly, this developmental delay is independent of the well-characterized Jumonji C (JmjC) domain-encoded histone demethylase activity and plant homedomain (PHD) motif-mediated chromatin binding activities of KDM5, suggesting key functions for less characterized domains. Consistent with the phenotypes observed, transcriptome analyses of kdm5 null mutant wing imaginal discs revealed the dysregulation of genes involved in several cellular processes, including cell cycle progression and DNA repair. Together, our data provide the first description of complete loss of KDM5 function in a metazoan and offer an invaluable tool for defining the biological activities of KDM5 family proteins.

Download Full-text

LSD1: more than demethylation of histone lysine residues

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00542-2 ◽

2020 ◽

Vol 52 (12) ◽

pp. 1936-1947

Author(s):

Bruno Perillo ◽

Alfonso Tramontano ◽

Antonio Pezone ◽

Antimo Migliaccio

Keyword(s):

Gene Expression ◽

Cancer Progression ◽

Regulation Of Gene Expression ◽

Histone H3 ◽

Histone Demethylase ◽

Special Role ◽

Histone H4 ◽

Nonhistone Proteins ◽

Lysine Residues ◽

Demethylase Activity

AbstractLysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.

Download Full-text