scholarly journals The emerging role of KDM5A in human cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Guan-Jun Yang ◽  
Ming-Hui Zhu ◽  
Xin-Jiang Lu ◽  
Yan-Jun Liu ◽  
Jian-Fei Lu ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Posttranslational Modification ◽  
Human Cancer ◽  
Histone H3 ◽  
Epigenetic Inheritance ◽  
Histone Demethylase ◽  
Genome Integrity ◽  
Methyl Groups ◽  
Lysine Specific Demethylase

AbstractHistone methylation is a key posttranslational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Variations in the pattern of histone methylation influence both physiological and pathological events. Lysine-specific demethylase 5A (KDM5A, also known as JARID1A or RBP2) is a KDM5 Jumonji histone demethylase subfamily member that erases di- and tri-methyl groups from lysine 4 of histone H3. Emerging studies indicate that KDM5A is responsible for driving multiple human diseases, particularly cancers. In this review, we summarize the roles of KDM5A in human cancers, survey the field of KDM5A inhibitors including their anticancer activity and modes of action, and the current challenges and potential opportunities of this field.

scholarly journals Histone Demethylase KDM7A Contributes to the Development of Hepatic Steatosis by Targeting Diacylglycerol Acyltransferase 2

2021 ◽  
Vol 22 (20) ◽  
pp. 11085
Author(s):  
Ji-Hyun Kim ◽  
Arukumar Nagappan ◽  
Dae Young Jung ◽  
Nanjoo Suh ◽  
Myeong Ho Jung
Keyword(s):  
Liver Disease ◽  
Hepatic Steatosis ◽  
Histone Methylation ◽  
Functional Role ◽  
Histone H3 ◽  
Diacylglycerol Acyltransferase ◽  
Histone Demethylase ◽  
Nonalcoholic Fatty Liver ◽  
Intracellular Triglyceride

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. While the development of NAFLD is correlated with aberrant histone methylation, modifiers of histone methylation involved in this event remain poorly understood. Here, we studied the functional role of the histone demethylase KDM7A in the development of hepatic steatosis. KDM7A overexpression in AML12 cells upregulated diacylglycerol acyltransferase 2 (DGAT2) expression and resulted in increased intracellular triglyceride (TG) accumulation. Conversely, KDM7A knockdown reduced DGAT2 expression and TG accumulation, and significantly reversed free fatty acids-induced TG accumulation. Additionally, adenovirus-mediated overexpression of KDM7A in mice resulted in hepatic steatosis, which was accompanied by increased expression of hepatic DGAT2. Furthermore, KDM7A overexpression decreased the enrichment of di-methylation of histone H3 lysine 9 (H3K9me2) and H3 lysine 27 (H3K27me2) on the promoter of DGAT2. Taken together, these results indicate that KDM7A overexpression induces hepatic steatosis through upregulation of DGAT2 by erasing H3K9me2 and H3K27me2 on the promoter.

scholarly journals LSD1, a double-edged sword, confers dynamic chromatin regulation but commonly promotes aberrant cell growth

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2016 ◽  
Author(s):  
Meghan M Kozub ◽  
Ryan M Carr ◽  
Gwen L Lomberk ◽  
Martin E Fernandez-Zapico
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Cellular Differentiation ◽  
Critical Role ◽  
Histone Demethylase ◽  
Epigenetic Changes ◽  
Lysine Specific Demethylase ◽  
Wide Range ◽  
Histone Modifying Enzymes

Histone-modifying enzymes play a critical role in chromatin remodeling and are essential for influencing several genome processes such as gene expression and DNA repair, replication, and recombination. The discovery of lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, dramatically revolutionized research in the field of epigenetics. LSD1 plays a pivotal role in a wide range of biological operations, including development, cellular differentiation, embryonic pluripotency, and disease (for example, cancer). This mini-review focuses on the role of LSD1 in chromatin regulatory complexes, its involvement in epigenetic changes throughout development, and its importance in physiological and pathological processes.

scholarly journals LSD1 prevents aberrant heterochromatin formation in Neurospora crassa

2020 ◽  
Vol 48 (18) ◽  
pp. 10199-10210
Author(s):  
William K Storck ◽  
Vincent T Bicocca ◽  
Michael R Rountree ◽  
Shinji Honda ◽  
Tereza Ormsby ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Neurospora Crassa ◽  
Constitutive Heterochromatin ◽  
Histone H3 ◽  
Feedback Mechanism ◽  
Histone Demethylase ◽  
Histone Deacetylation ◽  
Heterochromatin Formation ◽  
Lysine Specific Demethylase ◽  
Specialized Form

Abstract Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. We explored whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1. Strains deficient for any of these proteins exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains throughout the genome. Although establishment of H3K9me3 is typically independent of DNA methylation in Neurospora, instances of DNA methylation-dependent H3K9me3 have been found outside regions of canonical heterochromatin. Consistent with this, the hyper-H3K9me3 phenotype of Δlsd1 strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting that spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.

scholarly journals Reduced Histone H3 Lysine 9 Methylation Contributes to the Pathogenesis of Latent Autoimmune Diabetes in Adults via Regulation of SUV39H2 and KDM4C

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Xi-yu Liu ◽  
Hong Li
Keyword(s):  
Autoimmune Disease ◽  
T Lymphocytes ◽  
Histone Methylation ◽  
Autoimmune Diabetes ◽  
Glycosylated Hemoglobin ◽  
Methylation Status ◽  
Histone H3 ◽  
Histone Demethylase ◽  
Healthy Controls ◽  
Latent Autoimmune Diabetes

Aims. Latent autoimmune diabetes in adults (LADA) is an autoimmune disease of which the mechanism is not clear. Emerging evidence suggests that histone methylation contributes to autoimmunity.Methods. Blood CD4+T lymphocytes from 26 LADA patients and 26 healthy controls were isolated to detect histone H3 lysine 4 and H3 lysine 9 methylation status.Results. Reduced global H3 lysine 9 methylation was observed in LADA patients’ CD4+T lymphocytes, compared to healthy controls (P< 0.05). H3 lysine 4 methylation was not statistically different. The reduced H3 lysine 9 methylation was associated with GADA titer but not correlated with glycosylated hemoglobin (HbA1c). When the LADA patient group was divided into those with complication and those without, relatively reduced global H3 lysine 9 methylation was observed in LADA patients with complication (P< 0.05). The expression of histone methyltransferase SUV39H2 for H3 lysine 9 methylation was downregulated in LADA patients, and the expression of histone demethylase KDM4C which made H3 lysine 9 demethylation was upregulated.Conclusion. The reduction of histone H3 lysine 9 methylation which may due to the downregulation of methyltransferase SUV39H2 and the upregulation of demethylase KDM4C was found in CD4+T lymphocytes of LADA patients.

scholarly journals ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yan Gu ◽  
Yanrong Chen ◽  
Lai Wei ◽  
Shuang Wu ◽  
Kaicheng Shen ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Nuclear Translocation ◽  
Histone H3 ◽  
Suppressor Gene ◽  
Chromatin Accessibility ◽  
Tumour Suppressor Gene ◽  
Colon Cancer Cell ◽  
Cancer Stemness ◽  
The Core

AbstractCancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.

scholarly journals Epigenetic inheritance of centromere identity in a heterologous system

2019 ◽  
Author(s):  
Virginie Roure ◽  
Bethan Medina-Pritchard ◽  
Eduard Anselm ◽  
A. Arockia Jeyaprakash ◽  
Patrick Heun
Keyword(s):  
Chromosome Segregation ◽  
Chromosomal Region ◽  
Histone H3 ◽  
Epigenetic Inheritance ◽  
Centromeric Chromatin ◽  
Centromere Proteins ◽  
Heterologous System ◽  
Histone H3 Variant ◽  
Self Association

SUMMARYThe centromere is an essential chromosomal region required for accurate chromosome segregation. Most eukaryotic centromeres are defined epigenetically by the histone H3 variant, CENP-A, yet how its self-propagation is achieved remains poorly understood. Here we developed a heterologous system to reconstitute epigenetic inheritance of centromeric chromatin by ectopically targeting the Drosophila centromere proteins dCENP-A, dCENP-C and CAL1 to LacO arrays in human cells. Dissecting the function of these three components uncovers the key role of self-association of dCENP-C and CAL1 for their mutual interaction and dCENP-A deposition. Importantly, we identify the components required for dCENP-C loading onto chromatin, involving a cooperation between CAL1 and dCENP-A nucleosomes, thus closing the epigenetic loop to ensure dCENP-C and dCENP-A replenishment during the cell division cycle. Finally, we show that all three Drosophila factors are sufficient for dCENP-A propagation and propose a model for the epigenetic inheritance of centromere identity.

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

2007 ◽  
Vol 27 (11) ◽  
pp. 3951-3961 ◽  
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.

scholarly journals Expanding the Role of the Histone Lysine-Specific Demethylase LSD1 in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 324 ◽  
Author(s):  
Barbara Majello ◽  
Francesca Gorini ◽  
Carmen Saccà ◽  
Stefano Amente
Keyword(s):  
Histone Methylation ◽  
Noncoding Rna ◽  
Dependent Manner ◽  
Biological Processes ◽  
Histone Proteins ◽  
Histone Methyltransferases ◽  
Histone Lysine ◽  
Lysine Specific Demethylase ◽  
Novel Targets

Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes. LSD1 is highly expressed in various cancers, playing a pivotal role in different cancer-related processes. Here, we summarized recent findings on the role of LSD1 in the regulation of different biological processes in cancer cells through dynamic methylation of non-histone proteins and physical association with dedicated lncRNA.

scholarly journals Arabidopsis MZT1 homologs GIP1 and GIP2 are essential for centromere architecture

2015 ◽  
Vol 112 (28) ◽  
pp. 8656-8660 ◽  
Author(s):  
Morgane Batzenschlager ◽  
Inna Lermontova ◽  
Veit Schubert ◽  
Jörg Fuchs ◽  
Alexandre Berr ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Histone H3 ◽  
Genome Integrity ◽  
Interacting Proteins ◽  
Central Function ◽  
Chromatid Cohesion ◽  
Histone H3 Variant ◽  
Complex Protein ◽  
Cohesin Subunit

Centromeres play a pivotal role in maintaining genome integrity by facilitating the recruitment of kinetochore and sister-chromatid cohesion proteins, both required for correct chromosome segregation. Centromeres are epigenetically specified by the presence of the histone H3 variant (CENH3). In this study, we investigate the role of the highly conserved γ-tubulin complex protein 3-interacting proteins (GIPs) in Arabidopsis centromere regulation. We show that GIPs form a complex with CENH3 in cycling cells. GIP depletion in the gip1gip2 knockdown mutant leads to a decreased CENH3 level at centromeres, despite a higher level of Mis18BP1/KNL2 present at both centromeric and ectopic sites. We thus postulate that GIPs are required to ensure CENH3 deposition and/or maintenance at centromeres. In addition, the recruitment at the centromere of other proteins such as the CENP-C kinetochore component and the cohesin subunit SMC3 is impaired in gip1gip2. These defects in centromere architecture result in aneuploidy due to severely altered centromeric cohesion. Altogether, we ascribe a central function to GIPs for the proper recruitment and/or stabilization of centromeric proteins essential in the specification of the centromere identity, as well as for centromeric cohesion in somatic cells.

Sign in / Sign up

Export Citation Format

Share Document