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Background: SET domain-containing histone lysine methyltransferases (HKMTs) and JmjC domain-containing histone demethylases (JHDMs) are essential for maintaining dynamic changes in histone methylation across parasite development and infection. However, information on the HKMTs and JHDMs in human pathogenic piroplasms, such as Babesia duncani and Babesia microti, and in veterinary important pathogens, including Babesia bigemina, Babesia bovis, Theileria annulata and Theileria parva, is limited. Results: A total of 38 putative KMTs and eight JHDMs were identified using a comparative genomics approach. Phylogenetic analysis revealed that the putative KMTs can be divided into eight subgroups, while the JHDMs belong to the JARID subfamily, except for BdJmjC1 (BdWA1_000016) and TpJmjC1 (Tp Muguga_02g00471) which cluster with JmjC domain only subfamily members. The motifs of SET and JmjC domains are highly conserved among piroplasm species. Interspecies collinearity analysis provided insight into the evolutionary duplication events of some SET domain and JmjC domain gene families. Moreover, relative gene expression analysis by RT‒qPCR demonstrated that the putative KMT and JHDM gene families were differentially expressed in different intraerythrocytic developmental stages of B. duncani, suggesting their role in Apicomplexa parasite development. Conclusions: Our study provides a theoretical foundation and guidance for understanding the basic characteristics of several important piroplasm KMT and JHDM families and their biological roles in parasite differentiation. [ABSTRACT FROM AUTHOR]

Abstract Background SET domain-containing histone lysine methyltransferases (HKMTs) and JmjC domain-containing histone demethylases (JHDMs) are essential for maintaining dynamic changes in histone methylation across parasite development and infection. However, information on the HKMTs and JHDMs in human pathogenic piroplasms, such as Babesia duncani and Babesia microti, and in veterinary important pathogens, including Babesia bigemina, Babesia bovis, Theileria annulata and Theileria parva, is limited. Results A total of 38 putative KMTs and eight JHDMs were identified using a comparative genomics approach. Phylogenetic analysis revealed that the putative KMTs can be divided into eight subgroups, while the JHDMs belong to the JARID subfamily, except for BdJmjC1 (BdWA1_000016) and TpJmjC1 (Tp Muguga_02g00471) which cluster with JmjC domain only subfamily members. The motifs of SET and JmjC domains are highly conserved among piroplasm species. Interspecies collinearity analysis provided insight into the evolutionary duplication events of some SET domain and JmjC domain gene families. Moreover, relative gene expression analysis by RT‒qPCR demonstrated that the putative KMT and JHDM gene families were differentially expressed in different intraerythrocytic developmental stages of B. duncani, suggesting their role in Apicomplexa parasite development. Conclusions Our study provides a theoretical foundation and guidance for understanding the basic characteristics of several important piroplasm KMT and JHDM families and their biological roles in parasite differentiation.

Lysine-specific demethylase 4 A (KDM4A, also named JMJD2A, KIA0677, or JHDM3A) is a demethylase that can remove methyl groups from histones H3K9me2/3, H3K36me2/3, and H1.4K26me2/me3. Accumulating evidence suggests that KDM4A is not only involved in body homeostasis (such as cell proliferation, migration and differentiation, and tissue development) but also associated with multiple human diseases, especially cancers. Recently, an increasing number of studies have shown that pharmacological inhibition of KDM4A significantly attenuates tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. Although there are several reviews on the roles of the KDM4 subfamily in cancer development and therapy, all of them only briefly introduce the roles of KDM4A in cancer without systematically summarizing the specific mechanisms of KDM4A in various physiological and pathological processes, especially in tumorigenesis, which greatly limits advances in the understanding of the roles of KDM4A in a variety of cancers, discovering targeted selective KDM4A inhibitors, and exploring the adaptive profiles of KDM4A antagonists. Herein, we present the structure and functions of KDM4A, simply outline the functions of KDM4A in homeostasis and non-cancer diseases, summarize the role of KDM4A and its distinct target genes in the development of a variety of cancers, systematically classify KDM4A inhibitors, summarize the difficulties encountered in the research of KDM4A and the discovery of related drugs, and provide the corresponding solutions, which would contribute to understanding the recent research trends on KDM4A and advancing the progression of KDM4A as a drug target in cancer therapy.

In plant-pathogen interactions, Magnaporthe oryzae causes blast disease on more than 50 species of 14 monocot plants, including important crops such as rice, millet, and most 15 recently wheat. M. oryzae is a model fungus for studying plant-microbe interaction, and the main source for fungal pathogenesis in the field. Here we report that MoJMJD6 is required for conidium germination and appressorium formation in M. oryzae. We obtained MoJMJD6 mutants (ΔMojmjd6) using a target gene replacement strategy. The MoJMD6 deletion mutants were delayed for conidium germination, glycogen, and lipid droplets utilization and consequently had decreased virulence. In the ΔMojmjd6 null mutants, global histone methyltransferase modifications (H3K4me3, H3K9me3, H3K27me3, and H3K36me2/3) of the genome were unaffected. Taken together, our results indicated that MoJMJD6 function as a nuclear protein which plays an important role in conidium germination and appressorium formation in the M. oryzae. Our work provides insights into MoJMJD6-mediated regulation in the early stage of pathogenesis in plant fungi.

Magnaporthe oryzae (M. oryzae) is a devastating pathogenic fungal disease that has a serious threat to the global rice security. Recently, an in‐depth study of the pathogenic mechanism and developmental process of M. oryzae became a primary model in the study of host–fungal pathogen interactions. Here, we have identified a gene MoJMJD3 (MGG_02032, accession XM_003708733) encoding the JumonjiC (JmjC) domain through bioinformatics analysis in M. oryzae. The ΔMojmjd3 deletion mutants showed defects in early appressorium formation and fungal virulence during pathogenesis. At 4 h after inoculation, the early appressorium formation of ΔMojmjd3 was decreased when compared with that of the wild‐type P131. Analysis of intracellular localization of MoJMJD3 with RFP fluorescence observation showed that MoJMJD3 was mainly localized in the cytoplasm of the conidia, appressoria, hyphae, and infective hyphae. Furthermore, by spray inoculation analysis, the ΔMojmjd3deletion mutants reduced virulence on the leaves of rice. These data suggest that MoJMJD3 plays important roles in fungal virulence during pathogenesis in M. oryzae. [ABSTRACT FROM AUTHOR]

JMJD8 is a protein from the JMJD family that only has the JmjC domain. Studies on the function of JMJD8 indicate that JMJD8 is involved in signaling pathways, including AKT/NF-κB, and thus affects cell proliferation and development. Here, we reported the activity of JMJD8 as a non-histone demethylase. We investigated the demethylation of JMJD8 on trimethylated lysine of AKT1 in vivo and in vitro using trimethylated AKT1 short peptide and AKT1 protein, and we tracked the regulation of JMJD8 on AKT1 activity at the cellular level. The results showed that JMJD8, a mini lysine demethylase, altered AKT1 protein function via changing its degree of methylation. [ABSTRACT FROM AUTHOR]

JMJD8 is a protein from the JMJD family that only has the JmjC domain. Studies on the function of JMJD8 indicate that JMJD8 is involved in signaling pathways, including AKT/NF-κB, and thus affects cell proliferation and development. Here, we reported the activity of JMJD8 as a non-histone demethylase. We investigated the demethylation of JMJD8 on trimethylated lysine of AKT1 in vivo and in vitro using trimethylated AKT1 short peptide and AKT1 protein, and we tracked the regulation of JMJD8 on AKT1 activity at the cellular level. The results showed that JMJD8, a mini lysine demethylase, altered AKT1 protein function via changing its degree of methylation.

[Display omitted] • KDM4s are oncoproteins that are overexpressed in various human cancers. • Targeting KDM4s has a beneficial outcome in cancer therapy. • Small molecules and peptides can interact with the substrate-binding pocket of KDM4. • Challenges remain in developing biologically potent and selective KDM4 inhibitors. Epigenetic enzyme-targeted therapy is a promising new development in the field of drug discovery. To date, histone deacetylases and DNA methyltransferases have been investigated as druggable epigenetic enzyme targets in cancer therapeutics. Histone methyltransferases and lysine demethylase inhibitors are the latest groups of epi-drugs being actively studied in clinical trials. KDM4s are JmjC domain-containing histone H3 lysine 9/36 demethylase enzymes, belonging to the 2-OG-dependent oxygenases, which are upregulated in multiple malignancies. In the recent years, these enzymes have captured much attention as a novel target in cancer therapy. Herein, we traverse the discovery path and current challenges in designing potent KDM4 inhibitors as potential anticancer agents. We discuss the considerable efforts and proposed future strategies to develop selective small molecule inhibitors of KDM4s, highlighting scaffold candidates and cyclic skeletons for which activity data, selectivity profiles and structure–activity relationships (SARs) have been studied. [ABSTRACT FROM AUTHOR]

Abstract Background Histone methylation mainly occurs on the lysine residues and plays a crucial role during flowering and stress responses of plants, through changing the methylation status or ratio of lysine residues. Histone lysine residues of plants can arise in three forms of methylation (single, double and triple) and the corresponding demethylation can also ensue on certain occasions, by which the plants can accommodate the homeostasis of histone methylation by means of lysine methyltransferase and demethylase. The JmjC domain-containing proteins, an important family of histone lysine demethylases, play a vital role in maintaining homeostasis of histone methylation in vivo. Results In this study, we have identified 19 JmjC domain-containing histone demethylase (JHDM) proteins in maize. Based on structural characteristics and a comparison of phylogenetic relationships of JHDM gene families from Arabidopsis, rice and maize, all 19 JHDM proteins in maize were categorized into three different subfamilies. Furthermore, chromosome location and schematic structure revealed an unevenly distribution on chromosomes and structure features of ZmJMJ genes in maize, respectively. Eventually, the 19 ZmJMJ genes displayed different expression patterns at diverse developmental stages of maize based on transcriptome analysis. Further, quantitative real-time PCR analysis showed that all 19 ZmJMJ genes were responsive to heat stress treatment, suggesting their potential roles in heat stress response. Conclusions Overall, our study will serve to present an important theoretical basis for future functional verification of JHDM genes to further unravel the mechanisms of epigenetic regulation in plants.

The capacity for regeneration varies greatly among metazoans, yet little is known about the evolutionary processes leading to such different regeneration abilities. In particular, highly regenerative species such as planarians and cnidarians can regenerate the whole body from an amputated fragment; however, a common molecular basis, if any, among these species remains unclear. Here, we show that genes encoding Jumonji C (JmjC) domain-containing proteins are associated with high regeneration ability. We classified 132 fully sequenced metazoans into two groups with high or low regeneration abilities and identified 118 genes conserved in the high regenerative group that were lost in species in the low regeneration group during evolution. Ninety-six percent of them were JmjC domain-encoding genes. We denoted the candidate genes as high regenerative species-specific JmjC domain-encoding genes (HRJD s). We observed losses of HRJDs in Helobdella robusta, which lost its high regeneration ability during evolution based on phylogenetic analysis. By RNA sequencing analyses, we observed that HRJD orthologs were differentially expressed during regeneration in two Cnidarians, as well as Platyhelminthes and Urochordata, which are highly regenerative species. Furthermore, >50% of the head and tail parts of amputated planarians (Dugesia japonica) died during regeneration after RNA interference of HRJD orthologs. These results indicate that HRJD are strongly associated with a high regeneration ability in metazoans. HRJD paralogs regulate gene expression by histone demethylation; thus, HRJD may be related to epigenetic regulation controlling stem cell renewal and stem cell differentiation during regeneration. We propose that HRJD play a central role in epigenetic regulation during regeneration. [ABSTRACT FROM AUTHOR]

The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation.

Lysyl hydroxylation and arginyl demethylation are post-translational events that are important for many cellular processes. The jumonji domain containing protein 6 (JMJD6) has been reported to catalyze both lysyl hydroxylation and arginyl demethylation on diverse protein substrates. It also interacts directly with RNA. This review summarizes knowledge of JMJD6 functions that have emerged in the last 15 years and considers how a single Jumonji C (JmjC) domain-containing enzyme can target so many different substrates. New links and synergies between the three main proposed functions of Jmjd6 in histone demethylation, promoter proximal pause release of polymerase II and RNA splicing are discussed. The physiological context of the described molecular functions is considered and recently described novel roles for JMJD6 in cancer and immune biology are reviewed. The increased knowledge of JMJD6 functions has wider implications for our general understanding of the JmjC protein family of which JMJD6 is a member. [ABSTRACT FROM AUTHOR]

[Display omitted] Histone demethylation is a key post-translational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Lysine specific demethylase 6A (KDM6A, also known as UTX) is an Fe2+- and α-ketoglutarate- dependent oxidase which belongs to KDM6 Jumonji histone demethylase subfamily, and it can remove mono-, di- and tri-methyl groups from methylated lysine 27 of histone H3 (H3K27me1/2/3). Mounting studies indicate that KDM6A is responsible for driving multiple human diseases, particularly cancers and pharmacological inhibition of KDM6A is an effective strategy to treat varieties of KDM6A-amplified cancers in cellulo and in vivo. Although there are several reviews on the roles of KDM6 subfamily in cancer development and therapy, all of them only simply introduce the roles of KDM6A in cancer without systematically summarizing the specific mechanisms of KDM6A in tumorigenesis, which greatly limits the advances on the understanding of roles KDM6A in varieties of cancers, discovering targeting selective KDM6A inhibitors, and exploring the adaptive profiles of KDM6A antagonists. Herein, we present the structure and functions of KDM6A, simply outline the functions of KDM6A in homeostasis and non-cancer diseases, summarize the role of KDM6A and its distinct target genes/ligand proteins in development of varieties of cancers, systematically classify KDM6A inhibitors, sum up the difficulties encountered in the research of KDM6A and the discovery of related drugs, and provide the corresponding solutions, which will contribute to understanding the roles of KDM6A in carcinogenesis and advancing the progression of KDM6A as a drug target in cancer therapy. [ABSTRACT FROM AUTHOR]

In plant-pathogen interactions, Magnaporthe oryzae causes blast disease on more than 50 species of 14 monocot plants, including important crops such as rice, millet, and most 15 recently wheat. M. oryzae is a model fungus for studying plant-microbe interaction, and the main source for fungal pathogenesis in the field. Here we report that MoJMJD6 is required for conidium germination and appressorium formation in M. oryzae. We obtained MoJMJD6 mutants (ΔMojmjd6) using a target gene replacement strategy. The MoJMD6 deletion mutants were delayed for conidium germination, glycogen, and lipid droplets utilization and consequently had decreased virulence. In the ΔMojmjd6 null mutants, global histone methyltransferase modifications (H3K4me3, H3K9me3, H3K27me3, and H3K36me2/3) of the genome were unaffected. Taken together, our results indicated that MoJMJD6 function as a nuclear protein which plays an important role in conidium germination and appressorium formation in the M. oryzae. Our work provides insights into MoJMJD6-mediated regulation in the early stage of pathogenesis in plant fungi.

Lysine-specific demethylase 4 A (KDM4A, also named JMJD2A, KIA0677, or JHDM3A) is a demethylase that can remove methyl groups from histones H3K9me2/3, H3K36me2/3, and H1.4K26me2/me3. Accumulating evidence suggests that KDM4A is not only involved in body homeostasis (such as cell proliferation, migration and differentiation, and tissue development) but also associated with multiple human diseases, especially cancers. Recently, an increasing number of studies have shown that pharmacological inhibition of KDM4A significantly attenuates tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. Although there are several reviews on the roles of the KDM4 subfamily in cancer development and therapy, all of them only briefly introduce the roles of KDM4A in cancer without systematically summarizing the specific mechanisms of KDM4A in various physiological and pathological processes, especially in tumorigenesis, which greatly limits advances in the understanding of the roles of KDM4A in a variety of cancers, discovering targeted selective KDM4A inhibitors, and exploring the adaptive profiles of KDM4A antagonists. Herein, we present the structure and functions of KDM4A, simply outline the functions of KDM4A in homeostasis and non-cancer diseases, summarize the role of KDM4A and its distinct target genes in the development of a variety of cancers, systematically classify KDM4A inhibitors, summarize the difficulties encountered in the research of KDM4A and the discovery of related drugs, and provide the corresponding solutions, which would contribute to understanding the recent research trends on KDM4A and advancing the progression of KDM4A as a drug target in cancer therapy., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Histone modification regulates plant development events by epigenetically silencing or activating gene expression, and histone methylation is regulated by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The JmjC domain proteins, an important KDM family, erase methyl marks (CH3-) from histones and play key roles in maintaining homeostasis of histone methylation in vivo. Here, we analyzed 169 JmjC domain proteins from whole genomes of plants ranging from green alga to higher plants together with 36 from two animals (fruit fly and human). The plant JmjC domain proteins were divided into seven groups. Group-I KDM4/JHDM3 and Group-V JMJD6 were found in all the plant species and the other groups were detected mainly in vascular or seed plants. Group-I KDM4/JHDM3 was potentially associated with demethylation of H3K9me2/3, H3K27me2/3, and H3K36me1/2/3, Group-II KDM5A with H3K4me1/2/3, Group-III KDM5B with H3K4me1/2/3 and H3K9me1/2/3, Group-V JMJD6 with H3R2, H4R3, and hydroxylation of H4, and Group-VII KDM3/JHDM2 with H3K9me1/2/3. Group-IV/Group-VI JmjC domain-only A/B proteins were involved in hydroxylation and demethylation of unknown substrate sites. The binding sites for the cofactors Fe(II) and α-ketoglutarate in the JmjC domains also were analyzed. In the α-ketoglutarate binding sites, Thr/Phe/Ser and Lys were conserved and in the Fe(II) binding sites, two His and Glu/Asp were conserved. The results show that JmjC domain proteins are a conserved family in which domain organization and cofactor binding sites have been modified in some species. Our results provide insights into KDM evolution and lay a foundation for functional characterization of KDMs. [ABSTRACT FROM AUTHOR]

JMJD8 is a protein from the JMJD family that only has the JmjC domain. Studies on the function of JMJD8 indicate that JMJD8 is involved in signaling pathways, including AKT/NF-κB, and thus affects cell proliferation and development. Here, we reported the activity of JMJD8 as a non-histone demethylase. We investigated the demethylation of JMJD8 on trimethylated lysine of AKT1 in vivo and in vitro using trimethylated AKT1 short peptide and AKT1 protein, and we tracked the regulation of JMJD8 on AKT1 activity at the cellular level. The results showed that JMJD8, a mini lysine demethylase, altered AKT1 protein function via changing its degree of methylation.

Abstract: Jumonji C (JmjC) lysine demethylases (KDMs) are Fe(II)-dependent hydroxylases that catalyze the oxidative demethylation of methyllysine residues in histones and nonhistone proteins. These enzymes play vital roles in regulating cellular processes such as gene expression, cell cycle progression, and stem cell self-renewal and differentiation. Despite their biological importance, recombinant forms of JmjC KDMs generally display low enzymatic activity and have remained challenging to isolate in a highly active form. Here we present a simple affinity purification scheme for Strep(II)-tagged JmjC KDMs that minimizes contamination by transition state metal ions, yielding highly active and pure enzyme. We also describe an optimized continuous fluorescent assay for KDMs that detects formaldehyde production during demethylation via a coupled reaction using formaldehyde dehydrogenase. Purification and kinetic analysis of the human KDMs JMJD2A and JMJD2D using these methods yielded activities substantially higher than those previously reported for these enzymes, which are comparable to that of the flavin-dependent KDM LSD1. In addition, we show that JMJD2A exhibited a lower catalytic efficiency toward a histone peptide bearing a chemically installed trimethyllysine analog compared with a bona fide trimethylated substrate. The methodology described here is broadly applicable to other JmjC KDMs, facilitating their biochemical characterization and high-throughput screening applications. [Copyright &y& Elsevier]

Abstract: The JmjC-domain-containing protein Hairless (HR) and the vitamin D receptor (VDR) play a critical role in the maintenance of hair growth. Mutations in HR or VDR cause alopecia in humans and mice. Here we show that HR interacts with VDR and induces VDR relocalization in the nuclei. HR associates and colocalizes with nuclear receptor co-repressor (N-CoR) which is localized to subnuclear structures termed matrix-associated deacetylase (MAD) bodies. It is found that the HR mutants (C622G, N970S, D1012N, V1136D), associated with alopecia universalis congenita (AUC) or atrichia with papular lesions (APL), exhibit an abnormal subcellular distribution in addition to the impaired co-repressor activity with VDR. Studies on deletion mutants of HR indicate that the JmjC domain contributes to the co-repressor activity of HR. Our work provides new clues and evidence for the understanding on the role of HR in hair growth. [Copyright &y& Elsevier]

Abstract: Utx is a candidate tumor suppressor gene that encodes histone H3 lysine 27 (H3K27) demethylase. In this study, we found that ectopic expression of Utx enhanced the expression of retinoblastoma tumor suppressor gene Rb and its related gene Rbl2. This activation was dependent on the demethylase activity of Utx, and was suggested to contribute to the decreased cell proliferation induced by Utx. A chromatin immunoprecipitation assay showed that over-expressed Utx was associated with the promoter regions of Rb and Rbl2 resulting in the removal of repressive H3K27 tri-methylation and the increase in active H3K4 tri-methylation. Furthermore, siRNA-mediated knockdown of Utx revealed the recruitment of endogenous Utx protein on the promoters of Rb and Rbl2 genes. These results indicate that Rb and Rbl2 are downstream target genes of Utx and may play important roles in Utx-mediated cell growth control. [ABSTRACT FROM AUTHOR]

Mental retardation (MR) is characterized by cognitive impairment with an IQ <70. Many of the major causes are genetically determined and the ∼30% male excess suggests that mutations in genes carried on the X chromosome are disproportionably represented. One such gene, jumonji AT-rich interactive domain 1C (JARID1C) on Xp11.2, has been identified in families with X-linked MR (XLMR), with 18 different mutations reported to date. As part of a systematic resequencing of 720 genes in 208 XLMR families of the International Genetic of Learning Disability (IGOLD) consortium, two novel nucleotide changes in the JARID1C coding region were identified, with the nucleotide changes segregating with the disease phenotype in the two families. The first mutation is a single-nucleotide insertion in exon 21 (c.3258_3259insC p.K1087fs*43) causing a frameshift and resulting in a premature termination codon (PTC). Such PTC-containing mRNAs are generally degraded by nonsense-mediated mRNA decay (NMD) surveillance, but our results show that this is not the case with this mutation. The other change is a single-nucleotide substitution in exon 12 (c.1160C>A) in a published family with nonsyndromic MR, MRX13. This change occurs in a highly conserved amino acid, with proline (P) being substituted by threonine (T) (p.P544T). Functional analysis shows that this amino-acid substitution compromises both tri- and didemethylase activity of the JARID1C protein. We conclude that the two novel changes impair JARID1C protein function and are disease-causing mutations in these families. [ABSTRACT FROM AUTHOR]

Abstract: SMCX/JARID1C was recently shown to be a histone H3 lysine 4 (H3K4) demethylase. Here, we have identified an SMCX isoform that predominantly resides in the cytoplasm, but still efficiently demethylates trimethylated H3K4. SMCX requires several functional domains for its demethylase activity and is also capable of forming homomers through amino acids 204–493. Further, SMCX physically interacts with Smad3, a mediator of transforming growth factor-β (TGF-β), and overexpression of SMCX inhibits the ability of Smad3 to activate transcription. Thus, SMCX is a novel Smad3 corepressor that may antagonize the tumor suppressing activity of the TGF-β/Smad3 signaling pathway and thereby contribute to tumorigenesis. Indeed, SMCX is overexpressed in prostate tumors and seminomas, suggesting that SMCX might be a novel oncogene. [Copyright &y& Elsevier]

Jumonji (Jmj) is a transcriptional repressor that plays important roles in the suppression of cell proliferation and development of various tissues in the mouse. To further clarify the roles of Jmj during development and gain insight into mechanisms of Jmj-mediated transcriptional regulation, we have taken advantage of Drosophila as a model organism. Drosophila Jmj (dJmj) shares high homology with mammalian Jmj in the JmjN, JmjC and AT-rich interaction domains, as well as in the N-terminal repression domain. dJmj localizes to hundreds of euchromatic sites but not to chromocenter heterochromatin on salivary gland polytene chromosomes. In addition, dJmj is excluded from regions stained with an antibody against Ser5-phosphorylated RNA polymerase II, suggesting a function of dJmj in transcriptionally inactive chromatin. Loss of djmj results in larval and pupal lethality with phenotypes similar to those observed in mutants of ecdysone-regulated genes, implying the involvement of dJmj in the repression of gene expression in the ecdysone pathway. Transgenic mouse Jmj mostly colocalizes with dJmj and partially rescues the phenotypes of djmj mutants, indicating that dJmj is a functional homolog of mammalian Jmj. Furthermore, mutation in djmj suppresses position effect variegation of the T(2;3)Sb V rearrangement. These findings suggest that dJmj controls expression of developmentally important genes through modification of chromatin into a transcriptionally silenced state. [ABSTRACT FROM AUTHOR]

Heterochromatin normally has prescribed chromosomal positions and must not encroach on adjacent regions. We demonstrate that the fission yeast protein Epe1 stabilises silent chromatin, preventing the oscillation of heterochromatin domains. Epe1 loss leads to two contrasting phenotypes: alleviation of silencing within heterochromatin and expansion of silent chromatin into neighbouring euchromatin. Thus, we propose that Epe1 regulates heterochromatin assembly and disassembly, thereby affecting heterochromatin integrity, centromere function and chromosome segregation fidelity. Epe1 regulates the extent of heterochromatin domains at the level of chromatin, not via the RNAi pathway. Analysis of an ectopically silenced site suggests that heterochromatin oscillation occurs in the absence of heterochromatin boundaries. Epe1 requires predicted iron- and 2-oxyglutarate (2-OG)-binding residues for in vivo function, indicating that it is probably a 2-OG/Fe(II)-dependent dioxygenase. We suggest that, rather than being a histone demethylase, Epe1 may be a protein hydroxylase that affects the stability of a heterochromatin protein, or protein–protein interaction, to regulate the extent of heterochromatin domains. Thus, Epe1 ensures that heterochromatin is restricted to the domains to which it is targeted by RNAi. [ABSTRACT FROM AUTHOR]

Abstract: The androgen receptor (AR) is a transcription factor that is pivotal for the development of prostate cancer. Here, we have identified two related histone demethylases, JMJD2A and JMJD2D, which form complexes with ligand-bound AR. We found that AR interacts through its ligand binding domain with JMJD2A and JMJD2D. On the other hand, JMJD2A utilizes its catalytic domain or C-terminus to bind to AR, and JMJD2D does so via its C-terminus. Further, overexpression of JMJD2A or D stimulates AR function and this is dependent on JMJD2 catalytic activity. Conversely, downregulation of JMJD2A, which is often overexpressed in prostate tumors, reduces basal transcription of the AR target gene, prostate-specific antigen, in LNCaP prostate cancer cells. Altogether, our data have identified a novel class of AR coactivators, whose (over)expression in prostate tumors could contribute to the constitutive activation of AR and thus to androgen-depletion independency of advanced prostate cancer cells. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: JMJD2A–D belong to the JmjC domain-containing family of histone demethylases. JMJD2D is the most structurally divergent JMJD2 protein as it lacks the PHD and Tudor domains present in JMJD2A–C. Here, we systematically analyzed the histone demethylase specificity of JMJD2 proteins in vivo. We found that JMJD2A and C demethylate tri- and dimethylated H3K9 and H3K36, whereas JMJD2D demethylates tri-, di-, and monomethylated H3K9. Enzymatic activity requires the N-terminal JmjN domain. It also contributes to efficient nuclear localization together with the PHD and Tudor domains of JMJD2A and C. Furthermore, JMJD2 proteins form homomers, and JMJD2A and C, but not JMJD2D, can also heteromerize. Finally, we show that JMJD2 proteins promoter-specifically repress or activate gene transcription. Altogether, our results reveal novel properties of and functional differences between JMJD2 proteins that may therefore have different effects on chromatin structure. [Copyright &y& Elsevier]

Abstract: Histone lysine methylation plays a fundamental role in chromatin organization and function. This epigenetic mark is involved in many biological processes such as heterochromatin formation, chromosome X inactivation, genomic imprinting and transcriptional regulation. Here, we review recent advances in how histone lysine methylation participates in these biological events, and the enzymes that control histone lysine methylation and demethylation. [Copyright &y& Elsevier]

The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation. [ABSTRACT FROM AUTHOR]

Alcohol addiction is a serious condition perpetuated by enduring physiological and behavioral adaptations. An important component of these adaptations is the long-term rearrangement of neuronal gene expression in the brain of the addicted individual. Epigenetic histone modifications have recently surfaced as important modulators of the transcriptional adaptation to alcohol as these are thought to represent a form of transcriptional memory that is directly imprinted on the chromosome. Some histone modifications affect transcription by modulating the accessibility of the underlying DNA, whereas others have been proposed to serve as marks read by transcription factors as a "histone code" that helps to specify the expression level of a gene. Although the effects of some epigenetic modifications on the transcriptional activity of genes are well known, the mechanisms by which alcohol consumption produces this rearrangement and leads to lasting changes in behavior remain unresolved. Recent advances using the Drosophila model system have started to unravel the epigenetic modulators underlying functional alcohol neuroadaptations. In this review, we discuss the role of 3 different histone modification systems in Drosophila, which have a direct impact on key alcohol neuroadaptations associated with the addictive process. These systems involve the histone deacetylase Sirt1, the histone acetyltransferase CREB-binding protein (CBP), and a subset of the Drosophila JmjC-Domain histone demethylase family. [ABSTRACT FROM AUTHOR]

The mammalian hairless protein (HR) is a 130 kDa nuclear transcription factor that is essential for proper skin and hair follicle function. Previous studies have focused on the role of HR in skin maintenance and hair cycling. However, the hairless gene (HR) is also expressed in brain and other tissues, where its role remains poorly understood. HR has been reported to contain functional domains that potentially serve in DNA binding, histone demethylation, nuclear translocation and protein-protein interactions. Indeed, HR has been shown to interact with and repress the action of the nuclear receptors for vitamin D and thyroid hormone as well as RAR-related orphan receptor alpha, possibly via recruitment of histone deacetylases. HR may also have important functions in non-skin tissues given that nearly 200 HR mutations have been identified in patients with various cancers, including prostate, breast, lung, melanoma, uterine, and glioma. This suggests that HR and/or mutants thereof have relevance to the growth and survival of cancer cells. For example, the reported intrinsic histone H3K9 demethylase activity of HR may activate dormant genes to contribute to carcinogenesis. Alternatively, the demonstrated ability of HR to interact with p53 and/or the p53 DNA response element to influence p53-regulated pathways may explain, at least in part, why many cancers express mutated HR proteins. In this review, we summarize the current knowledge of HR bioactions, how HR mutations may be contributing to alopecia as well as to cancer, and, finally, outline future directions in the study of this largely enigmatic nuclear protein. J. Cell. Biochem. 119: 69-80, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Epigenetic regulation of chromatin structure is a fundamental process for eukaryotes. Regulators include DNA methylation, microRNAs and chromatin modifications. Within the chromatin modifiers, one class of enzymes that can functionally bind and modify chromatin, through the removal of methyl marks, is the histone lysine demethylases. Here, we summarize the current findings of the 13 known histone lysine demethylases in Drosophila melanogaster, and discuss the critical role of these histone-modifying enzymes in the maintenance of genomic functions. Additionally, as histone demethylase dysregulation has been identified in cancer, we discuss the advantages for using Drosophila as a model system to study tumorigenesis.

KDM4 histone demethylases catalyze the removal of methyl marks from histone lysine residues to epigenetically regulate chromatin structure and gene expression. KDM4 expression is tightly regulated to insure proper function in diverse biological processes, such as cellular differentiation. Mounting evidence has shown that disrupting KDM4 expression is implicated in the establishment and progression of multiple diseases including cancer. In particular, genomic regions encoding the KDM4A, B and C genes are often amplified, disrupting normal cellular proliferation. Furthermore, KDM4 demethylases are promising druggable targets. In this review, we highlight the latest advances in characterizing the structures and regulatory mechanisms of KDM4 proteins, as well as our current understanding of their alterations and roles in tumorigenesis. We also review the reported KDM4 inhibitors and discuss their potential as therapeutic agents.