The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A+/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.

Genome assembly of redclaw crayfish (Cherax quadricarinatus) provides insights into its immune adaptation and hypoxia tolerance.

BACKGROUND: The introduction of non-native species is a primary driver of biodiversity loss in freshwater ecosystems. The redclaw crayfish (Cherax quadricarinatus) is a freshwater species that exhibits tolerance to hypoxic stresses, fluctuating temperatures, high ammonia concentration. These hardy physiological characteristics make C. quadricarinatus a popular aquaculture species and a potential invasive species that can negatively impact tropical and subtropical ecosystems. Investigating the genomic basis of environmental tolerances and immune adaptation in C. quadricarinatus will facilitate the development of management strategies of this potential invasive species. RESULTS: We constructed a chromosome-level genome of C. quadricarinatus by integrating Nanopore and PacBio techniques. Comparative genomic analysis suggested that transposable elements and tandem repeats drove genome size evolution in decapod crustaceans. The expansion of nine immune-related gene families contributed to the disease resistance of C. quadricarinatus. Three hypoxia-related genes (KDM3A, KDM5A, HMOX2) were identified as being subjected to positive selection in C. quadricarinatus. Additionally, in vivo analysis revealed that upregulating KDM5A was crucial for hypoxic response in C. quadricarinatus. Knockdown of KDM5A impaired hypoxia tolerance in this species. CONCLUSIONS: Our results provide the genomic basis for hypoxic tolerance and immune adaptation in C. quadricarinatus, facilitating the management of this potential invasive species. Additionally, in vivo analysis in C. quadricarinatus suggests that the role of KDM5A in the hypoxic response of animals is complex.

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?).

The lysine demethylase KDM5A collaborates with PARP1 and the histone variant macroH2A1.2 to modulate chromatin to promote DNA repair. Indeed, KDM5A engages poly(ADP-ribose) (PAR) chains at damage sites through a previously uncharacterized coiled-coil domain, a novel binding mode for PAR interactions. While KDM5A is a well-known transcriptional regulator, its function in DNA repair is only now emerging. Here we review the molecular mechanisms that regulate this PARP1-macroH2A1.2-KDM5A axis in DNA damage and consider the potential involvement of this pathway in transcription regulation and cancer. Using KDM5A as an example, we discuss how multifunctional chromatin proteins transition between several DNA-based processes, which must be coordinated to protect the integrity of the genome and epigenome. The dysregulation of chromatin and loss of genome integrity that is prevalent in human diseases including cancer may be related and could provide opportunities to target multitasking proteins with these pathways as therapeutic strategies.

Epigenetic regulation by KDM5A mediates the effects of prenatal PM2.5 exposure on hippocampal development and synaptic integrity through the Shh signaling pathway.

Prenatal environmental exposure could be an essential health risk factor associated with neurodevelopmental disorders in offspring. However, the exact mechanisms underlying the impact of prenatal PM2.5 exposure on offspring cognition remain unclear. In our recent study using a PM2.5 exposed pregnant mouse model, we observed significant synaptic dysfunction in the hippocampi of the offspring. Concurrently, the epigenetic regulator of KDM5A and the Shh signaling pathway exhibited decreased activities. Significantly, changes in hippocampal KDM5A and Shh levels directly correlated with PM2.5 exposure intensity. Subsequent experiments revealed a marked reduction in the expression of Shh signaling and related synaptic proteins when KDM5A was silenced in cells. Notably, the effects of KDM5A deficiency were reversed significantly with the supplementation of a Shh activator. Furthermore, our findings indicate that Shh activation significantly attenuates PM2.5-induced synaptic impairments in hippocampal neurons. We further demonstrated that EGR1, a transcriptional inhibitor, plays a direct role in KDM5A's regulation of the Shh pathway under conditions of PM2.5 exposure. Our results suggest that the KDM5A's inhibitory regulation on the Shh pathway through the EGR1 gene is a crucial epigenetic mechanism underlying the synaptic dysfunction in hippocampal neurons caused by maternal PM2.5 exposure. This emphasizes the role of epigenetic regulations in neurodevelopmental disorders caused by environmental factors.

FOXP2 suppresses the proliferation, invasion, and aerobic glycolysis of hepatocellular carcinoma cells by regulating the KDM5A/FBP1 axis.

The Warburg effect is the preference of cancer cells to use glycolysis rather than oxidative phosphorylation to generate energy. Accumulating evidence suggests that aerobic glycolysis is widespread in hepatocellular carcinoma (HCC) and closely related to tumorigenesis. The purpose of this study was to investigate the role and mechanism of forkhead box P2 (FOXP2) in aerobic glycolysis and tumorigenesis in HCC. Here, we found that FOXP2 was lower expressed in HCC tissues and cells than in nontumor tissues and normal hepatocytes. Overexpression of FOXP2 suppressed cell proliferation and invasion of HCC cells and promoted cell apoptosis in vitro, and hindered the growth of mouse xenograft tumors in vivo. Further researches showed that FOXP2 inhibited the Warburg effect in HCC cells. Moreover, we demonstrated that FOXP2 up-regulated the expression of fructose-1, 6-diphosphatase (FBP1), and the inhibitory effect of FOXP2 on glycolysis was dependent on FBP1. Mechanistically, as a transcription factor, FOXP2 negatively regulated the transcription of lysine-specific demethylase 5A (KDM5A), and then blocked KDM5A-induced H3K4me3 demethylation in FBP1 promoter region, thereby promoting the expression of FBP1. Consistently, overexpressing KDM5A or silencing FBP1 effectively reversed the inhibitory effect of FOXP2 on HCC progression. Together, our findings revealed the mechanistic role of the FOXP2/KDM5A/FBP1 axis in glycolysis and malignant progression of HCC cells, providing a potential molecular target for the therapy of HCC.

Expression and clinical significance of KDM5A, KDM5B, and FOXO1 in endometrial cancer.

There is growing evidence that the KDM5 family of histone demethylases plays a causal role in human cancer. However, few studies have been reported on the KDM5 family in endometrial carcinoma (EC). Moreover, it was found that there was some correlation between the KDM5 family and FOXO1 in EC. The current study was performed to explore the expressions of KDM5A, KDM5B, and FOXO1 in endometrioid adenocarcinoma detected by immunohistochemistry; paracancer endometrium, simple hyperplastic endometrium, and normal endometrium were used as control groups to explore the possible diagnostic value of KDM5A and KDM5B expression in endometrioid adenocarcinoma, with the aim of evaluating the potential of this marker in predicting the prognosis of endometrioid adenocarcinoma.

Fbxo22 inhibits metastasis in triple-negative breast cancer through ubiquitin modification of KDM5A and regulation of H3K4me3 demethylation.

The importance of Fbxo22 in carcinogenesis has been highly documented. Here, we discussed downstream regulatory factors of Fbxo22 in TNBC. RNA-sequencing was conducted for identifying differentially expressed genes, followed by construction of a regulatory network. Expression patterns of Fbxo22/KDM5A in TNBC were determined by their correlation with the prognosis analyzed. Then, regulation mechanisms between Fbxo22 and KDM5A as well as between KDM5A and H3K4me3 were assayed. After silencing and overexpression experiments, the significance of Fbxo22 in repressing tumorigenesis in vitro and in vivo was explored. Fbxo22 was poorly expressed, while KDM5A was highly expressed in TNBC. Patients with elevated Fbxo22, decreased KDM5A, or higher p16 had long overall survival. Fbxo22 reduced the levels of KDM5A by ubiquitination. KDM5A promoted histone H3K4me3 demethylation to downregulate p16 expression. Fbxo22 reduced KDM5A expression to enhance p16, thus inducing DNA damage as well as reducing tumorigenesis and metastasis in TNBC. Our study validated FBXO22 as a tumor suppressor in TNBC through ubiquitination of KDM5A and regulation of p16.

Inhibition of KDM5A attenuates cisplatin-induced hearing loss via regulation of the MAPK/AKT pathway.

The study aimed to investigate the potential role of lysine-specific demethylase 5A (KDM5A) in cisplatin-induced ototoxicity. The effect of the KDM5A inhibitor CPI-455 was assessed by apoptosis assay, immunofluorescence, flow cytometry, seahorse respirometry assay, and auditory brainstem response test. RNA sequencing, qRT-PCR, and CUT&Tag assays were used to explore the mechanism underlying CPI-455-induced protection. Our results demonstrated that the expression of KDM5A was increased in cisplatin-injured cochlear hair cells compared with controls. CPI-455 treatment markedly declined KDM5A and elevated H3K4 trimethylation levels in cisplatin-injured cochlear hair cells. Moreover, CPI-455 effectively prevented the death of hair cells and spiral ganglion neurons and increased the number of ribbon synapses in a cisplatin-induced ototoxicity mouse model both in vitro and in vivo. In HEI-OC1 cells, KDM5A knockdown reduced reactive oxygen species accumulation and improved mitochondrial membrane potential and oxidative phosphorylation under cisplatin-induced stress. Mechanistically, through transcriptomics and epigenomics analyses, a set of apoptosis-related genes, including Sos1, Sos2, and Map3k3, were regulated by CPI-455. Altogether, our findings indicate that inhibition of KDM5A may represent an effective epigenetic therapeutic target for preventing cisplatin-induced hearing loss.

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells.

The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.

A computer aided drug discovery based discovery of lead-like compounds against KDM5A for cancers using pharmacophore modeling and high-throughput virtual screening.

KDM5A over-expression mediates cancer cell proliferation and promotes resistance toward chemotherapy through epigenetic modifications. As its complete mechanism of action is still unknown, there is no KDM5A specific drug available at clinical level. In the current study, lead compounds for KDM5A were determined through pharmacophore modeling and high-throughput virtual screening from Asinex libraries containing 0.5 million compounds. These virtual hits were further evaluated and filtered for ADMET properties. Finally, 726 compounds were used for docking analysis against KDM5A. On the basis of docking score, 10 top-ranked compounds were selected and further evaluated for non-central nervous system (CNS) and CNS drug-like properties. Among these compounds, N-{[(7-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta [c] chromen-9-yl) oxy]acetyl}-l-phenylalanine (G-score: -11.363 kcal/mol) was estimated to exhibit non-CNS properties while 2-(3,4-Dimethoxy-phenyl)-7-methoxy-chromen-4-one (G-score: -7.977 kcal/mol) was evaluated as CNS compound. Docked complexes of both compounds were finally selected for molecular dynamic simulation to examine the stability. This study concluded that both these compounds can serve as lead compounds in the quest of finding therapeutic agents against KDM5A associated cancers.

ELK4 promotes the development of gastric cancer by inducing M2 polarization of macrophages through regulation of the KDM5A-PJA2-KSR1 axis.

BACKGROUND: We tried to elaborate the molecular mechanism of ETS-like transcription factor 4 (ELK4) affecting gastric cancer (GC) progression through M2 polarization of macrophages mediated by lysine-specific demethylase 5A (KDM5A)-Praja2 (PJA2)-kinase suppressor of ras 1 (KSR1) axis. METHODS: GC expression dataset was obtained from GEO database, and the downstream regulatory mechanism of ELK4 was predicted. Tumor-associated macrophages (TAMs) were isolated from GC tissues. The interaction among ELK4, KDM5A, PJA2 and KSR1 was analyzed by dual luciferase reporter gene, ChIP and Co-IP assays. The stability of KSR1 protein was detected by cycloheximide (CHX) treatment. After TAMs were co-cultured with HGC-27 cells, HGC-27 cell biological processes were assessed through gain- and loss-of function assays. Tumorigenicity was detected by tumorigenicity test in nude mice. RESULTS: In GC and TAMs, ELK4, KDM5A and KSR1 were highly expressed, while PJA2 was lowly expressed. M2 polarization of macrophages promoted the development of GC. ELK4 activated KDM5A by transcription and promoted macrophage M2 polarization. KDM5A inhibited the expression of PJA2 by removing H3K4me3 of PJA2 promoter, which promoted M2 polarization of macrophages. PJA2 reduced KSR1 by ubiquitination. ELK4 promoted the proliferative, migrative and invasive potentials of GC cells as well as the growth of GC xenografts by regulating KSR1. CONCLUSION: ELK4 may reduce the PJA2-dependent inhibition of KSR1 by transcriptional activation of KDM5A to promote M2 polarization of macrophages, thus promoting the development of GC.

Identification of in vitro JMJD lysine demethylase candidate substrates via systematic determination of substrate preference.

A major regulatory influence over gene expression is the dynamic post translational methylation of histone proteins, with major implications from both lysine methylation and demethylation. The KDM5/JARID1 sub-family of Fe(II)/2-oxoglutarate dependent lysine-specific demethylases is, in part, responsible for the removal of tri/dimethyl modifications from lysine 4 of histone H3 (i.e., H3K4me3/2), a mark associated with active gene expression. Although the relevance of KDM5 activity to disease progression has been primarily established through its ability to regulate gene expression via histone methylation, there is evidence that these enzymes may also target non-histone proteins. To aid in the identification of new non-histone substrates, we examined KDM5A in vitro activity towards a library of 180 permutated peptide substrates derived from the H3K4me3 sequence. From this data, a recognition motif was identified and used to predict candidate KDM5A substrates from the methyllysine proteome. High-ranking candidate substrates were then validated for in vitro KDM5A activity using representative trimethylated peptides. Our approach correctly identified activity towards 90% of high-ranked substrates. Here, we have demonstrated the usefulness of our method in identifying candidate substrates that is applicable to any Fe(II)- and 2-oxoglutarate dependent demethylase.

Molecular mechanisms of KDM5A in cellular functions: Facets during development and disease.

Gene expression is influenced at many layers by a fine-tuned crosstalk between multiple extrinsic signalling pathways and intrinsic regulatory molecules that respond to environmental stimuli. Epigenetic modifiers like DNA methyltransferases, histone modifying enzymes and chromatin remodellers are reported to act as triggering factors in many scenarios by exhibiting their control over most of the cellular processes. These epigenetic players can either directly regulate gene expression or interact with some effector molecules that harmonize the expression of downstream genes. One such epigenetic regulator which exhibits multifaceted regulation over gene expression is KDM5A. It is classically a transcriptional repressor acting as H3K4me3 demethylase, but also is reported to act as an activator in many contexts either by loss of activity due to inhibition manifested by other interacting proteins or by downregulating the negative players of a given physiological process thereby escalating the framework. Through this review, we draw attention to the remarkable modes of functioning laid by KDM5A on transcriptional and translational processes, affecting gene expression during differentiation and development and finally summing up on role in disease causation (Fig. 1). We also shed light on different orthologs of KDM5A and their organism specific roles, along with comparison of the sequence similarity to extrapolate some unanswered questions about this protein.

Human papillomavirus type 16 E7 oncoprotein-induced upregulation of lysine-specific demethylase 5A promotes cervical cancer progression by regulating the microRNA-424-5p/suppressor of zeste 12 pathway.

Human papillomavirus (HPV) infection and viral protein expression cause several epigenetic alterations that lead to cervical carcinogenesis. Our previous study identified that upregulated lysine-specific demethylase (KDM) 2 A promotes cervical cancer progression by inhibiting mircoRNA (miR)-132 function. However, the roles of histone methylation modifiers in HPV-related cervical cancer remain unclear. In the present study, changes in the expression of 48 histone methylation modifiers were assessed following knockdown of HPV16 E6/E7 in CaSki cells. The dysregulated expression of KDM5A was identified, and its function in cervical cancer was investigated in vitro and in vivo. E7 oncoprotein-induced upregulation of KDM5A promoted cervical cancer cell proliferation and invasiveness in vitro and in vivo, which was correlated with poor prognosis in patients with cervical cancer. KDM5A was found to physically interact with the promoter region of miR-424-5p, and to suppress its expression by removing the tri- and di-methyl groups from H3K4 at the miR-424-5p locus. Furthermore, miR-424-5p repressed cancer cell proliferation and invasiveness by targeting suppressor of zeste 12 (Suz12). KDM5A upregulation promoted cervical cancer progression by repressing miR-424-5p, which resulted in a decrease in Suz12. Therefore, KDM5A functions as a tumor activator in cervical cancer pathogenesis by binding to the miR-424-5p promoter and inhibiting its tumor-suppressive function. These results indicate a function for KDM5A in cervical cancer progression and suggest its candidacy as a novel prognostic biomarker and target for the clinical management of this malignancy.

Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase.

Inactivation of the retinoblastoma gene (RB1) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline Rbp2 deletion significantly impedes tumorigenesis in Rb1+/- mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing Rb1+/- mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established Rb1-null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by RB1 inactivation.

Comparison of Histone H3K4me3 between IVF and ICSI Technologies and between Boy and Girl Offspring.

Epigenetics play a vital role in early embryo development. Offspring conceived via assisted reproductive technologies (ARTs) have a three times higher risk of epigenetic diseases than naturally conceived children. However, investigations into ART-associated placental histone modifications or sex-stratified analyses of ART-associated histone modifications remain limited. In the current study, we carried out immunohistochemistry, chip-sequence analysis, and a series of in vitro experiments. Our results demonstrated that placentas from intra-cytoplasmic sperm injection (ICSI), but not in vitro fertilization (IVF), showed global tri-methylated-histone-H3-lysine-4 (H3K4me3) alteration compared to those from natural conception. However, for acetylated-histone-H3-lysine-9 (H3K9ac) and acetylated-histone-H3-lysine-27 (H3K27ac), no significant differences between groups could be found. Further, sex -stratified analysis found that, compared with the same-gender newborn cord blood mononuclear cell (CBMC) from natural conceptions, CBMC from ICSI-boys presented more genes with differentially enriched H3K4me3 (n = 198) than those from ICSI-girls (n = 79), IVF-girls (n = 5), and IVF-boys (n = 2). We also found that varying oxygen conditions, RNA polymerase II subunit A (Polr2A), and lysine demethylase 5A (KDM5A) regulated H3K4me3. These findings revealed a difference between IVF and ICSI and a difference between boys and girls in H3K4me3 modification, providing greater insight into ART-associated epigenetic alteration.

Histone demethylase KDM5A is transactivated by the transcription factor C/EBPß and promotes preadipocyte differentiation by inhibiting Wnt/ß-catenin signaling.

ß-Catenin signaling is triggered by WNT proteins and is an important pathway that negatively regulates adipogenesis. However, the mechanisms controlling the expression of WNT proteins during adipogenesis remain incompletely understood. Lysine demethylase 5A (KDM5A) is a histone demethylase that removes trimethyl (me3) marks from lysine 4 of histone 3 (H3K4) and serves as a general transcriptional corepressor. Here, using the murine 3T3-L1 preadipocyte differentiation model and an array of biochemical approaches, including ChIP, immunoprecipitation, RT-qPCR, and immunoblotting assays, we show that Kdm5a is a target gene of CCAAT/enhancer-binding protein ß (C/EBPß), an important early transcription factor required for adipogenesis. We found that C/EBPß binds to the Kdm5a gene promoter and transactivates its expression. We also found that siRNA-mediated KDM5A down-regulation inhibits 3T3-L1 preadipocyte differentiation. The KDM5A knockdown significantly up-regulates the negative regulator of adipogenesis Wnt6, having increased levels of the H3K4me3 mark on its promoter. We further observed that WNT6 knockdown significantly rescues adipogenesis inhibited by the KDM5A knockdown. Moreover, we noted that C/EBPß negatively regulates Wnt6 expression by binding to the Wnt6 gene promoter and repressing Wnt6 transcription. Further experiments indicated that KDM5A interacts with C/EBPß and that their interaction cooperatively inhibits Wnt6 transcription. Of note, C/EBPß knockdown impaired the recruitment of KDM5A to the Wnt6 promoter, which had higher H3K4me3 levels. Our results suggest a mechanism involving C/EBPß and KDM5A activities that down-regulates the Wnt/ß-catenin pathway during 3T3-L1 preadipocyte differentiation.

In vitro evidence of NLRP3 inflammasome regulation by histone demethylase LSD2 in renal cancer: a pilot study.

NLRP3 pathway plays a vital role in the pathogenesis of different human cancers but still the regulation of NLRP3 pathway largely unknown. Therefore, we examined the levels of NLRP3 and its downstream components (caspase-1 and IL-1ß) and its relationship with histone modifiers in renal cancer pathogenesis. Total 30 cases of clear cell renal cell carcinoma (ccRCC), were studied for NLRP3, caspase-1 and IL-1ß expression using real-time PCR, which showed the augmented levels of all the three components of NLRP3 inflammasome pathway in ccRCC. Next, role of the FAD dependent monoamine oxidases (LSD2) and jumonji C (JmjC)-domain-containing, iron-dependent dioxygenases (KDM5A) histone demethylases were evaluated in regulation of NLRP3 inflammasome pathway in-vitro using RCC cell line. It was observed that silencing of KDM5A didn't alter the levels of neither of the NLRP3 component but inhibition of LSD2 showed significant effect on NLRP3 expression while no change in caspase-1 and IL-1ß levels. This study suggests that rather LSD2 not KDM5A lysine demethylase family might be involved in the regulation of NLRP3 inflammasome in cancer cells which could be useful for deciphering the future therapeutic targets for the disease.

Epigenetics in myelodysplastic syndromes.

Epigenetic regulators are the largest group of genes mutated in MDS patients. Most mutated genes belong to one of three groups of genes with normal functions in DNA methylation, in H3K27 methylation/acetylation or in H3K4 methylation. Mutations in the majority of epigenetic regulators disrupt their normal function and induce a loss-of-function phenotype. The transcriptional consequences are often failure to repress differentiation programs and upregulation of self-renewal pathways. However, the mechanisms how different epigenetic regulators result in similar transcriptional consequences are not well understood. Hypomethylating agents are active in higher risk MDS patients, but their efficacy does not correlate with mutations in epigenetic regulators and the median duration of hematologic response is limited to 10-13 months. Inhibitors of histone deacetylases (HDAC) yielded disappointing results so far, questioning this approach in MDS patients. We review the clinical relevance of epigenetic mutations in MDS, discuss their functional consequences and highlight the role of epigenetic therapies in this difficult to treat disease.

Microtubule dynamics decoded by the epigenetic state of centromeric chromatin.

Cell division with accurate chromosome segregation is fundamental to cell survival of all organisms. The precise molecular mechanisms that ensure accurate chromosome segregation are still being discovered using a variety of experimental systems and approaches. Microtubule attachment to the kinetochore is a prerequisite for mitotic progression, failure of which activates the spindle assembly checkpoint (SAC). The dynamic tension generated by interaction of the centromere, kinetochore and microtubules is a key regulator of the SAC. Here, in the context of current literature we discuss our recent observation in fission yeast that epigenetic alterations in centromeric and pericentromeric chromatin can compensate for altered dynamics of kinetochore-microtubule attachment to permit escape from mitotic arrest. A role for the spatial configuration of the centromere to influence the finely tuned regulators of mitotic progression opens up new avenues for research.