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.

RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter.

BACKGROUND: Megakaryocytes (MKs) are platelet precursors, which arise from hematopoietic stem cells (HSCs). While MK lineage commitment and differentiation are accompanied by changes in gene expression, many factors that modulate megakaryopoiesis remain to be uncovered. Replication initiation determinant protein (RepID) which has multiple histone-code reader including bromodomain, cryptic Tudor domain and WD40 domains and Cullin 4-RING E3 ubiquitin ligase complex (CRL4) recruited to chromatin mediated by RepID have potential roles in gene expression changes via epigenetic regulations. We aimed to investigate whether RepID-CRL4 participates in transcriptional changes required for MK differentiation. METHODS: The PCR array was performed using cDNAs derived from RepID-proficient or RepID-deficient K562 erythroleukemia cell lines. Correlation between RepID and DAB2 expression was examined in the Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal. The acceleration of MK differentiation in RepID-deficient K562 cells was determined by estimating cell sizes as well as counting multinucleated cells known as MK phenotypes, and by qRT-PCR analysis to validate transcripts of MK markers using phorbol 12-myristate 13-acetate (PMA)-mediated MK differentiation condition. Interaction between CRL4 and histone methylation modifying enzymes were investigated using BioGRID database, immunoprecipitation and proximity ligation assay. Alterations of expression and chromatin binding affinities of RepID, CRL4 and histone methylation modifying enzymes were investigated using subcellular fractionation followed by immunoblotting. RepID-CRL4-JARID1A-based epigenetic changes on DAB2 promoter were analyzed by chromatin-immunoprecipitation and qPCR analysis. RESULTS: RepID-deficient K562 cells highly expressing MK markers showed accelerated MKs differentiation exhibiting increases in cell size, lobulated nuclei together with reaching maximum levels of MK marker expression earlier than RepID-proficient K562 cells. Recovery of WD40 domain-containing RepID constructs in RepID-deficient background repressed DAB2 expression. CRL4A formed complex with histone H3K4 demethylase JARID1A in soluble nucleus and loaded to the DAB2 promoter in a RepID-dependent manner during proliferation condition. RepID, CRL4A, and JARID1A were dissociated from the chromatin during MK differentiation, leading to euchromatinization of the DAB2 promoter. CONCLUSION: This study uncovered a role for the RepID-CRL4A-JARID1A pathway in the regulation of gene expression for MK differentiation, which can form the basis for the new therapeutic approaches to induce platelet production. Video Abstract.

JARID1B represses the osteogenic potential of human periodontal ligament mesenchymal cells.

BACKGROUND: Here, we evaluated whether the histone lysine demethylase 5B (JARID1B), is involved in osteogenic phenotype commitment of periodontal ligament cells (PDLCs), by considering their heterogeneity for osteoblast differentiation. MATERIALS AND METHODS: Epigenetic, transcriptional, and protein levels of a gene set, involved in the osteogenesis, were investigated by performing genome-wide DNA (hydroxy)methylation, mRNA expression, and western blotting analysis at basal (without osteogenic induction), and at the 3rd and 10th days of osteogenic stimulus, in vitro, using PDLCs with low (l) and high (h) osteogenic potential as biological models. RESULTS: h-PDLCs showed reduced levels of JARID1B, compared to l-PDLCs, with significant inversely proportional correlations between RUNX2 and RUNX2/p57. Epigenetically, a significant reduction in the global H3K4me3 content was observed only in h-PDLCs. Immunoblotting data reveal a significant reduction in the global H3K4me3 content, at 3 days of induction only in h-PDLCs, while an increase in the global H3K4me3 content was observed at 10 days for both PDLCs. Additionally, positive correlations were found between global H3K4me3 levels and JARID1B gene expression. CONCLUSIONS: Altogether, our results show the crucial role of JARID1B in repressing PDLCs osteogenic phenotype and this claims to pre-clinical protocols proposing JARID1B as a potential therapeutic target.

Arabidopsis JMJ17 promotes cotyledon greening during de-etiolation by repressing genes involved in tetrapyrrole biosynthesis in etiolated seedlings.

Arabidopsis histone H3 lysine 4 (H3K4) demethylases play crucial roles in several developmental processes, but their involvement in seedling establishment remain unexplored. Here, we show that Arabidopsis JUMONJI DOMAIN-CONTAINING PROTEIN17 (JMJ17), an H3K4me3 demethylase, is involved in cotyledon greening during seedling establishment. Dark-grown seedlings of jmj17 accumulated a high concentration of protochlorophyllide, an intermediate metabolite in the tetrapyrrole biosynthesis (TPB) pathway that generates chlorophyll (Chl) during photomorphogenesis. Upon light irradiation, jmj17 mutants displayed decreased cotyledon greening and reduced Chl level compared with the wild-type; overexpression of JMJ17 completely rescued the jmj17-5 phenotype. Transcriptomics analysis uncovered that several genes encoding key enzymes involved in TPB were upregulated in etiolated jmj17 seedlings. Consistently, chromatin immunoprecipitation-quantitative PCR revealed elevated H3K4me3 level at the promoters of target genes. Chromatin association of JMJ17 was diminished upon light exposure. Furthermore, JMJ17 interacted with PHYTOCHROME INTERACTING FACTOR1 in the yeast two-hybrid assay. JMJ17 binds directly to gene promoters to demethylate H3K4me3 to suppress PROTOCHLOROPHYLLIDE OXIDOREDUCTASE C expression and TPB in the dark. Light results in de-repression of gene expression to modulate seedling greening during de-etiolation. Our study reveals a new role for histone demethylase JMJ17 in controlling cotyledon greening in etiolated seedlings during the dark-to-light transition.

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.

The H3K4 demethylase Jar1 orchestrates ROS production and expression of pathogenesis-related genes to facilitate Botrytis cinerea virulence.

Histone 3 Lysine 4 (H3K4) demethylation is ubiquitous in organisms, however the roles of H3K4 demethylase JARID1(Jar1)/KDM5 in fungal development and pathogenesis remain largely unexplored. Here, we demonstrate that Jar1/KDM5 in Botrytis cinerea, the grey mould fungus, plays a crucial role in these processes. The BcJAR1 gene was deleted and its roles in fungal development and pathogenesis were investigated using approaches including genetics, molecular/cell biology, pathogenicity and transcriptomic profiling. BcJar1 regulates H3K4me3 and both H3K4me2 and H3K4me3 methylation levels during vegetative and pathogenic development, respectively. Loss of BcJAR1 impairs conidiation, appressorium formation and stress adaptation; abolishes infection cushion (IC) formation and virulence, but promotes sclerotium production in the ΔBcjar1 mutants. BcJar1 controls reactive oxygen species (ROS) production and proper assembly of Sep4, a core septin protein and virulence determinant, to initiate infection structure (IFS) formation and host penetration. Exogenous cAMP partially restored the mutant appressorium, but not IC, formation. BcJar1 orchestrates global expression of genes for ROS production, stress response, carbohydrate transmembrane transport, secondary metabolites, etc., which may be required for conidiation, IFS formation, host penetration and virulence of the pathogen. Our work systematically elucidates BcJar1 functions and provides novel insights into Jar1/KDM5-mediated H3K4 demethylation in regulating fungal development and pathogenesis.

JARID1B promotes colorectal cancer proliferation and Wnt/ß-catenin signaling via decreasing CDX2 level.

BACKGROUND: Jumonji AT-rich interactive domain 1B(JARID1B) has been shown to be upregulated in many human cancers and plays a critical role in the development of cancers cells. Nevertheless, its functional role in colorectal cancer (CRC) progression is not fully understood. METHODS: Herein, JARID1B expression levels were detected in clinical CRC samples by western blotting and qRT-PCR. DLD-1 cells with JARID1B knockdown or overexpression by stably transfected plasmids were used in vitro and in vivo study. Colony formation, 5-ethynyl-20-deoxyuridine (EdU) and Real Time Cellular Analysis (RTCA) assays were used to detect cell proliferation and growth. Transcriptome and CHIP assays were used to examine the molecular biology changes and molecular interaction in these cells. Nude mice was utilized to study the correlation of JARID1B and tumor growth in vivo. RESULTS: Here, we first observed that JARID1B was significantly upregulated in CRC tissue compared to adjacent normal tissues. In CRC patients, JARID1B high expression was positively relation with poor overall survival. Multivariate analyses revealed that high JARID1B expression was an independent predictive marker for the poor prognosis of CRC. In addition, we found that JARID1B promoted CRC cells proliferation by Wnt/ß-catenin signaling pathway. Further studies demonstrated CDX2 as a downstream target of JARID1B, and our data demonstrated that CDX2 is crucial for JARID1B -mediated Wnt/ß-catenin signaling pathway. Mechanistically, we demonstrated that JARID1B regulated CDX2 expression through demethylation of H3K4me3. CONCLUSIONS: CDX2 inhibited by JARID1B-derived H3K4me3 methylation promoted cells proliferation of CRC via Wnt/ß-catenin signaling pathway. Therefore, our studies provided a novel insight into the role of JARID1B in CRC cells proliferation and potential new molecular target for treating CRC. Video abstract.

Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.

The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity.

Prognostic significance of RBP2-H1 variant of JARID1B in melanoma.

BACKGROUND: Histone demethylase JARID1B plays several context dependent roles in epigenetic regulation of cellular differentiation in normal development and is highly expressed in multiple human cancers. The protein is a strong transcriptional repressor capable of downregulating numerous genes. There are three splicing isoforms of JARID1B, however the links between the protein structure and function are not clear. The expression pattern of JARID1B in human melanoma seems to be different from observed in other cancers. Moreover, up to now no data on the impact of JARID1B expression in cutaneous melanoma on the patients' prognosis have been reported. METHODS: We investigated immunohistochemically the association of intratumoral expression of total JARID1B protein and its RBP2-H1 isoform in primary and metastatic melanomas with prognosis for the patients. RESULTS: Expression of both total JARID1B protein and its RBP2-H1 variant was found in all the melanomas investigated. Our results indicate, however, that only high (above 90% of the cells) intratumoral expression of RBP2-H1 can be considered prognostic factor associated with worse overall survival of the patients. CONCLUSIONS: Such results if considered together with data demonstrating a switch to enhanced expression of RBP2-H1 at early stages of malignant transformation of melanocytes are in agreement with hypothetical crucial role of JARID1B in the course of melanoma development and progression and suggest that altered splicing of JARID1B may be important factor increasing melanoma aggressiveness.

Identification of potent, selective KDM5 inhibitors.

This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization.

Histone demethylase JARID1C promotes breast cancer metastasis cells via down regulating BRMS1 expression.

Metastasis is the leading cause of death in breast cancer patients. However, until now, the mechanisms of breast cancer metastasis remain elusive. Epigenetic switch, including histone methylation or demethylation, which can either activates or represses transcription. The JARID1C is a histone demethylase that promotes cancer cell growth and is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. But the pathogenic breadth and mechanistic aspects of this effect relative to breast cancer have not been defined. In this study, we aimed to investigate the role of JARID1C in breast cancer. In clinical breast cancer samples, we found that JARID1C expression was significantly upregulated in cancer lesions compared with paired normal breast tissues and its expression level is positively correlated with metastasis. Silencing JARID1C in breast cancer cells could inhibit cell migration and invasion. Moreover, we also found that the expression of BRMS1 was modulated by JARID1C. Silencing of JARID1C dramatically increased BRMS1 expression both at mRNA and protein level. Mechanistically, we found JARID1C exerts its function through modulation of H3K4me3 at the BRMS1 gene promoter, which was associated with inactive BRMS1 transcription. BRMS1 knockdown reversed shJARID1C-induced migration inhibition. Further, BRMS1 expression in human breast cancer is negatively correlated with JARID1C expression. Our results, for the first time, portray a pivotal role of JARID1C in regulating metastatic behaviors of breast cancer cells.

JARID1B modulates lung cancer cell proliferation and invasion by regulating p53 expression.

Although three therapeutic modalities (surgical resection, chemotherapy, and radiotherapy) have been established, long-term survival for lung cancer patients is still generally poor. Until now, the mechanisms of lung cancer genesis remain elusive. The JARID1B is a histone demethylase that has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear. In present study, we found that JARID1B was overexpressed in lung cancer cell lines and lung cancer tissues but not in normal lung tissues. The proliferation and invasive potential of lung cancer cells was significantly increased by ectopic expression of JARID1B. Contrarily, RNA interference targeting JARID1B in lung cancer cells significantly decreased the proliferation and invasive potential of cells. Moreover, we also found that the expression of p53 was modulated by JARID1B. Overexpressed JARID1B cell exhibited greatly decreased p53 expression, whereas silencing of JARID1B expression dramatically increased p53 expression at both the messenger RNA (mRNA) and protein levels. Inhibition of p53 by small interfering RNA (siRNA) reversed the shJARID1B-induced suppression of proliferation and invasion. Our results collectively suggested that JARID1B expressed in lung cancer played a role in lung cancer cells proliferation and invasion, which may be partly associated with the p53 expression.

Prevention of inorganic arsenic induced squamous cell carcinoma of the skin in Swiss albino mice by black tea through epigenetic modulation.

Consumption of inorganic Arsenic (iAs) above the safe level may lead to many diseases including cancers of skin. It is known that carcinogenicity of iAs is mediated through generation of excessive reactive oxygen species and polyphenols present in black tea extract (BTE) ameliorate the deleterious effect. Epigenetics also plays vital roles in carcinogenesis. The aim of this paper is to study the influence of iAs on epigenetics and the modulatory effect of BTE. Male Swiss albino mice were divided into three groups, (i) control, (ii) iAs-administered and (iii) iAs + BTE administered. Group (ii) developed invasive squamous cell carcinoma (SCC) of the skin after 330 days, while only hyperplasic and dysplastic changes were observed in group (iii). Expression levels of histone methylation, acetylation marks and several histone methylases, demethylases and acetylases due to iAs were studied; most aberrant expression levels due to iAs were modulated by BTE. JARID1B, a histone demethylase implicated as one of the markers in SCC and a therapeutic target gets upregulated by iAs, but is not influenced by BTE. However, SCC is prevented by BTE. Upregulation of JARID1B by iAs represses H3K4me3; BTE upregulates H3K4me3 without influencing JARID1B expression level. It is known that theaflavin compounds in BTE are transported to the nucleus and interact with histone proteins. in-silico findings in this paper hint that theaflavin compounds present in BTE are very good inhibitors of JARID1B and BTE inhibits its demethylating activity. BTE reverses the epigenetic alterations caused by iAs, thus aids in prevention of SCC.

Biological Sex As a Critical Variable in CD4+ Effector T Cell Function in Preclinical Models of Multiple Sclerosis.

Significance: T cells play a pivotal role in maintaining adaptive immune responses against pathogens. However, misdirected T cell responses against self-tissues may lead to autoimmune disease. Biological sex has profound effects on T cell function and is an important determinant of disease incidence and severity in autoimmune diseases such as multiple sclerosis (MS). Recent Advances: Many autoimmune diseases skew toward higher female incidence, including MS; however, it is has become increasingly more accepted that men living with MS are more prone to developing a progressive disease course and to having worsened disease outcomes. Critical Issues: In this review, we discuss what is known about the role of biological sex on T cell development and differentiation, examining evidence that male sex can augment T helper 17 (Th17) responses. Next, we outline what is known about sex differences in animal models of MS, and about the distinct roles played by sex hormones versus sex chromosomes in pathogenesis in these models. Finally, we discuss recent advances that examine the molecular basis for worsened disease outcomes in males, with a particular focus on the role played by Th17 cells in these models. Future Directions: Better understanding the role of biological sex in T cell function may pave the way to effective personalized treatment strategies in MS and other autoimmune diseases. Antioxid. Redox Signal. 37, 135-149.

Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells.

Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present.

Mechanisms of JARID1B Up-Regulation and Its Role in Helicobacter pylori-Induced Gastric Carcinogenesis.

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Helicobacter pylori infection can induce GC through a serial cascade of events, with emerging evidence suggesting the important role of epigenetic alterations in the development and progression of the disease. Here, we report on mechanisms responsible for Jumonji AT-rich interactive domain1B (JARID1B) upregulation in GC and its role in the malignant transformation induced by H. pylori infection. We found that upregulation of JARID1B was associated with poorer prognosis, greater tumor purity, and less immune cell infiltration into the tumor. Mechanistically, we showed that the upregulation of JARID1B in human GC was attributed to JARID1B amplification and its induction by H. pylori infection. Furthermore, we identified miR-29c as a negative regulator of JARID1B in GC. H. pylori caused downregulation of miR-29c in human GC and thereby contributed to JARID1B upregulation through relieving posttranscriptional regulation. Functionally, we showed that knockdown of JARID1B reduced GC cell proliferation induced by H. pylori infection. Subsequently, cyclinD1 (CCND1), a key molecule in GC, was shown to be a target gene of JARID1B. In conclusion, these results suggest that JARID1B may be an oncogene upregulated in human GC and could represent a novel therapeutic target to prevent malignant transformation induced by H. pylori infection.

Prenatal Iron Deficiency and Choline Supplementation Interact to Epigenetically Regulate Jarid1b and Bdnf in the Rat Hippocampus into Adulthood.

Early-life iron deficiency (ID) causes long-term neurocognitive impairments and gene dysregulation that can be partially mitigated by prenatal choline supplementation. The long-term gene dysregulation is hypothesized to underlie cognitive dysfunction. However, mechanisms by which iron and choline mediate long-term gene dysregulation remain unknown. In the present study, using a well-established rat model of fetal-neonatal ID, we demonstrated that ID downregulated hippocampal expression of the gene encoding JmjC-ARID domain-containing protein 1B (JARID1B), an iron-dependent histone H3K4 demethylase, associated with a higher histone deacetylase 1 (HDAC1) enrichment and a lower enrichment of acetylated histone H3K9 (H3K9ac) and phosphorylated cAMP response element-binding protein (pCREB). Likewise, ID reduced transcriptional capacity of the gene encoding brain-derived neurotrophic factor (BDNF), a target of JARID1B, associated with repressive histone modifications such as lower H3K9ac and pCREB enrichments at the Bdnf promoters in the adult rat hippocampus. Prenatal choline supplementation did not prevent the ID-induced chromatin modifications at these loci but induced long-lasting repressive chromatin modifications in the iron-sufficient adult rats. Collectively, these findings demonstrated that the iron-dependent epigenetic mechanism mediated by JARID1B accounted for long-term Bdnf dysregulation by early-life ID. Choline supplementation utilized a separate mechanism to rescue the effect of ID on neural gene regulation. The negative epigenetic effects of choline supplementation in the iron-sufficient rat hippocampus necessitate additional investigations prior to its use as an adjunctive therapeutic agent.

Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity.

Sex differences in multiple sclerosis (MS) incidence and severity have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive disease remain poorly defined. Using a T cell adoptive transfer model of chronic experimental autoimmune encephalomyelitis (EAE), we find that male Th17 cells induce disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produce IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, XY chromosomal complement increases the pathogenicity of male Th17 cells. An X-linked immune regulator, Jarid1c, is downregulated in pathogenic male murine Th17 cells, and functional experiments reveal that it represses the severity of Th17-mediated EAE. Furthermore, Jarid1c expression is downregulated in CD4+ T cells from MS-affected individuals. Our data indicate that male sex chromosomal complement critically regulates Th17 cell pathogenicity.

Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways.

Recently an outbreak that emerged in Wuhan, China in December 2019, spread to the whole world in a short time and killed >1,410,000 people. It was determined that a new type of beta coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) was causative agent of this outbreak and the disease caused by the virus was named as coronavirus disease 19 (COVID19). Despite the information obtained from the viral genome structure, many aspects of the virus-host interactions during infection is still unknown. In this study we aimed to identify SARS-CoV-2 encoded microRNAs and their cellular targets. We applied a computational method to predict miRNAs encoded by SARS-CoV-2 along with their putative targets in humans. Targets of predicted miRNAs were clustered into groups based on their biological processes, molecular function, and cellular compartments using GO and PANTHER. By using KEGG pathway enrichment analysis top pathways were identified. Finally, we have constructed an integrative pathway network analysis with target genes. We identified 40 SARS-CoV-2 miRNAs and their regulated targets. Our analysis showed that targeted genes including NFKB1, NFKBIE, JAK1-2, STAT3-4, STAT5B, STAT6, SOCS1-6, IL2, IL8, IL10, IL17, TGFBR1-2, SMAD2-4, HDAC1-6 and JARID1A-C, JARID2 play important roles in NFKB, JAK/STAT and TGFB signaling pathways as well as cells' epigenetic regulation pathways. Our results may help to understand virus-host interaction and the role of viral miRNAs during SARS-CoV-2 infection. As there is no current drug and effective treatment available for COVID19, it may also help to develop new treatment strategies.

JARID1a Ablation in the Liver Alters Systemic Metabolism and Adaptation to Feeding.

The liver is a key regulator of systemic energy homeostasis whose proper function is dependent on the circadian clock. Here, we show that livers deficient in the oscillator component JARID1a exhibit a dysregulation of genes involved in energy metabolism. Importantly, we find that mice that lack hepatic JARID1a have decreased lean body mass, decreased respiratory exchange ratios, faster production of ketones, and increased glucose production in response to fasting. Finally, we find that JARID1a loss compromises the response of the hepatic transcriptome to nutrient availability. In all, ablation of hepatic JARID1a disrupts the coordination of hepatic metabolic programs with whole-body consequences.