H3K27me3 Demethylase Research Articles

The H3K27me3 Demethylase RELATIVE OF EARLY FLOWERING6 Suppresses Seed Dormancy by Inducing Abscisic Acid Catabolism.

Seed dormancy is an adaptive trait that is crucial to plant survival. Abscisic acid (ABA) is the primary phytohormone that induces seed dormancy. However, little is known about how the level of ABA in seeds is determined. Here we show that the Arabidopsis (Arabidopsis thaliana) H3K27me3 demethylase RELATIVE OF EARLY FLOWERING6 (REF6) suppresses seed dormancy by inducing ABA catabolism in seeds. Seeds of the ref6 loss-of-function mutants displayed enhanced dormancy that was associated with increased endogenous ABA content. We further show that the transcripts of two genes key to ABA catabolism, CYP707A1 and CYP707A3, but not genes involved in ABA biosynthesis, were significantly reduced in ref6 mutants during seed development and germination. In developing siliques, REF6 bound directly to CYP707A1 and CYP707A3, and was responsible for reducing their H3K27me3 levels. Genetic analysis demonstrated that the enhanced seed dormancy and ABA concentration in ref6 depended mainly on the reduced expression of CYP707A1 and CYP707A3 Conversely, overexpression of CYP707A1 could offset the enhanced seed dormancy of ref6 Taken together, our results revealed an epigenetic regulation mechanism that is involved in the regulation of ABA content in seeds.

JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency

The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3’s catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.

Gallic acid attenuates blood-spinal cord barrier disruption by inhibiting Jmjd3 expression and activation after spinal cord injury

After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption results in secondary injury including apoptotic cell death of neurons and oligodendrocytes, thereby leads to permanent neurological deficits. Recently, we reported that the histone H3K27me3 demethylase Jmjd3 plays a role in regulating BSCB integrity after SCI. Here, we investigated whether gallic acid (GA), a natural phenolic compound that is known to be anti-inflammatory, regulates Jmjd3 expression and activation, thereby attenuates BSCB disruption following the inflammatory response and improves functional recovery after SCI. Rats were contused at T9 and treated with GA (50 mg/kg) via intraperitoneal injection immediately, 6 h and 12 h after SCI, and further treated for 7 d with the same dose once a day. To elucidate the underlying mechanism, we evaluated Jmjd3 activity and expression, and assessed BSCB permeability by Evans blue assay after SCI. GA significantly inhibited Jmjd3 expression and activation after injury both in vitro and in vivo. GA also attenuated the expression and activation of matrix metalloprotease-9, which is well known to disrupt the BSCB after SCI. Consistent with these findings, GA attenuated BSCB disruption and reduced the infiltration of neutrophils and macrophages compared with the vehicle control. Finally, GA significantly alleviated apoptotic cell death of neurons and oligodendrocytes and improved behavior functions. Based on these data, we propose that GA can exert a neuroprotective effect by inhibiting Jmjd3 activity and expression followed the downregulation of matrix metalloprotease-9, eventually attenuating BSCB disruption after SCI.

N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2.

A dynamic epigenome is critical for appropriate gene expression in development and health1-5. Central to this is the intricate process of transcription6-11, which integrates cellular signaling with chromatin changes, transcriptional machinery and modifications to messenger RNA, such as N6-methyladenosine (m6A), which is co-transcriptionally incorporated. The integration of these aspects of the dynamic epigenome, however, is not well understood mechanistically. Here we show that the repressive histone mark H3K9me2 is specifically removed by the induction of m6A-modified transcripts. We demonstrate that the methyltransferase METTL3/METTL14 regulates H3K9me2 modification. We observe a genome-wide correlation between m6A and occupancy by the H3K9me2 demethylase KDM3B, and we find that the m6A reader YTHDC1 physically interacts with and recruits KDM3B to m6A-associated chromatin regions, promoting H3K9me2 demethylation and gene expression. This study establishes a direct link between m6A and dynamic chromatin modification and provides mechanistic insight into the co-transcriptional interplay between RNA modifications and histone modifications.

UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters.

SummaryUTX, a H3K27me3 demethylase, plays an important role in mouse brain development. However, so little is known about the function of UTX in human neural differentiation and dendritic morphology. In this study, we generated UTX-null human embryonic stem cells using CRISPR/Cas9, and differentiated them into neural progenitor cells and neurons to investigate the effects of UTX loss of function on human neural development. The results showed that the number of differentiated neurons significantly reduced after loss of UTX, and that the dendritic morphology of UTX KO neurons tended to be simplified. The electrophysiological recordings showed that most of the UTX KO neurons were immature. Finally, RNA sequencing identified dozens of differentially expressed genes involved in neural differentiation and synaptic function in UTX KO neurons and our results demonstrated that UTX regulated these critical genes by resolving bivalent promoters. In summary, we establish a reference for the important role of UTX in human neural differentiation and dendritic morphology.

Removal of H2Aub1 by ubiquitin-specific proteases 12 and 13 is required for stable Polycomb-mediated gene repression in Arabidopsis

BackgroundStable gene repression is essential for normal growth and development. Polycomb repressive complexes 1 and 2 (PRC1&2) are involved in this process by establishing monoubiquitination of histone 2A (H2Aub1) and subsequent trimethylation of lysine 27 of histone 3 (H3K27me3). Previous work proposed that H2Aub1 removal by the ubiquitin-specific proteases 12 and 13 (UBP12 and UBP13) is part of the repressive PRC1&2 system, but its functional role remains elusive.ResultsWe show that UBP12 and UBP13 work together with PRC1, PRC2, and EMF1 to repress genes involved in stimulus response. We find that PRC1-mediated H2Aub1 is associated with gene responsiveness, and its repressive function requires PRC2 recruitment. We further show that the requirement of PRC1 for PRC2 recruitment depends on the initial expression status of genes. Lastly, we demonstrate that removal of H2Aub1 by UBP12/13 prevents loss of H3K27me3, consistent with our finding that the H3K27me3 demethylase REF6 is positively associated with H2Aub1.ConclusionsOur data allow us to propose a model in which deposition of H2Aub1 permits genes to switch between repression and activation by H3K27me3 deposition and removal. Removal of H2Aub1 by UBP12/13 is required to achieve stable PRC2-mediated repression.

Targeting JMJD3 histone demethylase mediates cardiac fibrosis and cardiac function following myocardial infarction

Myocardial fibrosis is the pathological consequence of injury-induced fibroblastto-myofibroblast transition, resulting in increased stiffness and diminished cardiac function. Histone modification has been shown to play an important role in the pathogenesis of cardiac fibrosis. Here, we identified H3K27me3 demethylase JMJD3/KDM6B promotes cardiac fibrosis via regulation of fibrogenic pathways. Using neonatal rat cardiac fibroblasts (NRCF), we show that the expression of endogenous JMJD3 is induced by angiotensin II (Ang II), while the principle extracellular matrix (ECM) such as fibronectin, CTGF, collagen I and III are increased. We find that JMJD3 inhibition markedly enhances the suppressive mark (H3K27me3) at the beta (β)-catenin promoter in activated cardiac fibroblasts, and then substantially decreases expression of fibrogenic gene. Both inhibition of β-catenin-mediated transcription with ICG-001 and genetic loss of β-catenin can prevent Ang II-induced ECM deposition. Most importantly, in vivo inhibition of JMJD3 rescues myocardial ischemia-induced cardiac fibrosis and cardiac dysfunction. Collectively, our findings are the first to report a novel role of histone demethylase JMJD3 in the pro-fibrotic cardiac fibroblast phenotype, pharmacological targeting of JMJD3 might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.

Cryopreserved Human Oocytes and Cord Blood Cells Can Produce Somatic Cell Nuclear Transfer-Derived Pluripotent Stem Cells with a Homozygous HLA Type.

SummaryHuman pluripotent stem cells (PSCs) through somatic cell nuclear transfer (SCNT) may be an important source for regenerative medicine. The low derivation efficiency of stem cells and the accessibility of human oocytes are the main obstacles to their application. We previously reported that the efficiency of SCNT was increased by overexpression of H3K9me3 demethylase. Here, we applied a modified derivation method to the PSC line and first obtained human SCNT-PSC lines derived from both donated cryopreserved oocytes and cord blood cells with a homozygous human leukocyte antigen (HLA) type. The SCNT-PSCs have very similar characteristics with embryonic stem cells (ESCs) and additionally have shown immunocompatibility in an in vitro and in vivo humanized mouse with a matching HLA type. Our study demonstrates that SCNT technology using donated cryopreserved oocytes and cord blood cells with a known HLA type provides a promising method for establishing a human HLA-matched SCNT-PSC bank for regenerative medicine.

GSK-J4 induces cell cycle arrest and apoptosis via ER stress and the synergism between GSK-J4 and decitabine in acute myeloid leukemia KG-1a cells

BackgroundGSK-J4 is the inhibitor of H3K27me3 demethylase. Recent studies demonstrated that GSK-J4 could affect the proliferation and apoptosis of a variety of cancer cells. However, the effects and underlying mechanisms of GSK-J4 on the proliferation and apoptosis of human acute myeloid leukemia (AML) KG-1a cells have not been explored thoroughly.MethodsThe effect of GSK-J4 on cell proliferation was assessed with CCK8, while cell cycle distribution and apoptosis were analyzed using flow cytometry. The proteins related to cell cycle, cell apoptosis, endoplastic reticulum (ER) stress and PKC-α/p-Bcl2 pathway were detected by Western blotting. The expression level of PKC-α mRNA was measured by quantitative real-time PCR.ER stress inhibitor 4-phenyl butyric acid (4-PBA) was used to explore the role of ER stress in GSK-J4 induced cell-cycle arrest and cell apoptosis. The combination effects of Decitabine and GSK-J4 on KG-1a cells proliferation and apoptosis were also evaluated by CCK8, flow cytometry and immunoblot analysis.ResultsGSK-J4 reduced cell viability and arrested cell cycle progression at the S phase by decreasing the expression of CyclinD1 and CyclinA2 and increasing that of P21. Moreover, GSK-J4 enhanced the expression of apoptosis-related proteins (cle-caspase-9 and bax) and inhibited PKC-a/p-Bcl2 pathway to promote cell apoptosis. In addition, ER stress-related proteins (caspase-12, GRP78 and ATF4) were increased markedly after exposure to GSK-J4. The effects of GSK-J4 on cell cycle, apoptosis and PKC-a/p-Bcl2 pathway were attenuated after treatment with ER stress inhibitor. Furthermore, decitabine could significantly inhibit the proliferation and induce the apoptosis of KG-1a cells after combined treatment with GSK-J4.ConclusionTaken together, this study provided evidence that ER stress could regulate the process of GSK-J4-induced cell cycle arrest, cell apoptosis and PKC-α/p-bcl2 pathway inhibition and demonstrated a potential combinatory effect of decitabine and GSK-J4 on leukemic cell proliferation and apoptosis.

TET3 controls the expression of the H3K27me3 demethylase Kdm6b during neural commitment.

The acquisition of cell identity is associated with developmentally regulated changes in the cellular histone methylation signatures. For instance, commitment to neural differentiation relies on the tightly controlled gain or loss of H3K27me3, a hallmark of polycomb-mediated transcriptional gene silencing, at specific gene sets. The KDM6B demethylase, which removes H3K27me3 marks at defined promoters and enhancers, is a key factor in neurogenesis. Therefore, to better understand the epigenetic regulation of neural fate acquisition, it is important to determine how Kdm6b expression is regulated. Here, we investigated the molecular mechanisms involved in the induction of Kdm6b expression upon neural commitment of mouse embryonic stem cells. We found that the increase in Kdm6b expression is linked to a rearrangement between two 3D configurations defined by the promoter contact with two different regions in the Kdm6b locus. This is associated with changes in 5-hydroxymethylcytosine (5hmC) levels at these two regions, and requires a functional ten-eleven-translocation (TET) 3 protein. Altogether, our data support a model whereby Kdm6b induction upon neural commitment relies on an intronic enhancer the activity of which is defined by its TET3-mediated 5-hmC level. This original observation reveals an unexpected interplay between the 5-hmC and H3K27me3 pathways during neural lineage commitment in mammals. It also questions to which extent KDM6B-mediated changes in H3K27me3 level account for the TET-mediated effects on gene expression.

Histone demethylase SlJMJ6 promotes fruit ripening by removing H3K27 methylation of ripening-related genes in tomato.

Fruit ripening is governed by a complex regulatory network. Reversible histone methylation and demethylation regulate chromatin structure and gene expression. However, little is known about the involvement of histone demethylases in regulating fruit ripening. Here, we found that the tomato (Solanum lycopersicum) SlJMJ6 encodes a histone lysine demethylase that specifically demethylates H3K27 methylation. Overexpression of SlJMJ6 accelerates tomato fruit ripening, which is associated with the upregulated expression of a large number of ripening-related genes. Integrated analysis of RNA-seq and chromatin immunoprecipitation followed by sequencing identified 32 genes directly targeted by SlJMJ6 and transcriptionally upregulated with decreased H3K27m3 in SlJMJ6-overexpressed fruit. Numerous SlJMJ6-regulated genes are involved in transcription regulation, ethylene biosynthesis, cell wall degradation and hormone signaling. Eleven ripening-related genes including RIPENING INHIBITOR (RIN), 1-aminocyclopropane 1-carboxylate synthase-4 (ACS4), 1-aminocyclopropane-1-carboxylate oxidase 1 (ACO1), pectate lyase (PL) and beta-galactosidase 4 (TBG4), and a DNA demethylase DML2, were confirmed to be regulated directly by SlJMJ6 through removing H3K27me3. Our results demonstrate that SlJMJ6 is a ripening-prompting H3K27me3 demethylase that activates the expression of the ripening-related genes by modulating H3K27me3, thereby facilitating tomato fruit ripening. Our work also reveals a novel link between histone demethylation and DNA demethylation in regulating fruit ripening. To our knowledge, this is the first report of the involvement of a histone lysine demethylase in the regulation of fruit ripening.

Role of PIWI-like 4 in modulating neuronal differentiation from human embryonal carcinoma cells

ABSTRACT PIWI homologs constitute a subclass of the Argonaute family. Traditionally, they have been shown to associate with a specific class of small RNAs, piRNAs, to suppress transposable elements and protect genomic integrity in germ cells. Recent studies imply that PIWI proteins may also exert important biological functions in somatic contexts, including the brain. However, their exact role in neural development remains unknown. Hence we investigated whether PIWI proteins are involved in neuronal differentiation. By using an established cell model for studying neurogenesis, NTera2/D1 (NT2) cells, we found that a particular PIWI homolog, PIWIL4 was increasingly upregulated throughout the course of all-trans retinoic acid (RA)-mediated neuronal differentiation. During this process, PIWIL4 knockdown led to partial recovery of embryonic stem cell markers, while suppressing RA-induced expression of neuronal markers. Consistently, PIWIL4 overexpression further elevated their expression levels. Furthermore, co-immunoprecipitation revealed an RA-induced interaction between PIWIL4 and the H3K27me3 demethylase UTX. Chromatin immunoprecipitation showed that this interaction could be essential for the removal of H3K27me3 from the promoters of RA-inducible genes. By a similar mechanism, PIWIL4 knockdown also suppressed the expression of PTN and NLGN3, two important neuronal factors secreted to regulate glioma activity. We further noted that the conditioned medium collected from PIWIL4-silenced NT2 cells significantly reduced the proliferation of glioma cells. Thus, our data suggest a novel somatic role of PIWIL4 in modulating the expression of neuronal genes that can be further characterized to promote neuronal differentiation and to modulate the activity of glioma cells.

Histone demethylase KDM6A promotes somatic cell reprogramming by epigenetically regulating the PTEN and IL-6 signal pathways.

Aberrant epigenetic reprogramming is one of the major barriers for somatic cell reprogramming. Although our previous study has indicated that H3K27me3 demethylase KDM6A can improve the nuclear reprogramming efficiency, the mechanism remains unclear. In this study, we demonstrate that the overexpression of Kdm6a may improve induced pluripotent stem cell (iPSC) reprogramming efficiency in a demethylase enzymatic activity-dependent manner. KDM6A erased H3K27me3 on pluripotency- and metabolism-related genes, and consequently facilitated changing the gene expression profile and metabolic pattern to an intermediate state. Furthermore, KDM6A may promote IL-6 expression, and the secreted IL-6 may further improve iPSC reprogramming efficiency. In addition, KDM6A may promote PTEN expression to decrease p-AKT and p-mTOR levels, which in turn facilitates reprogramming. Overall, our results reveal that KDM6A may promote iPSC reprogramming efficiency by accelerating changes in the gene expression profile and the metabolic pattern in a demethylation-activity-dependent manner. These results may provide an insight into the relationship between epigenomics, transcriptomics, metabolomics, and reprogramming.

Wnt/β-catenin signaling contributes to prostate cancer heterogeneity through reciprocal suppression of H3K27 trimethylation

Intratumoral heterogeneity remains as a major challenge in the treatment resistance of prostate cancer. Understanding the mechanism of prostate cancer heterogeneity is essential for developing effective therapies. In this study, we reported the heterogeneous activation of Wnt/β-catenin signaling in prostate cancer. We developed a Wnt/β-catenin signaling reporting system to directly characterize the differences between Wnt/β-catenin signaling active (GFP+) and inactive (GFP−) cells. Compared to GFP− cells, GFP+ cells demonstrated cancer stem cell properties with higher colony formation efficiency, slower cell cycle, higher resistance to docetaxel and higher expression of cancer stem cell markers. In addition, we found that Wnt/β-catenin signaling is negatively correlated with H3K27me3 levels. Further studies demonstrated that Wnt/β-catenin signaling affected H3K27me3 levels by regulating the expression of KDM6A, one of the H3K27me3 demethylases. H3K27me3 suppressed Wnt/β-catenin signaling by directly silencing LEF1 promoter. Together, our studies suggest that Wnt/β-catenin signaling makes a major contribution to prostate cancer heterogeneity and targeting both Wnt/β-catenin signaling active and inactive populations is essential for developing more effective therapies.

H3K27me3 demethylases are important epigenetic regulators of B cell differentiation

Abstract The humoral immune response relies on robust differentiation of naïve B cells into antibody secreting plasma cells (PC) in response to foreign, but not self-antigens. To ensure proper immune responses, B cell differentiation is regulated through processes that remodel the epigenome. The histone modification H3 lysine 27 trimethylation (H3K27me3) is associated with a repressive chromatin state and gene silencing. This histone modification is deposited by EZH2, which has been shown to regulate all stages of B cell differentiation leading to PC. However, a role for the two demethylases UTX and JMJD3 that remove H3K27me3 in B cells is still to be elucidated. To determine how these enzymes modulate B cell differentiation, we crossed Utxfl/flJmjd3fl/flmice onto the Cd19Cre/+background (dKO mice). Stimulation of Cd19Cre/+(CreCtrl) and dKO mice with the T cell independent antigen LPS led to a significant increase in PC in dKO mice. This phenotype was attributed to enhanced differentiation of marginal zone (MZ), but not follicular B cells (FoB). UTX- and JMJD3-deficient PC unregulated genes associated with oxidative phosphorylation metabolism and resulted in a significantly higher spare respiratory capacity. In response to infection with influenza virus, we observed a significant increase in GC B cells in UTX- and JMJD3-deficient mice. Taken together, our data place H3K27me3 demethylases as critical epigenetic regulators that restrict B cell responses to T cell dependent and independent stimuli.

H3K27me3 demethylase UTX regulates the differentiation of a subset of bipolar cells in the mouse retina.

Di- and trimethylation of lysine 27 on histone 3 (H3K27me2/3) is a critical gene repression mechanism. We previously showed that down-regulation of the H3K27 demethylase, Jumonji domain-containing protein 3 (JMJD3), resulted in a reduced number of protein kinase C (PKC)α-positive rod ON-bipolar cells. In this work, we focused on the role of another H3K27 demethylase, ubiquitously transcribed tetratricopeptide repeat X chromosome (UTX), in retinal development. UTX was expressed in the retinal progenitor cells of the embryonic mouse retina and was observed in the inner nuclear layer during late retinal development and in the mature retina. The short hairpin RNA-mediated knockdown of Utx in a mouse retinal explant led to a reduced number of PKCα-positive rod ON-bipolar cells. However, other retinal subtypes were unaffected by this knockdown. Using a retina-specific knockout of Utx in mice, the in vivo effects of UTX down-regulation were examined. Again, the number of PKCα-positive rod ON-bipolar cells was reduced, and no other apparent phenotypes, including retinal progenitor proliferation, apoptosis or differentiation, were observed. Finally, we examined retina-specific Utx and Jmjd3 double-knockout mice and found that although the number of rod ON-bipolar cells was reduced, no additional effects from the loss of Utx and Jmjd3 were observed. Taken together, our data show that UTX contributes to retinal differentiation in a lineage-specific manner.

KSHV ORF59 and PAN RNA Recruit Histone Demethylases to the Viral Chromatin during Lytic Reactivation.

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes multiple malignancies in immunocompromised individuals. KSHV primarily establishes a lifelong latency in infected humans during which only a subset of viral genes is expressed while most of the viral genome remains transcriptionally silent with condensed chromatin. However, during the lytic phase, the viral genome undergoes dramatic changes in chromatin landscape leading to a transcriptionally active state with the expression of most of the viral genes and production of progeny virions. Multiple cellular and viral factors influence the epigenetic gene regulation and transitioning of virus from latency to the lytic state. We have earlier shown that KSHV ORF59, viral processivity factor, binds to a protein arginine methyl transferase 5 (PRMT5) to alter the histone arginine methylation during reactivation. Additionally, ORF59 has been shown to interact with most abundantly expressed KSHV long noncoding polyadenylated nuclear RNA (PAN RNA), which associates with the viral epigenome during reactivation. Interestingly, PAN RNA interacts with UTX and JMJD3, cellular H3K27me3 demethylases, and removes the repressive marks on the chromatin. In this study, we report that the recruitment of histone demethylases to the viral chromatin is facilitated by the expression of ORF59 protein and PAN RNA. Using biochemical and localization assays including co-immunoprecipitation and immunofluorescence, we demonstate ORF59 localizes with UTX and JMJD3. Our results confirm that PAN RNA enhances the interaction of ORF59 with the chromatin modifying enzymes UTX and JMJD3.

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.

Jmjd3 is involved in the susceptibility to depression induced by maternal separation via enhancing the neuroinflammation in the prefrontal cortex and hippocampus of male rats

Adverse childhood experience is a major risk factor for the onset of depression in adulthood. Neuroinflammation characterized by microglial activation and cytokine secretion is involved in susceptibility to depression induced by early life stress. Jumonji domain-containing protein 3 (Jmjd3), a trimethylated lysine 27 in histone 3 (H3K27me3) demethylase, can be activated by nuclear factor-kappa B (NF-κB), further regulating the expression of pro-inflammatory cytokines and resulting in neuroinflammation. However, its involvement in susceptibility to early life stress-related depression is unknown. In the current study, maternal separation (MS) was utilized as a model of early life stress and systemic lipopolysaccharide (LPS) administration in adulthood was used as a later-life challenge. Depressive- and anxiety-like behaviors and memory impairment were detected by behavioral tests. Microglial activation, pro-inflammatory cytokine expression, and NF-κB, Jmjd3, and H3K27me3 expression were detected in the prefrontal cortex and hippocampus in both infant and adult rats. Meanwhile, the Jmjd3 inhibitor GSK-J4 was used as an intervention in vivo and in vitro. Our results showed that MS induced depression-like behaviors and synchronously caused microglial activation, pro-inflammatory cytokine over-expression, NF-κB and Jmjd3 over-expression, and decreased H3K27me3 expression in infant rats. All these alterations could also be detected in adulthood. Seven-day LPS administration in adult rats induced similar changes of behaviors and biomarkers. Interestingly, compared with rats not exposed to MS, MS-exposed rats receiving LPS administration developed more severe depression-like behaviors and neuroinflammatory status, higher levels of NF-κB and Jmjd3 expression, and lower levels of H3K27me3 expression. In addition, LPS induced microglial activation, pro-inflammatory cytokine expression and increased Jmjd3 expression in vitro. Furthermore, GSK-J4 treatment alleviated these alterations in vivo and in vitro. Thus, our data indicate that Jmjd3 is involved in the susceptibility to depression induced by MS via enhancement of neuroinflammation in the prefrontal cortex and hippocampus of rats.

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62.

In female mammals, the size of the initially established primordial follicle (PF) pool within the ovaries determines the reproductive lifespan of females. Interestingly, the establishment of the PF pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Although apoptosis and autophagy are involved in the process of oocyte loss, the underlying mechanisms require substantial study. Here, we identify a new role of lysine‐specific demethylase 1 (LSD1) in controlling the fate of oocytes in perinatal mice through regulating the level of autophagy. Our results show that the relatively higher level of LSD1 in fetal ovaries sharply reduces from 18.5 postcoitus (dpc). Meanwhile, the level of autophagy increases while oocytes are initiating programmed death. Specific disruption of LSD1 resulted in significantly increased autophagy and obviously decreased oocyte number compared with the control. Conversely, the oocyte number is remarkably increased by the overexpression of Lsd1 in ovaries. We further demonstrated that LSD1 exerts its role by regulating the transcription of p62 and affecting autophagy level through its H3K4me2 demethylase activity. Finally, in physiological conditions, a decrease in LSD1 level leads to an increased level of autophagy in the oocyte when a large number of oocytes are being lost. Collectively, LSD1 may be one of indispensible epigenetic molecules who protects oocytes against preterm death through repressing the autophagy level in a time‐specific manner. And epigenetic modulation contributes to programmed oocyte death by regulating autophagy in mice.