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In acute cold stress in mammals, JMJD1A, a histone H3 lysine 9 (H3K9) demethylase, upregulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals have another mechanism to cope with long-term cold stress by inducing the browning of the subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation-independent acute Ucp1 induction in BAT and demethylation-dependent chronic Ucp1 expression in beige scWAT provides complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namely, β-adrenergic receptor and peroxisome proliferator-activated receptor-γ (PPARγ) activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis. S265 phosphorylation of JMJD1A, and the following demethylation of H3K9me2 might prove to be a novel molecular target for the treatment of metabolic disorders, via promoting beige adipogenesis. JMJD1A is essential for thermogenic gene induction in brown adipose tissue. Here the authors show that white adipose tissue beige-ing requires both β-adrenergic-dependent phosphorylation of S265 and demethylation activity of JMJD1A while brown adipose tissue-driven thermogenesis requires β-adrenergic dependent phosphorylation of S265 but is independent of H3K9me2 demethylation.

Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG–independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.

Acclimation to high temperature increases plants’ tolerance of subsequent lethal high temperatures. Although epigenetic regulation of plant gene expression is well studied, how plants maintain a memory of environmental changes over time remains unclear. Here, we show that JUMONJI (JMJ) proteins, demethylases involved in histone H3 lysine 27 trimethylation (H3K27me3), are necessary for Arabidopsis thaliana heat acclimation. Acclimation induces sustained H3K27me3 demethylation at HEAT SHOCK PROTEIN22 ( HSP22 ) and HSP17.6C loci by JMJs, poising the HSP genes for subsequent activation. Upon sensing heat after a 3-day interval, JMJs directly reactivate these HSP genes. Finally, jmj mutants fail to maintain heat memory under fluctuating field temperature conditions. Our findings of an epigenetic memory mechanism involving histone demethylases may have implications for environmental adaptation of field plants. Acclimation to high temperature increases tolerance of heat shock in plants. Here the authors show that JUMONJI H3K27me3 demethylases are needed for heat acclimation in Arabidopsis and act at loci encoding HEAT SHOCK PROTEINS to facilitate induction upon heat stress.

Cancer-associated IDH mutants that produce 2-hydroxyglutarate are shown to prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. Cancer induction by isocitrate dehydrogenase mutation Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in gliomas, the most common form of brain tumour, and in other cancers including leukaemias. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a potential oncometabolite. Three papers in this issue of Nature examine the mechanisms through which IDH mutations promote cancers. Lu et al . show that 2HG-producing IDH mutants can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Turcan et al . show that IDH1 mutation in primary human astrocytes induces DNA hypermethylation and reshapes the methylome to resemble that of the CIMP phenotype, a common feature of gliomas and other solid tumours. Koivunen et al . show that the ( R )-enantiomer of 2HG (but not the ( S )-enantiomer) can stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of hypoxia-inducible factor (HIF), which in turn can enhance cell proliferation. These papers establish a framework for understanding gliomagenesis and highlight the interplay between genomic and epigenomic changes in human cancers. Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate 1 , 2 , 3 , 4 , 5 , 6 . Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro . Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.

Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.

Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb , Atg7 , Atgl , and Fgf21 , through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals. Fasting induces hepatic autophagy to preserve energy homeostasis. Here the authors report that fasting induced fibroblast growth factor 21 signalling induces autophagy by activating lysine-specific demethylase 6B, leading to histone demethylation mediated activation of autophagy genes.

Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.

Macrophages can be divided into two subsets, M1 and M2, which have crucial differences in their function. Akira and colleagues identify the histone demethylase Jmjd3 as a key factor in M2 development. Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infections, respectively. Jumonji domain containing-3 (Jmjd3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in the activation of macrophages. Here we show that Jmjd3 is essential for M2 macrophage polarization in response to helminth infection and chitin, though Jmjd3 is dispensable for M1 responses. Furthermore, Jmjd3 (also known as Kdm6b ) is essential for proper bone marrow macrophage differentiation, and this function depends on demethylase activity of Jmjd3. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited number of genes. Among them, we identified Irf4 as encoding a key transcription factor that controls M2 macrophage polarization. Collectively, these results show that Jmjd3-mediated H3K27 demethylation is crucial for regulating M2 macrophage development leading to anti-helminth host responses.

Methods for quantifying gene expression 1 and chromatin accessibility 2 in single cells are well established, but single-cell analysis of chromatin regions with specific histone modifications has been technically challenging. In this study, we adapted the CUT&Tag method 3 to scalable nanowell and droplet-based single-cell platforms to profile chromatin landscapes in single cells (scCUT&Tag) from complex tissues and during the differentiation of human embryonic stem cells. We focused on profiling polycomb group (PcG) silenced regions marked by histone H3 Lys27 trimethylation (H3K27me3) in single cells as an orthogonal approach to chromatin accessibility for identifying cell states. We show that scCUT&Tag profiling of H3K27me3 distinguishes cell types in human blood and allows the generation of cell-type-specific PcG landscapes from heterogeneous tissues. Furthermore, we used scCUT&Tag to profile H3K27me3 in a patient with a brain tumor before and after treatment, identifying cell types in the tumor microenvironment and heterogeneity in PcG activity in the primary sample and after treatment. An improved method for single-cell analysis of histone modifications is applied to stem cell differentiation and cancer.

ObjectiveCancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells.DesignTwelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database.ResultsCAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration.ConclusionsH3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.