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The RNA modification N 6 -methyladenosine (m 6 A) has critical roles in many biological processes 1 , 2 . However, the function of m 6 A in the early phase of mammalian development remains poorly understood. Here we show that the m 6 A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m 6 A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m 6 A RNAs act upstream of SETDB1 to repress retrotransposons and Dux , the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m 6 A RNA and YTHDC1 in chromatin modification and retrotransposon repression. N 6 -methyladenosine RNA and its reader YTHDC1 serve as a bridge to silencing retrotransposons through the RNA derived from these retrotransposons in mouse ES cells.

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed 1 – 5 . Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance. . Androgen-receptor blockade can overcome immunotherapy resistance in prostate cancer by intrinsically enhancing T cell function and IFNγ responses. 

Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression and plant development. Here, we identified 6,510 lncRNAs in Arabidopsis under normal or stress conditions. We found that the expression of natural antisense transcripts (NATs) that are transcribed in the opposite direction of protein-coding genes often positively correlates with and is required for the expression of their cognate sense genes. We further characterized MAS , a NAT-lncRNA produced from the MADS AFFECTING FLOWERING4 ( MAF4) locus. MAS is induced by cold and indispensable for the activation of MAF4 transcription and suppression of precocious flowering. MAS activates MAF4 by interacting with WDR5a, one core component of the COMPASS-like complexes, and recruiting WDR5a to MAF4 to enhance histone 3 lysine 4 trimethylation (H3K4me3). Our study greatly extends the repertoire of lncRNAs in Arabidopsis and reveals a role for NAT-lncRNAs in regulating gene expression in vernalization response and likely in other biological processes. Long non-coding RNAs regulate developmental transitions and stress responses in plants. Here Zhao et al. show that a non-coding antisense transcript MAS transcribed from the Arabidopsis MAF4 locus activates H3K4me3 deposition and MAF4 transcription to suppress precocious flowering.

Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME −/− /ApoE −/− mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis. Macrophages have been shown to have an important function in atherosclerosis. Here the authors show that, in human atherosclerotic plaques and mouse models, GSDME and pyroptosis promote atherosclerosis and inhibition of these pathways could reduce pathology associated with atherosclerotic disease.

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed 1 . Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx , thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC. The growth of colorectal cancer is reduced by ketogenic diet consumption, the properties of which are mediated by the ketone body β-hydroxybutyrate.

The simultaneous improvement of grain quality and yield of cereal crops is a major challenge for modern agriculture. Here we show that a rice grain yield quantitative trait locus qLGY3 encodes a MADS-domain transcription factor OsMADS1, which acts as a key downstream effector of G-protein βγ dimers. The presence of an alternatively spliced protein OsMADS1 lgy3 is shown to be associated with formation of long and slender grains, resulting in increases in both grain quality and yield potential of rice. The Gγ subunits GS3 and DEP1 interact directly with the conserved keratin-like domain of MADS transcription factors, function as cofactors to enhance OsMADS1 transcriptional activity and promote the co-operative transactivation of common target genes, thereby regulating grain size and shape. We also demonstrate that combining OsMADS1 lgy3 allele with high-yield-associated dep1-1 and gs3 alleles represents an effective strategy for simultaneously improving both the productivity and end-use quality of rice. Cereal crops' grain yield and quality are traits that are usually considered to be negatively correlated. Here, the authors show that interaction of G-protein βγ subunits with an alternatively spliced MADS1 lgy3 protein can increase rice grain yield and quality simultaneously in field conditions.

Arbuscular mycorrhiza (AM) is a widespread symbiosis between roots of the majority of land plants and Glomeromycotina fungi. AM is important for ecosystem health and functioning as the fungi critically support plant performance by providing essential mineral nutrients, particularly the poorly accessible phosphate, in exchange for organic carbon. AM fungi colonize the inside of roots and this is promoted at low but inhibited at high plant phosphate status, while the mechanistic basis for this phosphate-dependence remained obscure. Here we demonstrate that a major transcriptional regulator of phosphate starvation responses in rice PHOSPHATE STARVATION RESPONSE 2 (PHR2) regulates AM. Root colonization of phr2 mutants is drastically reduced, and PHR2 is required for root colonization, mycorrhizal phosphate uptake, and yield increase in field soil. PHR2 promotes AM by targeting genes required for pre-contact signaling, root colonization, and AM function. Thus, this important symbiosis is directly wired to the PHR2-controlled plant phosphate starvation response. Arbuscular mycorrhiza support plant phosphate uptake. Here Das et al. show that PHR transcription factors permit arbuscular mycorrhiza symbiosis by promoting gene expression related to symbiosis development and maintenance.

Inflammation is a complex physiological process triggered in response to harmful stimuli 1 . It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases 2 – 4 . The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper (ii) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD + enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper (ii) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states. Cellular uptake of copper( ii ) by CD44 has a key role in regulating cellular plasticity via copper( ii )-dependent downstream signalling events.

The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human haematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains the nucleoporin IDR—tandemly dispersed repeats of phenylalanine and glycine residues 1 , 2 . However, how unstructured IDRs contribute to oncogenesis remains unclear. Here we show that IDRs contained within NUP98–HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias 1 , 2 , are essential for establishing liquid–liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. Notably, LLPS of NUP98–HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad ‘super-enhancer’-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein 3 , 4 , had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. Deeply sequenced Hi-C revealed that phase-separated NUP98–HOXA9 induces CTCF-independent chromatin loops that are enriched at proto-oncogenes. Together, this report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumourous transformation. As LLPS-competent molecules are frequently implicated in diseases 1 , 2 , 4 – 7 , this mechanism can potentially be generalized to many malignant and pathological settings. The NUP98–HOXA9 oncogenic fusion protein found in leukaemia undergoes phase separation in the nucleus, which helps to promote activation of leukaemic genes and to establish aberrant chromatin looping.

Phytochromes are bilin-binding photosensory receptors which control development over a broad range of environmental conditions and throughout the whole plant life cycle. Light-induced conformational changes enable phytochromes to interact with signaling partners, in particular transcription factors or proteins that regulate them, resulting in large-scale transcriptional reprograming. Phytochromes also regulate promoter usage, mRNA splicing and translation through less defined routes. In this review we summarize our current understanding of plant phytochrome signaling, emphasizing recent work performed in Arabidopsis. We compare and contrast phytochrome responses and signaling mechanisms among land plants and highlight open questions in phytochrome research. Perception of red and far-red light by photosensory phytochromes regulates plant development and adaptive responses to light. Here, Legris et al. review current models of phytochrome function connecting light-induced conformational changes to physiological outputs and highlight open questions for future research.