ABSTRACT
N6-methyladenosine (m6A) is the most prevalent RNA modification and is associated with various biological processes. Proteins that function as readers and writers of m6A modifications have been shown to play critical roles in human malignancies. Here, we identified KH-type splicing regulatory protein (KHSRP) as an m6A binding protein that contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). High KHSRP levels were detected in PDAC and predicted poor patient survival. KHSRP deficiency suppressed PDAC growth and metastasis in vivo. Mechanistically, KHSRP recognized and stabilized FAK pathway mRNAs, including MET, ITGAV and ITGB1, in an m6A-dependent manner, which led to activation of downstream FAK signaling that promoted PDAC progression. Targeting KHSRP with a PROTAC showed promising tumor suppressive effects in mouse models, leading to prolonged survival. Together, these findings indicate that KHSRP mediates FAK pathway activation in an m6A-dependent manner to support PDAC growth and metastasis, highlighting the potential of KHSRP as a therapeutic target in pancreatic cancer.
ABSTRACT
Post-earthquake rescue missions are full of challenges due to the unstable structure of ruins and successive aftershocks. Most of the current rescue robots lack the ability to interact with environments, leading to low rescue efficiency. The multimodal electronic skin (e-skin) proposed not only reproduces the pressure, temperature, and humidity sensing capabilities of natural skin but also develops sensing functions beyond it-perceiving object proximity and NO2 gas. Its multilayer stacked structure based on Ecoflex and organohydrogel endows the e-skin with mechanical properties similar to natural skin. Rescue robots integrated with multimodal e-skin and artificial intelligence (AI) algorithms show strong environmental perception capabilities and can accurately distinguish objects and identify human limbs through grasping, laying the foundation for automated post-earthquake rescue. Besides, the combination of e-skin and NO2 wireless alarm circuits allows robots to sense toxic gases in the environment in real time, thereby adopting appropriate measures to protect trapped people from the toxic environment. Multimodal e-skin powered by AI algorithms and hardware circuits exhibits powerful environmental perception and information processing capabilities, which, as an interface for interaction with the physical world, dramatically expands intelligent robots' application scenarios.
ABSTRACT
The construction of Cu-In bi-component catalysts is an effective strategy to enhance the electrocatalytic properties towards the CO2 reduction reaction (CO2RR). However, realizing the co-promotion of In and heteroatom P on the electrocatalytic performance is still a challenge due to the poor selectivity of metal phosphides. Herein, a novel bi-component catalyst (CuO-In(PO3)3/C) was successfully synthesized via a facile one-pot reaction to realize the integration of Cu, In, and P species for the enhancement of electrocatalysis. In particular, the as-obtained nanorod-like Cu-In(PO3)3/C exhibits superior electrocatalysis towards the CO2RR, with the highest Faraday efficiency of CO (FECO) of 88.5% at -0.586 V. Furthermore, Cu-In(PO3)3/C shows better activity, selectivity, and stability in the CO2RR; in particular, the total current density can reach 178.09 mA cm-2 at -0.886 V in 2.0 M KOH solution when a flow cell is employed. This work provides a reliable method for simplifying the synthesis of novel Cu-based catalysts and exploits the application of heteroatom P in the field of efficient CO2RR.
ABSTRACT
The construction of heterostructure materials has been demonstrated as the promising approach to design high-performance anode materials for sodium ion batteries (SIBs). Herein, micro-mesoporous cobalt phosphosulfide nanowires (Co3S4/CoP/NC) with Co3S4/CoP hetero-nanocrystals encapsulating into N-doped carbon frameworks were successfully synthesized via hydrothermal reaction and subsequent phosphosulfidation process. The obtained micro-mesoporous nanowires greatly improve the charge transport kinetics from the facilitation of the charge transport into the inner part of nanowire. When evaluated as SIBs anode material, the Co3S4/CoP/NC presents outstanding electrochemical performance and battery properties owing to the synergistic effect between Co3S4 and CoP nanocrystals and the conductive carbon frameworks. The electrode material delivers outstanding reversible rate capacity (722.33 mAh/g at 0.1 A/g) and excellent cycle stability with 522.22 mAh/g after 570 cycles at 5.0 A/g. Besides, the Ex-situ characterizations including XRD, XPS, and EIS further revealed and demonstrated the outstanding sodium ion storage mechanism of Co3S4/CoP/NC electrode. These findings pave a promising way for the development of novel metal phosphosulfide anodes with unexpected performance for SIBs and other alkali ion batteries.
ABSTRACT
The relevance of biopterin metabolism in resistance to immune checkpoint blockade (ICB) therapy remains unknown. We demonstrate that the deficiency of quinoid dihydropteridine reductase (QDPR), a critical enzyme regulating biopterin metabolism, causes metabolite dihydrobiopterin (BH2) accumulation and decreases the ratio of tetrahydrobiopterin (BH4) to BH2 in pancreatic ductal adenocarcinomas (PDACs). The reduced BH4/BH2 ratio leads to an increase in reactive oxygen species (ROS) generation and a decrease in the distribution of H3K27me3 at CXCL1 promoter. Consequently, myeloid-derived suppressor cells are recruited to tumor microenvironment via CXCR2 causing resistance to ICB therapy. We discovered that BH4 supplementation is capable to restore the BH4/BH2 ratio, enhance anti-tumor immunity, and overcome ICB resistance in QDPR-deficient PDACs. Tumors with lower QDPR expression show decreased responsiveness to ICB therapy. These findings offer a novel strategy for selecting patient and combining therapies to improve the effectiveness of ICB therapy in PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/metabolism , Humans , Animals , Mice , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Tumor Microenvironment , Cell Line, Tumor , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Mice, Inbred C57BL , Biopterins/analogs & derivatives , Biopterins/metabolism , Female , Male , Reactive Oxygen Species/metabolismABSTRACT
Flexible zinc-ion batteries have garnered significant attention in the realm of wearable technology. However, the instability of hydrogel electrolytes in a wide-temperature range and uncontrollable side reactions of the Zn electrode have become the main problems for practical applications. Herein, N,N-dimethylformamide (DMF) to design a binary solvent (H2O-DMF) is introduced and combined it with polyacrylamide (PAM) and ZnSO4 to synthesize a hydrogel electrolyte (denoted as PZD). The synergistic effect of DMF and PAM not only guides Zn2+ deposition on Zn(002) crystal plane and isolates H2O from the Zn anode, but also breaks the hydrogen bonding network between water to improve the wide-temperature range stability of hydrogel electrolytes. Consequently, the symmetric cell utilizing PZD can stably cycle over 5600 h at 0.5 mA cm- 2@0.5 mAh cm-2. Furthermore, the Zn//PZD//MnO2 full cell exhibits favorable wide-temperature range adaptability (for 16000 cycles at 3 A g-1 under 25 °C, 750 cycles with 98 mAh g-1 at 0.1 A g-1 under -20 °C) and outstanding mechanical properties (for lighting up the LEDs under conditions of pressure, bending, cutting, and puncture). This work proposes a useful modification for designing a high-performance hydrogel electrolyte, which provides a reference for investigating the practical flexible aqueous batteries.
ABSTRACT
Synthesis of advanced structure and multiple heteroatom-doped carbon based heterostructure materials are the key to the preparation of high-performance energy storage electrode materials. Herein, the hexapod-shaped Co1-xS@NPSC has been triumphantly prepared using hexapod ZIF-67 as the sacrificial template to prepare Co1-xS inner core and N, P, and S tri-doped carbon (NPSC) as the shell through the carbonization of the organic polymer precursor. When applied as anode for Na+ batteries (SIBs) and K+ batteries (PIBs), Co1-xS@NPSC presents the high reversible specific capability of 747.4 mAh/g at 1.0 A/g after 235 cycles and 387.8 mAh/g at 5.0 A/g after 760 cycles for SIBs, as well as 326.7 mAh/g at 1.0 A/g after 180 cycles for PIBs. The excellent storage capacity and rate capability of Co1-xS@NPSC is ascribed to hexapod structure of ZIF-67 unlike the common dodecahedron, which is constructed with interior porous and exterior framework repository, donating supplemental active sites, and doping of multiple heteroatoms forming organic polymer coating inhibiting the volume expansion and restrains the agglomeration of Co1-xS nanoparticles. This approach has paved a bright avenue to exploit promising anode materials with novel structure and hetero-atom doping for high-performance energy storage devices.
ABSTRACT
OBJECTIVE: Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered. DESIGN: We performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). We also conducted immunofluorescence staining and functional experiments to examine the mechanism. RESULTS: Integrative analyses of epithelial cells reveal a stem-like cell cluster with high protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA) expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary. CONCLUSION: We uncover a mechanism for organ-specific CRC metastasis.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Female , Humans , Colorectal Neoplasms/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Liver Neoplasms/pathology , Gene Expression Profiling , Signal Transduction/genetics , Gene Expression Regulation, Neoplastic , Neoplasm Metastasis/genetics , Tumor Microenvironment/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolismABSTRACT
The biological functions of noncoding RNA N6-methyladenosine (m6A) modification remain poorly understood. In the present study, we depict the landscape of super-enhancer RNA (seRNA) m6A modification in pancreatic ductal adenocarcinoma (PDAC) and reveal a regulatory axis of m6A seRNA, H3K4me3 modification, chromatin accessibility and oncogene transcription. We demonstrate the cofilin family protein CFL1, overexpressed in PDAC, as a METTL3 cofactor that helps seRNA m6A methylation formation. The increased seRNA m6As are recognized by the reader YTHDC2, which recruits H3K4 methyltransferase MLL1 to promote H3K4me3 modification cotranscriptionally. Super-enhancers with a high level of H3K4me3 augment chromatin accessibility and facilitate oncogene transcription. Collectively, these results shed light on a CFL1-METTL3-seRNA m6A-YTHDC2/MLL1 axis that plays a role in the epigenetic regulation of local chromatin state and gene expression, which strengthens our knowledge about the functions of super-enhancers and their transcripts.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Chromatin/genetics , RNA , Epigenesis, Genetic , Carcinoma, Pancreatic Ductal/genetics , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Oncogenes/genetics , Methyltransferases/geneticsABSTRACT
The violent side reactions of Zn metal in aqueous electrolyte lead to sharp local-pH fluctuations at the interface, which accelerate Zn anode breakdown; thus, the development of an optimization strategy to accommodate a wide pH range is particularly critical for improving aqueous Zn metal batteries. Herein, we report a pH-adaptive electric double layer (EDL) tuned by glycine (Gly) additive with pH-dependent ionization, which exhibits excellent capability to stabilize Zn anodes in wide-pH aqueous electrolytes. It is discovered that a Gly-ionic EDL facilitates the directed migration of charge carriers in both mildly acidic and alkaline electrolytes, leading to the successful suppression of local saturation. It is worth mentioning that the regulation effect of the additive concentration on the inner Helmholtz plane (IHP) structure of Zn electrodes is clarified in depth. It is revealed that the Gly additives without dimerization can develop orderly and dense vertical adsorption within the IHP to effectively reduce the EDL repulsive force of Zn2+ and isolate H2O from the anode surface. Consequently, they Zn anode with tunable EDL exhibits superior electrochemical performance in a wide range of pH and temperature, involving the prodigious cycle reversibility of 7000 h at Zn symmetric cells with ZnSO4-Gly electrolytes and an extended lifespan of 50 times in Zn symmetric cells with KOH-Gly electrolytes. Moreover, acidic Zn powder||MnO2 pouch cells, and alkaline high-voltage Zn||Ni0.8Co0.1Mn0.1O2 cells, and Zn||NiCo-LDH cells also deliver excellent cycling reversibility. The tunable EDL enables the ultrahigh depth of discharge (DOD) of 93%. This work elucidates the design of electrolyte additives compatible in a wide range of pH and temperature, which might cause inspiration in the fields of practical multiapplication scenarios for Zn anodes.
ABSTRACT
The electrocatalytic carbon dioxide reduction (CO2RR) is one of the emerging technologies that can effectively transform carbon dioxide (CO2) into valuable products. Electrocatalysts deriving from green synthesis methods will significantly help to establish a new green carbon cycle. Herein, a green electrodeposition method without additional reducing agents was used to synthesize Cu-Ag bimetallic catalysts, and it is shown that the combination of Cu and Ag obviously affects the morphology of the Cu-Ag catalysts, resulting in the formation of elaborate tree-like Cu-Ag clusters. An as-deposited Cu-Ag/carbon fiber (Cu-Ag/CF) catalyst exhibits high activity, selectivity and stability toward the CO2RR; in particular, the elaborate dendritic Cu-Ag/CF can efficiently reduce CO2 to syngas with high selectivity (Faradaic efficiency (FE) > 95%) at a low onset potential (-0.5 V). This work provides a rational strategy to overcome the significantly different reaction capacities during the reduction of Ag+ and Cu2+, leading to the formation of a controlled morphology of Cu-Ag, which is favourable for the design and development of highly efficient Cu or Ag catalysts via green methods for electrocatalyzing the CO2RR.
ABSTRACT
N6-methyladenosine (m6A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m6A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m6A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m6A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m6A regulator CSTF2 that co-transcriptionally regulates m6A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m6As have positive effects on the RNA level of host genes, and CSTF2-regulated m6As are mainly recognized by IGF2BP2, an m6A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , RNA, Messenger/genetics , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/pathology , Gene Expression Regulation, Neoplastic , RNA-Binding Proteins/genetics , Pancreatic NeoplasmsABSTRACT
C-Myc overexpression contributes to multiple hallmarks of human cancer but directly targeting c-Myc is challenging. Identification of key factors involved in c-Myc dysregulation is of great significance to develop potential indirect targets for c-Myc. Herein, a collection of long non-coding RNAs (lncRNAs) interacted with c-Myc is detected in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, lncRNA BCAN-AS1 is identified as the one with highest c-Myc binding enrichment. BCAN-AS1 was abnormally elevated in PDAC tumors and high BCAN-AS1 level was significantly associated with poor prognosis. Mechanistically, Smad nuclear-interacting protein 1 (SNIP1) was characterized as a new N6-methyladenosine (m6A) mediator binding to BCAN-AS1 via recognizing its m6A modification. m6A-modified BCAN-AS1 acts as a scaffold to facilitate the formation of a ternary complex together with c-Myc and SNIP1, thereby blocking S phase kinase-associated protein 2 (SKP2)-mediated c-Myc ubiquitination and degradation. Biologically, BCAN-AS1 promotes malignant phenotypes of PDAC in vitro and in vivo. Treatment of metastasis xenograft and patient-derived xenograft mouse models with in vivo-optimized antisense oligonucleotide of BCAN-AS1 effectively represses tumor growth and metastasis. These findings shed light on the pro-tumorigenic role of BCAN-AS1 and provide an innovant insight into c-Myc-interacted lncRNA in PDAC.
ABSTRACT
Herein, a well-designed hierarchical architecture of bimetallic transition sulfide FeIn2S4 nanoparticles anchoring on the Ti3C2 MXene flakes has been prepared by cation exchange and subsequent high-temperature sulfidation processes. The introduction of MXene substrate with excellent conductivity not only accelerates the migration rate of Na+ to achieve fast reaction dynamics but provides abundant deposition sites for the FeIn2S4 nanoparticles. In addition, this hierarchical structure of MXene@FeIn2S4 can effectively restrain the accumulation of MXene to guarantee the maximized exposure of redox active sites into the electrolyte, and simultaneously relieve the volume expansion in the repeated discharging/charging processes. The MXene@FeIn2S4 displays outstanding rate capability (448.2 mAh g-1 at 5 A g-1) and stable long cycling performance (428.1 mAh g-1 at 2 A g-1 after 200 cycles). Moreover, the Nay-In6S7 phase detected by ex-situ XRD and XPS characterization may be regarded as a "buffer" to maintain the stability of the Fe-based components and enhance the reversibility of the electrochemical reaction. This work confirms the practicability of constructing the hierarchical structure bimetallic sulfides with the promising electrochemical performance.
ABSTRACT
The therapeutic options for treating pancreatic ductal adenocarcinoma (PDAC) are limited, and resistance to gemcitabine, a cornerstone of PDAC chemotherapy regimens, remains a major challenge. N6-methyladenosine (m6A) is a prevalent modification in mRNA that has been linked to diverse biological processes in human diseases. Herein, by characterizing the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified a key role for elevated m6A modification of the master G0-G1 regulator FZR1 in regulating gemcitabine sensitivity. Targeting FZR1 m6A modification augmented the response to gemcitabine treatment in gemcitabine-resistant PDAC cells both in vitro and in vivo. Mechanistically, GEMIN5 was identified as a novel m6A mediator that specifically bound to m6A-modified FZR1 and recruited the eIF3 translation initiation complex to accelerate FZR1 translation. FZR1 upregulation maintained the G0-G1 quiescent state and suppressed gemcitabine sensitivity in PDAC cells. Clinical analysis further demonstrated that both high levels of FZR1 m6A modification and FZR1 protein corresponded to poor response to gemcitabine. These findings reveal the critical function of m6A modification in regulating gemcitabine sensitivity in PDAC and identify the FZR1-GEMIN5 axis as a potential target to enhance gemcitabine response. SIGNIFICANCE: Increased FZR1 translation induced by m6A modification engenders a gemcitabine-resistant phenotype by inducing a quiescent state and confers a targetable vulnerability to improve treatment response in PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cdh1 Proteins , Cell Line, Tumor , Gemcitabine/pharmacology , Gemcitabine/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , RNA, Messenger/genetics , Pancreatic NeoplasmsABSTRACT
RNA N6 -methyladenosine modification is the most prevalent internal modification of eukaryotic RNAs and has emerged as a novel field of RNA epigenetics, garnering increased attention. To date, m6 A modification has been shown to impact multiple RNA metabolic processes and play a vital role in numerous biological processes. Recent evidence suggests that aberrant m6 A modification is a hallmark of cancer, and it plays a critical role in cancer development and progression through multiple mechanisms. Here, we review the biological functions of mRNA m6 A modification in various types of cancers, with a particular focus on metabolic reprogramming, programmed cell death and tumor metastasis. Furthermore, we discuss the potential of targeting m6 A modification or its regulatory proteins as a novel approach of cancer therapy and the progress of research on m6 A modification in tumor immunity and immunotherapy. Finally, we summarize the development of different m6 A detection methods and their advantages and disadvantages.
Subject(s)
Neoplasms , Humans , RNA, Messenger/genetics , RNA, Messenger/metabolism , Methylation , Neoplasms/genetics , Neoplasms/therapy , Neoplasms/metabolism , RNA/genetics , RNA/metabolism , Epigenesis, GeneticABSTRACT
In this work, selenide-doped bismuth sulfides (Bi2S3-xSex) was successfully prepared through Se doping Bi2S3 Se to improve the electronic conductivity and increase the interlayer spacing. Then the anisotropic ReS2 nanosheet arrays were grown on the surface of Bi2S3-xSex to form a hierarchical heterostructure (Bi2S3-xSex@ReS2). The doping and construction of heterostructure processes can greatly improve the electrochemical conductivity of electrode materials and relieve the volume expansion during the continuous charge/discharge processes. While applied as SIBs anode, the specific capacity of 330 mAh g-1 was maintained after 450 cycles at the current density of 1.0 A g-1. It can also keep 200 mAh g-1 specific capacity after 900 cycles at 1.0 A g-1 for the anode of PIBs. This heterogeneous engineering and doping dual strategies could provide a good idea for the synthesis of new bimetallic sulfides with outstanding battery performance for SIBs and PIBs.
ABSTRACT
Rechargeable aqueous zinc-ion batteries have great promise for becoming next-generation storage systems, although the irreversible intercalation of Zn2+ and sluggish reaction kinetics impede their wide application. Therefore, it is urgent to develop highly reversible zinc-ion batteries. In this work, we modulate the morphology of vanadium nitride (VN) with different molar amounts of cetyltrimethylammonium bromide (CTAB). The optimal electrode has porous architecture and excellent electrical conductivity, which can alleviate volume expansion/contraction and allow for fast ion transmission during the Zn2+ storage process. Furthermore, the CTAB-modified VN cathode undergoes a phase transition that provides a better framework for vanadium oxide (VOx). With the same mass of VN and VOx, VN provides more active material after phase conversion due to the molar mass of the N atom being less than that of the O atom, thus increasing the capacity. As expected, the cathode displays an excellent electrochemical performance of 272 mAh g-1 at 5 A g-1, high cycling stability up to 7000 cycles, and excellent performance over a wide temperature range. This discovery creates new possibilities for the development of high-performance multivalent ion aqueous cathodes with rapid reaction mechanisms.
ABSTRACT
Covalent organic frameworks (COFs) are regarded as the potential and promising anode materials for potassium ion batteries (PIBs) on account of their robust and porous crystalline structure. In this work, multilayer structural COF connected by double functional groups, including imine and amidogent through a simple solvothermalprocess, have been successfully synthesized. The multilayer structure of COF can provide fast charge transfer and combine the merits of imine (the restraint of irreversible dissolution) and amidogent (the supply of more active sites). It presents superior potassium storage performance, including the high reversible capacity of 229.5 mAh g-1 at 0.2 A g-1 and outstanding cycling stability of 106.1 mAh g-1 at the high current density of 5.0 A g-1 after 2000 cycles, which is superior to the individual COF. The structural advantages of the covalent organic framework linking by double functional groups (d-COF) can develop a new road for that COF anode material for PIBs in further research.
ABSTRACT
Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining cell identity. The interplay between different epigenetic modifications and its contribution to transcriptional regulation remains elusive. Here, we show that METTL3-mediated RNA N6-methyladenosine (m6A) formation leads to DNA demethylation in nearby genomic loci in normal and cancer cells, which is mediated by the interaction between m6A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1. Upon recognizing RNA m6A, FXR1 recruits TET1 to genomic loci to demethylate DNA, leading to reprogrammed chromatin accessibility and gene transcription. Therefore, we have characterized a regulatory mechanism of chromatin accessibility and gene transcription mediated by RNA m6A formation coupled with DNA demethylation, highlighting the importance of the crosstalk between RNA m6A and DNA modification in physiologic and pathogenic process.