H6N2 reassortant avian influenza virus isolate in wild birds in Jiangxi Province, China.

H6 avian influenza virus is widely prevalent in wild birds and poultry and has caused human infection in 2013 in Taiwan, China. During our active influenza surveillance program in wild waterfowl at Poyang Lake, Jiangxi Province, an H6N2 AIV was isolated and named A/bean goose/JiangXi/452-4/2013(H6N2). The isolate was characterized as a typical low pathogenic avian influenza virus (LPAIV) due to the presence of the amino acid sequence PQIETR↓GLFGAI at the cleavage site of the hemagglutinin (HA) protein. The genetic evolution analysis revealed that the NA gene of the isolate originated from North America and exhibited the highest nucleotide identity (99.29%) with a virus recovered from wild bird samples in North America, specifically A/bufflehead/California/4935/2012(H11N2). Additionally, while the HA and PB1 genes belonged to the Eurasian lineage, they displayed frequent genetic interactions with the North American lineage. The remaining genes showed close genetic relationships with Eurasian viruses. The H6N2 isolate possessed a complex genome, indicating it is a multi-gene recombinant virus with genetic material from both Eurasian and North American lineages.

Emergence, Evolution, and Pathogenicity of Influenza A(H7N4) Virus in Shorebirds in China.

A 2-year surveillance study of influenza A viruses in migratory birds was conducted to understand the subsequent risk during the migratory seasons in Dandong Yalu River Estuary Coastal Wetland National Nature Reserve, Liaoning Province, China, a major stopover site on the East Asian-Australasian flyway. Overall, we isolated 27 influenza A viruses with multiple subtypes, including H3N8 (n = 2), H4N6 (n = 2), H4N7 (n = 2), H7N4 (n = 9), H7N7 (n = 1), H10N7 (n = 7), and H13N6 (n = 4). Particularly, a novel reassortant influenza A(H7N4) virus was first identified in a woman and her backyard poultry flock in Jiangsu Province, China, posing a serious threat to public health. Here, we describe the genetic characterization and pathogenicity of the nine influenza A(H7N4) isolates. Phylogenetic analysis indicated that complex viral gene flow occurred among Asian countries. We also demonstrated a similar evolutionary trajectory of the surface genes of the A(H7N4) isolates and Jiangsu human-related A(H7N4) viruses. Our A(H7N4) isolates exhibited differing degrees of virulence in mice, suggesting a potential risk to other mammalian species, including humans. We revealed multiple mutations that might affect viral virulence in mice. Our report highlights the importance and need for the long-term surveillance of avian influenza virus in migratory birds combined with domestic poultry surveillance along migratory routes and flyways and, thereby, the development of measures to manage potential health threats. IMPORTANCE The H7 subtype avian influenza viruses, such as H7N2, H7N3, H7N4, H7N7, and H7N9, were documented as being capable of infecting humans, and the H7 subtype low pathogenicity avian influenza viruses are capable of mutating into highly pathogenic avian influenza; therefore, they pose a serious threat to public health. Here, we investigated the evolutionary history, molecular characteristics, and pathogenicity of shorebird-origin influenza A(H7N4) viruses, showing a similar evolutionary trajectory with Jiangsu human A(H7N4) viruses in HA and NA genes. Moreover, our isolates exhibited variable virulence (including moderate virulence) in mice, suggesting a potential risk to other mammalian species, including humans.

Highly Pathogenic Avian Influenza A(H5N8) Clade 2.3.4.4b Viruses in Satellite-Tracked Wild Ducks, Ningxia, China, 2020.

During October 2020, we identified 13 highly pathogenic avian influenza A(H5N8) clade 2.3.4.4b viruses from wild ducks in Ningxia, China. These viruses were genetically related to H5N8 viruses circulating mainly in poultry in Europe during early 2020. We also determined movements of H5N8 virus‒infected wild ducks and evidence for spreading of viruses.

Two-stage particle separation channel based on standing surface acoustic wave.

Microfluidic technology has great advantages in the precise manipulation of micro and nano particles, and the collection method of micro and nano particles based on ultrasonic standing waves has attracted much attention for its high efficiency and simplicity of structure. This article proposes a two-stage particle separation channel using ultrasound. In the microfluidic channel, two different sound pressure regions are used to achieve the separation of particles with positive acoustic contrast factors. Through numerical simulation, the performance of three common piezoelectric substrate materials was compared qualitatively and quantitatively, and it was found that the output sound pressure intensity of 128°YX-LiNbO3 was high and the output was stable. At the same time, the influence of the number of electrode pairs of the interdigital transducer and the electrode voltage on the output sound wave is studied. Finally, 15 pairs of electrode pairs are selected, and the electrode voltages of the two sound pressure regions are 2.0 V and 3.0 V, respectively. After selecting the corresponding parameters, the separation process was numerically simulated, and the separation of three kinds of particles was successfully achieved. This work has laid a certain theoretical foundation for rapid disease diagnosis and real-time monitoring of the environment in practical applications.

Ecosystem services in conservation planning: Assessing compatible vs. incompatible conservation.

The compatible conservation of ecosystem services (ES) refers to the sustainable development of a region and the multiple dimensions of the region population's well-being. Applying the ES relationship to systematic conservation planning (SCP) can help determine the protection priorities associated with ES and support good zoning decisions. This study uses Nanchang, China as a case study to construct a multi-scenario ES protection scheme. This includes evaluating the spatial distribution characteristics of four core ES, and the ES relationships in the subregion in Nanchang. The ES relationship is then used to construct three ES conservation scenarios (synergetic, trade-off and incompatible), and the SCP tool is used for zoning. The results show the following. First, the incompatible scenario prioritizes the conservation of supporting services and provisioning services, which support ecological protection and cultivated land security. Second, given a land management and control threshold, the management zones can be compatible with a large proportion of secondary services in the synergetic scenario (22%). Fewer secondary services are compatible under the trade-off scenario (8%). As the compatible secondary service targets increase, each management zone area experiences a nonlinear change. The spatial change is more stable in the synergetic scenario compared to the trade-off scenario, and the space of management zone becomes discrete under the trade-off scenario. Third, the compatibility process has a feedback effect on the ES relationship. Compared with the trade-off scenario, compatible synergetic services are more stable with respect to changes in the ES relationship. Constructing ecological buffer zones takes up cultivated land, decreasing the synergy between carbon sequestration services and food production services. However, ecological buffer zones should play a role in certain areas. The compatibility of increased food production services and habitat services in priority conservation and controlled development zones enhance ES trade-offs. An increase in cultural services is compatible with carbon sequestration services in the ecological buffer zone. This changes the relationship between ES, from having a weak trade-off to having a weak synergy. Creating a compatible ES is a spatial trade-off process; these synergies and trade-offs should be considered in spatial planning. An appropriate proportion of ES should be allocated to each zone, to increase the coordinated management of the urban-rural ecology.

Polarization enhancement of linearly polarized light through foggy environments at UV-NIR wavelengths.

Wavelength is an essential factor affecting polarization propagation. We investigate the polarization persistence of linearly polarized light from ultraviolet to near-IR in foggy environments. Certain spectral bands, from ultraviolet to IR wavelengths that exhibit lower path loss, were initially selected. Using polarization-tracking Monte Carlo simulations for varying particle size, wavelength, refractive index and detection range, it is shown that linear polarization exhibits different persistence performance at different wavelengths in various foggy environments. For wet haze of 0.6 µm or 1 µm droplets, parallel polarization increases persistently as the wavelength increases, and has superior persistence in the near-IR region. For radiation fog of 5 µm or 7.5 µm droplets, parallel polarization shows superior persistence in the ultraviolet region. For advection fog of 15 µm or 45 µm droplets, parallel polarization shows a superior persistence in the ultraviolet region. It is therefore shown that changing the wavelength can improve linear polarization persistence in foggy environments.

Forward transmission characteristics in polystyrene solution with different concentrations by use of circularly and linearly polarized light.

Polarized light forward propagation in scattering environments is important basic research. Polystyrene microspheres in water are common scattering environments that can be helpful to investigate in existing literature research. In this paper, we investigated the polarization state persistence of both linearly and circularly polarized light. We used a single active source with a wavelength of 532 nm to illuminate 1 µm diameter polystyrene spheres immersed in water. To evaluate the polarization state persistence of linearly and circularly polarized light, a parameter change of polarization state was used to replace the Stokes parameters. In the setting environments of different concentrations, circularly polarized light has superior polarization state persistence to that of linearly polarized light.

Cost-effective mid-infrared micropolarizer fabricated on common silicon by soft nanoimprint lithography.

We fabricated a cost-effective mid-IR micropolarizer on a common Si substrate. To improve the transmittance of Si, we performed a double oxidation on the silicon substrate. The SiO2-Si-SiO2 structure improved the transmittance of Si from 54% to 63%-83%. Then, the mid-IR micropolarizer with multidirectional gratings was fabricated using a soft nanoimprint process followed by the thermal evaporation of Al. Experimental measurements showed a transverse magnetic transmittance in the range of 61%-80% at wavelengths of 4-5 µm, and the extinction ratio was greater than 19 dB.

Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction.

Among the five serine incorporator (SERINC) family members, SERINC5 (Ser5) was reported to strongly inhibit HIV-1 replication, which is counteracted by Nef. Ser5 produces 5 alternatively spliced isoforms: Ser5-001 has 10 putative transmembrane domains, whereas Ser5-004, -005, -008a, and -008b do not have the last one. Here, we confirmed the strong Ser5 anti-HIV-1 activity and investigated its isoforms' expression and antiviral activities. It was found that Ser5-001 transcripts were detected at least 10-fold more than the other isoforms by real-time quantitative PCR. When Ser5-001 and its two isoforms Ser5-005 and Ser5-008a were expressed from the same mammalian expression vector, only Ser5-001 was stably expressed, whereas the others were poorly expressed due to rapid degradation. In addition, unlike the other isoforms, which are located mainly in the cytoplasm, Ser5-001 is localized primarily to the plasma membrane. To map the critical determinant, Ser5 mutants bearing C-terminal deletions were created. It was found that the 10th transmembrane domain is required for Ser5 stable expression and plasma membrane localization. As expected, only Ser5-001 strongly inhibits HIV-1 infectivity, whereas the other Ser5 isoforms and mutants that do not have the 10th transmembrane domain show very poor activity. It was also observed that the Nef counteractive activity could be easily saturated by Ser5 overexpression. Thus, we conclude that Ser5-001 is the predominant antiviral isoform that restricts HIV-1, and the 10th transmembrane domain plays a critical role in this process by regulating its protein stability and plasma membrane targeting.IMPORTANCE Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) express a small protein, Nef, to enhance viral pathogenesis in vivo Nef has an important in vitro function, which is to make virus particles more infectious, but the mechanism has been unclear. Recently, Nef was reported to counteract a novel anti-HIV host protein, SERINC5 (Ser5). Ser5 has five alternatively spliced isoforms, Ser5-001, -004, -005, -008a, and -008b, and only Ser5-001 has an extra C-terminal transmembrane domain. We now show that the Ser5-001 transcripts are produced at least 10-fold more than the others, and only Ser5-001 produces stable proteins that are targeted to the plasma membrane. Importantly, only Ser5-001 shows strong anti-HIV-1 activity. We further demonstrate that the extra transmembrane domain is required for Ser5 stable expression and plasma membrane localization. These results suggest that plasma membrane localization is required for Ser5 antiviral activity, and Ser5-001 is the predominant isoform that contributes to the activity.

Voltage-Dependent Anion Channel 1 Interacts with Ribonucleoprotein Complexes To Enhance Infectious Bursal Disease Virus Polymerase Activity.

Infectious bursal disease virus (IBDV) is a double-stranded RNA (dsRNA) virus. Segment A contains two overlapping open reading frames (ORFs), which encode viral proteins VP2, VP3, VP4, and VP5. Segment B contains one ORF and encodes the viral RNA-dependent RNA polymerase, VP1. IBDV ribonucleoprotein complexes are composed of VP1, VP3, and dsRNA and play a critical role in mediating viral replication and transcription during the virus life cycle. In the present study, we identified a cellular factor, VDAC1, which was upregulated during IBDV infection and found to mediate IBDV polymerase activity. VDAC1 senses IBDV infection by interacting with viral proteins VP1 and VP3. This association is caused by RNA bridging, and all three proteins colocalize in the cytoplasm. Furthermore, small interfering RNA (siRNA)-mediated downregulation of VDAC1 resulted in a reduction in viral polymerase activity and a subsequent decrease in viral yield. Moreover, overexpression of VDAC1 enhanced IBDV polymerase activity. We also found that the viral protein VP3 can replace segment A to execute polymerase activity. A previous study showed that mutations in the C terminus of VP3 directly influence the formation of VP1-VP3 complexes. Our immunoprecipitation experiments demonstrated that protein-protein interactions between VDAC1 and VP3 and between VDAC1 and VP1 play a role in stabilizing the interaction between VP3 and VP1, further promoting IBDV polymerase activity.IMPORTANCE The cellular factor VDAC1 controls the entry and exit of mitochondrial metabolites and plays a pivotal role during intrinsic apoptosis by mediating the release of many apoptogenic molecules. Here we identify a novel role of VDAC1, showing that VDAC1 interacts with IBDV ribonucleoproteins (RNPs) and facilitates IBDV replication by enhancing IBDV polymerase activity through its ability to stabilize interactions in RNP complexes. To our knowledge, this is the first report that VDAC1 is specifically involved in regulating IBDV RNA polymerase activity, providing novel insight into virus-host interactions.

Infrared micropolarizer array fabricated using a reversal nanoimprint.

Using a reversal nanoimprint and metal evaporation process, we fabricated a micropolarizer array for the 2.5-7 µm wavelength region. The micropolarizer array has a unique unit, which is composed of 2×3 arrays on an intrinsic silicon substrate. Each array consists of a 200 nm period bilayer Al grating in a 1.3 mm×1.3 mm aperture. The transmittance of transverse magnetic polarization of each array is greater than 65% in the 2.5-7 µm wavelength range, and the extinction ratio is over 35 dB in the 3-4 µm and 6-7 µm wavelength range. This fabricated micropolarizer array has lower costs and better compatibility with microfabrication processes.

Large-area flexible infrared nanowire grid polarizer fabricated using nanoimprint lithography.

We fabricated a 4-in large-area flexible infrared nanowire grid polarizer using a nanoimprint and metal thermal evaporation process. To protect the Si master template, as well as to prolong the service life of it, we first fabricated a nickel template as an alternative by an electroforming process. Then, the nanowire grid structure was transferred from this template to IPS substrate by a thermal nanoimprint process. Finally, Al was deposited on the IPS nanowire structure by vertical thermal evaporation technology. The results of the infrared optical test reveal that the TM transmittance of the polarizer is greater than 60% in the 4-5.71 µm and 5.73-6.7 µm wavelength ranges, and, especially, it is greater than 70% in the wavelength ranges of 4.70-5.69 µm and 5.75-6.59 µm. The extinction ratio is more than 20 dB in the wavelength range of 3.6-6.7 µm, proving that the polarizer has good polarization characteristics. The flexible infrared nanowire grid polarizer has potential applications in the fields of curved surface monitoring equipment and polarized imaging equipment.

Visible-IR transmission enhancement through fog using circularly polarized light.

Detection range is an important factor affecting the transmission characteristics of polarized light through fog. We first selected certain spectral bands from visible to IR wavelengths that exhibit lower path loss. For both radiation fog and advection fog, these optimized wavelength ranges include 0.4-1.1 µm, 1.48-1.56 µm, 1.63-1.86 µm, 2.03-2.18 µm, and 2.39-2.45 µm, and radiation fog in particular contains 3.5-4.3 µm. The long-wave IR wavelengths were excluded due to higher absorption losses. We further investigated the transmission performance of circular and linear polarization in variable foggy environments, exploring the impact of the detection range in particular. Using polarization-tracking Monte Carlo simulations for varying particle size, wavelength, refractive index, and detection range, we show that circular polarization outperforms linear polarization when transmitting in both radiation and advection fog. For radiation fog, circular polarization persists longer than linear polarization for 5 µm and 9 µm particles over the entire optimized wavelength range from the visible to mid-wave IR (MWIR). However, linear polarization outperforms circular polarization for 1 µm particles over the entire MWIR and a part of the short-wave IR (SWIR). For advection fog, circular polarization persists longer than linear polarization for all three particle sizes (10, 20, and 40 µm) over the entire optimized wavelength range from the visible to SWIR. We show that circular polarization retains a higher degree of polarization and has better enhancement in some detection ranges.

Puerarin inhibits TRPM3/miR-204 to promote MC3T3-E1 cells proliferation, differentiation and mineralization.

Puerarin is an isoflavonoid phytoestrogen extracted from the root of Radix Pueraria, has attracted increasing attention because of its beneficial effects on anti-osteoporosis, but the molecular mechanisms underlying its actions on osteoblasts are not fully understood. The current study aimed to investigate the effect of puerarin on MC3T3-E1 osteoblastic cells proliferation, differentiation and mineralization, in vitro and its underlying mechanisms. The results indicated that puerarin significantly promoted the osteoblasts proliferation, enhanced alkaline phosphatase activity and increased the formation of mineralized nodules. Following treatment with puerarin, the expression levels of transient receptor potential Melastatin 3 (TRPM3) and microRNA-204 (miR-204) were decreased, whereas that of Runt-related transcription Factor 2 (Runx2) increased. TRPM3-small interfering RNA and 2-aminoethoxydiphenyl borate (2-APB, inhibitor of TRPM3) promoted the expression of Runx2 and thus improved the development of osteoblasts, but pregnenolone sulfate, which is the agonist of TRPM3, inhibited the effects. In addition, puerarin induced the changes of intracellular Ca2+ concentration ([Ca2+ ]i ) and extracellular Ca2+ concentration ([Ca2+ ]0 ) through TRPM3 might be involved in the biological process of MC3T3-E1 cells. These results suggested that puerarin may promote MC3T3-E1 cell proliferation, differentiation and mineralization, which may be related to the downregulation of TRPM3/miR-204 and following regulating [Ca2+ ]i and [Ca2+ ]0 , and activation of Runx2.

Molecular characterization of 3'UTRs of J subgroup avian leukosis virus in passerine birds in China.

To assess the status of avian leukosis virus subgroup J (ALV-J) infection in passerine birds in China, 365 passerine birds collected from northeast China from 2011 to 2013 were tested, and two ALV-J strains were isolated from yellow-browed warbler and marsh tit. The 3'untranslated regions (3'UTRs) of the two strains were amplified, cloned, and sequenced, with the results showing that the 3'UTRs of the two strains contained multiple mutations and deletions, which are similar to viral strains isolated from Chinese layer chickens. These results demonstrate the presence of ALV-J in passerine birds and reveal the molecular characteristics of the 3'UTRs of ALV-J from passerine birds.

Genetic diversity and phylogenetic analysis of glycoprotein gp85 of avian leukosis virus subgroup J wild-bird isolates from Northeast China.

Avian leukosis virus subgroup J (ALV-J), first isolated in 1989, preferentially infects meat-type birds. Chinese layer flocks have experienced outbreaks of this virus since 2008. To analyze the status of ALV-J infection in wild birds in China, 585 wild birds collected from three provinces of Northeast China from 2010 to 2012 were tested, and six ALV-J strains were isolated for the first time. Furthermore, the gp85 genes of the six strains were amplified, cloned, and sequenced. The results indicated that two different ALV-J strains coexisted in Chinese wild birds from 2010 to 2012. These results not only expand the epidemiological data available for ALV-J and provide necessary information for the further understanding of the evolution of ALV-J, but they also highlight the potential role of wild-bird migration in the spread of ALV-J.

Molecular characteristics of the complete genome of a J-subgroup avian leukosis virus strain isolated from Eurasian teal in China.

The J-subgroup avian leukosis virus (ALV-J) strain WB11098J was isolated from a wild Eurasian teal, and its proviral genomic sequences were determined. The complete proviral sequence of WB11098J was 7868 nt long. WB11098J was 95.3.9 % identical to the prototype strain HPRS-103, 94.2 % identical to the American strain ADOL-7501, 94.5-94.7 % identical to Chinese broiler isolates, 94.8-97.5 % identical to layer chicken isolates, and 94.4-95.0 % identical to Chinese local chicken isolates at the nucleotide level. Phylogenetic analysis showed that the WB11098J isolate shared the greatest homology with the layer strain SD09DP03 and was included in the same cluster. Interestingly, two 19-bp insertions in the U3 regions of the 5'LTR and 5'UTR that were most likely derived from other retroviruses were found in the WB11098J isolate. These insertions separately introduced one E2BP-binding site in the U3 region of the 5'LTR and a RNA polymerase II transcription factor IIB and core promoter motif of ten elements in the 5'UTR. A 5-bp deletion was identified in the U3 region of the 5'LTR. No nucleotides were deleted in the rTM or DR-1 regions in the 3'UTR. A 1-bp deletion was detected in the E element and introduced a specific and distinct binding site for c-Ets-1. Our study is the first to report the molecular characteristics of the complete genome of an ALV-J that was isolated from a wild bird and will provide necessary information for further understanding of the evolution of ALV-J.

Novel insights into aerobic 17ß-estradiol degradation by enriched microbial communities from mangrove sediments.

Various persistent organic pollutants (POPs) including estrogens are often enriched in mangrove regions. This research investigated the estrogens pollution levels in six mangroves located in the Southern China. The estrogen levels were found to be in the range of 5.3-24.9 ng/g dry weight, suggesting that these mangroves had been seriously contaminated. The bacterial communities under estrogen stress were further enriched by supplementing 17ß-estradiol (E2) as the sole carbon source. The enriched bacterial communities showed an excellent E2 degradation capacity > 95 %. These communities were able to transform E2 into estrone (E1), 4-hydroxy-estrone, and keto-estrone, etc. 16 S rDNA sequencing and metagenomics analysis revealed that bacterial taxa Oleiagrimonas, Pseudomonas, Terrimonas, and Nitratireductor etc. were the main contributors to estrogen degradation. Moreover, the genes involved in E2 degradation were enriched in the microbial communities, including the genes encoding 17ß-hydroxysteroid dehydrogenase, estrone 4-hydroxylase, etc. Finally, the analyses of functional genes and binning genomes demonstrated that E2 was degraded by bacterial communities via dehydrogenation into E1 by 17ß-hydroxysteroid dehydrogenase. E1 was then catabolically converted to 3aα-H-4α(3'-propanoate)- 7aß-methylhexahydro-1,5-indanedione via 4,5-seco pathway. Alternatively, E1 could also be hydroxylated to keto-estrone, followed by B-ring cleavage. This study provides novel insights into the biodegradation of E2 by the bacterial communities in estrogen-contaminated mangroves.

KMT2D-mediated H3K4me1 recruits YBX1 to facilitate triple-negative breast cancer progression through epigenetic activation of c-Myc.

BACKGROUND: Lysine methyltransferase 2D (KMT2D) mediates mono-methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved in establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying the KMT2D-mediated H3K4me1 mark modulates gene expression in triple-negative breast cancer (TNBC) progression is unresolved. METHODS AND RESULTS: We recognized Y-box-binding protein 1 (YBX1) as a "reader" of the H3K4me1 mark, and a point mutation of YBX1 (E121A) disrupted this interaction. We found that KMT2D and YBX1 cooperatively promoted cell growth and metastasis of TNBC cells in vitro and in vivo. The expression levels of KMT2D and YBX1 were both upregulated in tumour tissues and correlated with poor prognosis for breast cancer patients. Combined analyses of ChIP-seq and RNA-seq data indicated that YBX1 was co-localized with KMT2D-mediated H3K4me1 in the promoter regions of c-Myc and SENP1, thereby activating their expressions in TNBC cells. Moreover, we demonstrated that YBX1 activated the expressions of c-Myc and SENP1 in a KMT2D-dependent manner. CONCLUSION: Our results suggest that KMT2D-mediated H3K4me1 recruits YBX1 to facilitate TNBC progression through epigenetic activation of c-Myc and SENP1. These results together unveil a crucial interplay between histone mark and gene regulation in TNBC progression, thus providing novel insights into targeting the KMT2D-H3K4me1-YBX1 axis for TNBC treatment. HIGHLIGHTS: YBX1 is a KMT2D-mediated H3K4me1-binding effector protein and mutation of YBX1 (E121A) disrupts its binding to H3K4me1. KMT2D and YBX1 cooperatively promote TNBC proliferation and metastasis by activating c-Myc and SENP1 expression in vitro and in vivo. YBX1 is colocalized with H3K4me1 in the c-Myc and SENP1 promoter regions in TNBC cells and increased YBX1 expression predicts a poor prognosis in breast cancer patients.

The SMARCA4R1157W mutation facilitates chromatin remodeling and confers PRMT1/SMARCA4 inhibitors sensitivity in colorectal cancer.

Genomic studies have demonstrated a high frequency of genetic alterations in components of the SWI/SNF complex including the core subunit SMARCA4. However, the mechanisms of tumorigenesis driven by SMARCA4 mutations, particularly in colorectal cancer (CRC), remain largely unknown. In this study, we identified a specific, hotspot mutation in SMARCA4 (c. 3721C>T) which results in a conversion from arginine to tryptophan at residue 1157 (R1157W) in human CRC tissues associated with higher-grade tumors and controls CRC progression. Mechanistically, we found that the SMARCA4R1157W mutation facilitated its recruitment to PRMT1-mediated H4R3me2a (asymmetric dimethylation of Arg 3 in histone H4) and enhanced the ATPase activity of SWI/SNF complex to remodel chromatin in CRC cells. We further showed that the SMARCA4R1157W mutant reinforced the transcriptional expression of EGFR and TNS4 to promote the proliferation of CRC cells and patient-derived tumor organoids. Importantly, we demonstrated that SMARCA4R1157W CRC cells and mutant cell-derived xenografts were more sensitive to the combined inhibition of PRMT1 and SMARCA4 which act synergistically to suppress cell proliferation. Together, our findings show that SMARCA4-R1157W is a critical activating mutation, which accelerates CRC progression through facilitating chromatin recruitment and remodeling. Our results suggest a potential precision therapeutic strategy for the treatment of CRC patients carrying the SMARCA4R1157W mutation.