Biology subjects

Yamaguchi, K.

Publications and source records attributed to Yamaguchi, K..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Transposon fusion gave birth to Fem, Bombyx mori female determining gene

Fem is a W-linked piRNA precursor, and Fem piRNA is a master gene of female determination in Bombyx mori. Since Fem has significantly low similarity to any known sequences and the origin of Fem remains unclear, two hypotheses have been proposed for the origin of Fem. The first one is that Fem is an allele of Masc, while the second one is that Fem arose by transposition of Masc. To draw a solid conclusion, we determined the W chromosome sequences of B. mori and a closely relative bombycid species of Trilocha varians with a Fem-independent sex determination system. Comprehensive genome comparison led us to the "third" hypothesis: Fem is a chimeric sequence of transposons. Although we still cannot completely exclude the first hypothesis, at least a large portion of the parts other than the 44-bp Masc similarity region is derived from transposons, and even the 44-bp region could correspond to the boundary of the two transposons, gypsy and satellite DNA.

genetics↗

bioRxiv2023

LsTT2 encoding R2R3-MYB transcription factor is responsible for a shift from black to white in lettuce seed

Prickly lettuce (Lactuca serriola), which is considered the wild ancestor of lettuce, has black seeds, whereas the major seed color of domesticated lettuce is black or white. The successfully-selected white seed trait is a key domestication trait for lettuce cultivation and breeding; however, the mechanism underlying the shift from black to white seeds remains to be clarified. We aimed to identify the gene/s responsible for white seed trait in lettuce. Genetic mapping of a candidate gene was performed with double-digest RAD sequencing using an F2 population derived from a cross between ShinanoPower (white seed) and Escort (black seed). The white seed trait was controlled by a single recessive locus (48.055-50.197 Mbp) in linkage group 7. Narrowing down using five PCR-based markers and 84 cultivars, eight candidate genes were mapped in the locus. Only the LG7_v8_49.251Mbp_HinfI marker, which employs a single nucleotide mutation in the stop codon of Lsat_1_v5_gn_7_35020.1 was completely linked to the seed color phenotype. In addition, the sequences of the coding region for candidate genes except for Lsat_1_v5_gn_7_35020.1 were identical in the resequence analysis of ShinanoPower (white seed) and Escort (black seed). Therefore, we proposed Lsat_1_v5_gn_7_35020.1, a gene located in the locus, as the candidate gene and designated it as LsTT2, an ortholog encoding the R2R3 MYB transcription factor in Arabidopsis. When we validated the role of LsTT2 in seed color through genome editing, LsTT2 knockout mutants harboring an early termination codon showed a change in seed color from black to white. White seeds accumulated less proanthocyanidins than black seeds, which was similar to the phenotype observed in Arabidopsis TRANSPARENT TESTA 2 (TT2) mutants. Therefore, LsTT2 was the allele responsible for the shift in seed color from black to white. The development of a robust marker for marker-assisted selection and identification of the gene responsible for white seeds has implications for future breeding technology and physiological analysis.

genetics↗

bioRxiv2023

Correlating stress reduction and eye movement patterns in a world famous Kyoto Japanese garden

Visual stimuli have been repeatedly shown to elicit significant non-visual responses. In a continuing effort to explore the unique effects of viewing a Japanese garden on the physiological and psychological metrics of stress, we gained access to the world famous Murin-an garden in Kyoto, Japan. This well-maintained observation garden was designed to be viewed while seated at a single vantage point to maximize the impact of the visual scene. As a control, we used a public garden on the campus of Kyoto University that was designed in a similar style. Sixteen college age students were asked to view both gardens while we monitored their pulse rates and tracked their eye movements. We used the POMS questionnaire to determine the effect of the garden viewing on the mood of the participants. We found that the Murin-an garden was more effective in decreasing pulse rate and improving mood than the University garden. The eye tracking data showed that during their Murin-an viewing the participants gaze ranged far more broadly across the visual field both the X-Y plane and in depth, and the speed with which the eyes moved from point-to-point was greater. Taken together, our data suggest that no one element in the garden was dominant in eliciting the changes in heart rate and mood. Rather, it was the breadth and rapidity of the shifts in gaze that drove the effects, a conclusion with implications for other interventions aimed stress reduction. SignificanceViews of nature and natural phenomena have a well-recognized calming effect on humans that has recognized therapeutic value in both medical and psychological settings. Our work explores the source of this effect by having participants view Murin-an, a world-famous Japanese style garden. Using both psychological and physiological measures, we confirm and extend earlier findings showing that a well constructed garden can effectively lower heart rate and improve mood within minutes. We also find, by analogy with eye movement desensitization and reprograming (EMDR), that it is participants rapidly shifting gaze rather than a single specific visual object is the most likely source of the calming effect.

neuroscience↗

bioRxiv2023

Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

molecular biology↗

bioRxiv2023

Comparative analysis of gonadal transcriptomes between turtle and alligator identifies common molecular cues activated during the temperature-sensitive period for sex determination

The mode of sex determination in vertebrates can be categorized as genotypic or environmental. In the case of genotypic sex determination (GSD), the sexual fate of an organism is determined by the chromosome composition with some having dominant genes, named sex-determining genes, that drive the sex phenotypes. By contrast, many reptiles exhibit environmental sex determination (ESD), whereby environmental stimuli drive sex determination, and most notably temperature. To date, temperature-dependent sex determination (TSD) has been found in most turtles, some lizards, and all crocodilians, but commonalities in the controlling processes are not well established. Recent innovative sequencing technology has enabled investigations into gonadal transcriptomic profiles during temperature-sensitive periods (TSP) in various TSD species which can help elucidate the controlling mechanisms. In this study, we conducted a time-course analysis of the gonadal transcriptome during the male-producing temperature (26L) of the Reeves turtle (Chinese three-keeled pond turtle) Mauremys reevesii. We then compared the transcriptome profiles for this turtle species during the TSP with that for the American alligator Alligator mississippiensis to identify conserved reptilian TSD-related genes. Our transcriptome-based findings provide an opportunity to retrieve the candidate molecular cues that are activated during TSP and compare these target responses between TSD and GSD turtle species, and between TSD species. Highlights- A time-course gonadal RNA-seq was conducted using Mauremys reevesii. - Sexual differentiation genes in males were activated at an earlier stage than the ones in females. - Turtle-alligator comparative analysis revealed novel candidate TSD genes.

developmental biology↗

bioRxiv2023

Microbiome ssRNA as an environmental cue to activate TLR13-dependent tissue-protective programs in CD5Lhi hepatic macrophages

Hepatic macrophages maintain liver homeostasis, but little is known about the signals that activate the hepatoprotective programs within macrophages. Here, we show that toll-like receptor 13 (TLR13), a sensor of bacterial 23S ribosomal RNA (rRNA), senses microbiome RNAs to drive tissue-protective responses in CD5Lhi hepatic macrophages. Splenomegaly and hepatomegaly developed in the absence of the endosomal RNase, RNaseT2, via TLR13-dependent macrophage proliferation. Furthermore, TLR13 in hepatic Ly6Clo macrophages activated the transcription factors LXR and MafB, leading to expression of tissue-clearance molecules, such as CD5L, C1qb, and Axl. Consequently, Rnaset2-/- mice developed resistance to acute liver injury caused by challenges with acetaminophen and lipopolysaccharide + D-galactosamine. TLR13 responses in Rnaset2-/- mice were impaired by antibiotics, suggesting that TLR13 were activated by microbiome rRNAs, which was detected in the sera and hepatic macrophages. Repeated administration of wild-type mice with the TLR13 ligand, rather than other TLR ligands, selectively increased the number of Kupffer cells, which expressed immunoregulatory and tissue-clearance genes as hepatic macrophages in Rnaset2-/- mice did. Our results suggest that microbiome ssRNA serves as an environmental cue for initiating tissue-protective TLR13 responses in hepatic macrophages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/540294v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@69614eorg.highwire.dtl.DTLVardef@737c69org.highwire.dtl.DTLVardef@1ecd9eforg.highwire.dtl.DTLVardef@d7e10d_HPS_FORMAT_FIGEXP M_FIG In the absence of an endosomal RNase, RNase T2, microbiome RNAs circulating in the vasculature activate TLR13 in hepatic macrophages to drive hepatoprotective responses through expression of immunoregulatory and tissue-clearance molecules. Consequently, mice lacking RNase T2 are resistant against acute liver injuries caused by acetaminophen and LPS + D-galactosamine. C_FIG

immunology↗

bioRxiv2023

Orchid seed germination through auto-activation of mycorrhizal symbiosis signaling regulated by gibberellin

Orchids parasitically depend on external nutrients from mycorrhizal fungi for seed germination. Previous findings suggest that orchids utilize a genetic system of mutualistic arbuscular mycorrhizal (AM) symbiosis to establish parasitic symbiosis. In AM symbiosis, recent studies have revealed that the plant hormone gibberellin (GA) negatively affects fungal colonization and development. Although previous studies imply that GA is important for orchid mycorrhizal symbiosis, the molecular mechanism of seed germination in which mycorrhizal symbiosis co-occurs remains unclear because, in AM plants, GA regulates seed germination and symbiosis positively and negatively, respectively. To elucidate this conflict, we investigated the effect of GA on Bletilla striata seed germination and mycorrhizal symbiosis using asymbiotic and symbiotic germination methods. Additionally, we compared the transcriptome profiles between asymbiotically and symbiotically germinated seeds. Exogenous GA negatively affected seed germination and fungal colonization, and endogenous bioactive GA was actively converted to the inactive form during seed germination. Transcriptome analysis showed that B. striata shared many of the induced genes between asymbiotically and symbiotically germinated seeds, including GA metabolism- and signaling-related genes and AM-specific marker homologs. Our study suggests that orchids have evolved in a manner that they do not use bioactive GA as a positive regulator of seed germination and instead, auto-activate the mycorrhizal symbiosis pathway through GA inactivation to accept the fungal partner immediately during seed germination.

plant biology↗

bioRxiv2023

Monoterpene glucosides accumulated in Eustoma grandiflorum roots promote hyphal branching in arbuscular mycorrhizal fungi

Host plant-derived strigolactones trigger hyphal branching in arbuscular mycorrhizal (AM) fungi, initiating a symbiotic interaction between land plants and AM fungi. However, our previous studies revealed that gibberellin-treated Eustoma grandiflorum (Gentianaceae) activates rhizospheric hyphal branching in AM fungi using unidentified molecules other than strigolactones. In this study, we analyzed independent transcriptomic data of E. grandiflorum and found that the gentiopicroside (GPS) and swertiamarin (SWM), which are characteristic monoterpene glucosides in Gentianaceae, were highly biosynthesized in gibberellin-treated E. grandiflorum roots. Moreover, these metabolites considerably promoted hyphal branching in the Glomeraceae AM fungi Rhizophagus irregularis and R. clarus. GPS treatment also enhanced R. irregularis colonization of the monocotyledonous crop Allium schoenoprasum. Interestingly, these metabolites did not provoke the germination of the root parasitic plant Orobanche minor. Altogether, our study unveiled the crucial role of GPS and SWM in activating the symbiotic relationship between AM fungi and E. grandiflorum.

plant biology↗

bioRxiv2023

plasma: Partial LeAst Squares for Multiomics Analysis

Recent growth in the number and applications of high-throughput "omics" technologies has created a need for better methods to integrate multiomics data. Much progress has been made in developing unsupervised methods, but supervised methods have lagged behind. We present a novel algorithm, plasma, to learn models to predict time-to-event outcomes from multiomics data sets. Plasma uses two layers of existing partial least squares algorithms to first select components that covary with the outcome and then construct a joint Cox proportional hazards model. We apply plasma to the stomach adenocarcinoma (STAD) data from The Cancer Genome Atlas. We validate the model both by splitting the STAD data into training and test sets and by applying it to the subset of esophageal cancer (ESCA) containing adenocarcinomas. We use the other half of the ESCA data, which contains squamous cell carcinomas dissimilar to STAD, as a negative control. Our model successfully separates both the STAD test set (p = 2.73 x 10-8) and the independent ESCA validation data (p = 0.025) into high risk and low risk patients. It does not separate the negative control data set (ESCA squamous cell carcinomas, p = 0.57). The performance of the joint multiomics model is superior to that of the individually trained models. It is also superior to the performance of an unsupervised method (Multi Omics Factor Analysis; MOFA) that finds latent factors to be used as putative predictors in a post-hoc survival analysis. Many of the factors that contribute strongly to the plasma model can be justified from the biological literature. SignificanceTo fill the unmet need for supervised multiomics methods, we introduce plasma, an algorithm based on partial least squares that integrates multiomics features into biologically relevant "components" that can predict patient outcomes. Availability and ImplementationThe plasma R package can be obtained from The Comprehensive R Archive Network (CRAN) athttps://CRAN.R-project.org/package=plasma. The latest version of the package can always be obtained from R-Forge at https://r-forge.r-project.org/R/?group_id=1746. Source code and data for the analysis presented here can be obtained from GitLab, at https://gitlab.com/krcoombes/plasma. ContactEmail: kcoombes@augusta.edu Supplementary InformationSupplementary material is available from the journal web site.

bioinformatics↗

bioRxiv2023

Shark and ray genome size estimation: methodological optimization for inclusive and controllable biodiversity genomics

Estimate of nuclear DNA content serves as an independent tool for validating the completeness of whole genome sequences and investigating the among-species variation of genome sizes, but for some species, the requirement of fresh cells makes this tool highly inaccessible. Here we focused on elasmobranch species (sharks and rays), and using flow cytometry or quantitative PCR (qPCR), estimated the nuclear DNA contents of brownbanded bamboo shark, white spotted bamboo shark, zebra shark, small-spotted catshark, sandbar shark, slendertail lanternshark, megamouth shark, red stingray, and ocellate spot skate. Our results revealed their genome sizes spanning from 3.40 pg (for ocellate spot skate) to 13.34 pg (for slendertail lanternshark), in accordance with the huge variation of genome sizes already documented for elasmobranchs. Our improved qPCR-based method enabled accurate genome size estimation without using live cells, which has been a severe limitation with elasmobranchs. These findings and our methodology are expected to contribute to better understanding of the diversity of genome sizes in elasmobranchs even including species with limited availability of fresh tissue materials. It will also help validate the completeness of already obtained or anticipated whole genome sequences.

genomics↗

bioRxiv2023

A chromosome-level genome assembly of amodel conifer plant, the Japanese cedar,Cryptomeria japonica D. Don

Japanese cedar (Cryptomeria japonica D. Don) is the most important Japanese forest tree, occupying about 44% of artificial forests in Japan, and planted in East Asia, Azores Archipelago, and some islands in the Indian Ocean. Although the huge genome of the species (ca. 11 Gb) with abundant repeat elements might have been an obstacle for genetic analysis, the species is easily propagated by cutting, flowered by plant hormones like gibberellic acid, transformed by agrobacterium, and edited by CRISPR/Cas9. These characteristics of C. japonica are preferable to make the species a model conifer for which reference genome sequences are necessary. In this study, we report the first chromosome-level assembly for C. japonica (2n = 22) using a third generation selfed progeny with an estimated homozygosity of 0.96. Young leaf tissue was used to extract high-molecular-weight DNA (>50 kb) for HiFi PacBio long read sequencing and to construct Hi-C/Omni-C library for Illumina short read sequencing. Using the 29x and 26x genome coverage of HiFi and Illumina reads, respectively, de novo assembly resulted in 2,650 contigs (9.1 Gb in total) with N50 contig size of 12.0 Mb. The Hi-C analysis mapped 97% of the nucleotides on the 11 chromosomes. The assembly was verified by comparing with a consensus linkage map of 7,785 markers. The BUSCO analysis confirmed ~91% of conserved genes. Annotations of genes, repeat elements and synteny with other Cupressaceae and Pinaceae species were performed, providing fundamental resources for genomic research of conifers.

genomics↗

bioRxiv2023

Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia

Therapeutic angiogenesis using mesenchymal stem/stromal cell grafts have shown modest and controversial effects in preventing amputation for patients with critical limb ischemia. Through single-cell transcriptomic analysis of human tissues, we identified CD271+ progenitors specifically from subcutaneous adipose tissue (AT) as having the most prominent pro-angiogenic gene profile distinct from other stem cell populations. AT-CD271+ progenitors demonstrated robust in vivo angiogenic capacity, over conventional adipose stromal cell grafts, characterized by long-term engraftment, augmented tissue regeneration, and significant recovery of blood flow in a xenograft model of limb ischemia. Mechanistically, the angiogenic capacity of CD271+ progenitors is dependent on functional CD271 and mTOR signaling. Notably, the number and angiogenic capacity of CD271+ progenitors was strikingly reduced in insulin resistant donors. Our study highlights the identification of AT-CD271+ progenitors with in vivo superior efficacy for limb ischemia. Furthermore, we showcase comprehensive single-cell transcriptomics strategies for identification of suitable grafts for cell therapy. HIGHLIGHTSO_LIAdipose tissue stromal cells have a distinct angiogenic gene profile among human cell sources. C_LIO_LICD271+ progenitors in adipose tissue have a prominent angiogenic gene profile. C_LIO_LICD271+ progenitors show superior therapeutic capacities for limb ischemia. C_LIO_LICD271+ progenitors are reduced and functionally impaired in insulin resistant donors. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/527726v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@1b5e1aorg.highwire.dtl.DTLVardef@bf2c34org.highwire.dtl.DTLVardef@ef0e68org.highwire.dtl.DTLVardef@9aee1f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Molecular engineering of emicizumab to improve hemophilia A treatment

Emicizumab, a factor (F)VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment for people with hemophilia A (PwHA). Although emicizumab is very potent, long-term outcomes from the clinical studies suggest that a small proportion of PwHA still experiences bleeds. Additionally, non-clinical studies indicate that the maximum cofactor activity of emicizumab is lower than international standard activity (100 IU/dL of FVIII). An increased cofactor activity BsAb would benefit such patients. Here, we report NXT007, a BsAb binding FIXa and FX developed through further engineering of emicizumab. Emicizumab has a common light chain, but through advances in antibody engineering, we were able to create a more potent BsAb with two new non-common light chains. After extensive optimization of the heavy and light chains, the resulting BsAb, NXT007, exerted in vitro thrombin generation (TG) activity in hemophilia A plasma equivalent to 100 IU/dL of FVIII when triggered by tissue factor. NXT007 demonstrated potent hemostatic activity in an acquired hemophilia A model in non-human primates at a much lower dosage than emicizumab, consistent with an around 30-fold dose shift in the in vitro TG activity between NXT007 and emicizumab. Moreover, together with Fc engineering that enhanced FcRn binding and reduced in vivo clearance, we demonstrate that NXT007 could be effective at a much lower dosage with a longer dosing interval compared to emicizumab. These non-clinical results suggest that NXT007 could maintain a non-hemophilic range of coagulation potential in PwHA and provides a rationale for its clinical testing.

bioengineering↗

bioRxiv2022

TLR7/8 stress response drives histiocytosis in SLC29A3 disorders

SLC29A3, also known as ENT3, is a lysosomal transmembrane protein that transports nucleosides from the lysosomes to the cytoplasm1. Loss-of-function mutations in SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs2,3. However, little is known about the mechanism through which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was demonstrated to depend on TLR7, which senses a combination of nucleosides and oligoribonucleotides4,5. TLR7 responded to lysosomal nucleoside storage and enhanced proliferation of Ly6Chi CX3CR1low immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Because accumulated nucleosides primarily originated from cell corpse phagocytosis, TLR7 in immature monocytes recognized nucleoside storage as lysosomal stress and increased phagocyte numbers. This non-inflammatory compensatory response is referred to as the TLR7 stress response where Syk, GSK3{beta}, {beta}-catenin, and mTORC1 serve as downstream signalling molecules. In SLC29A3 disorders, histiocytosis accompanies inflammation6,7. Nucleoside storage failed to induce pro-inflammatory cytokine production in Slc29a3-/- mice, but enhanced ssRNA-dependent pro-inflammatory cytokine production in Ly6Chi classical monocytes and peripheral macrophages, not proliferating immature monocytes. Patient-derived monocytes harbouring G208R SLC29A3 mutation showed higher survival and proliferation in the presence of M-CSF and produced larger amounts of IL-6 upon ssRNA stimulation than did those derived from healthy subjects. A TLR8 antagonist inhibited the survival/proliferation of patient-derived macrophages. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.

immunology↗

bioRxiv2022

Elasmobranch genome sequencing reveals evolutionary trends of vertebrate karyotypic organization

Genomic studies of vertebrate chromosome evolution have long been hindered by the scarcity of chromosome-scale DNA sequences of some key taxa. One of those limiting taxa has been the elasmobranchs (sharks and rays), which harbor species often with numerous chromosomes and enlarged genomes. Here, we report the chromosome-scale genome assembly for the zebra shark Stegostoma tigrinum, an endangered species that has the smallest genome sequenced to date among sharks (3.71 Gb), as well as for the whale shark Rhincodon typus. Our analysis employing a male-female comparison identified an X chromosome, the first genomically characterized shark sex chromosome. The X chromosome harbors a Hox C cluster whose intact linkage has not been shown for an elasmobranch fish. The sequenced shark genomes exhibit a gradualism of chromosome length with remarkable length-dependent characteristics--shorter chromosomes tend to have higher GC content, gene density, synonymous substitution rate, and simple tandem repeat content as well as smaller gene length, which resemble the edges of longer chromosomes. This pattern of intragenomic heterogeneity, previously recognized as peculiar to species with so-called microchromosomes, occurs in more vertebrates including elasmobranchs. We challenge the traditional binary classification of karyotypes as with and without microchromosomes, as even without microchromosomes, shorter chromosomes tend to have higher contents of GC and simple tandem repeats and harbor shorter and more rapid-evolving genes. Such characteristics also appear on the edges of longer chromosomes. Our investigation of elasmobranch karyotypes underpins their unique characteristics and provides clues for understanding how vertebrate karyotypes accommodate intragenomic heterogeneity to realize a complex readout.

evolutionary biology↗

bioRxiv2022

The histone methyltransferase DOT1L regulates chromatin reorganization and gene expression during the postmeiotic differentiation of male germ cells

Spermatozoa have a unique genome organization: their chromatin is almost completely devoid of histones and is formed instead of protamines which confer a high level of compaction and preserve paternal genome integrity until fertilization. Histone-to-protamine transition takes place in spermatids and is indispensable for the production of functional sperm. Here we show that the H3K79-methyltransferase DOT1L controls spermatid chromatin remodelling and subsequent reorganization and compaction of spermatozoon genome. Using a mouse model in which Dot1l is knocked-out (KO) in postnatal male germ cells, we found that Dot1l-KO sperm chromatin is less compact and has an abnormal content, characterized by the presence of transition proteins, immature protamine 2 forms and a higher level of histones. Proteomics and transcriptomics analyses performed on spermatids reveal that Dot1l-KO modifies the chromatin prior to histone removal, and leads to the deregulation of genes involved in flagellum formation and apoptosis during spermatid differentiation. As a consequence of these chromatin and gene expression defects, Dot1l-KO spermatozoa have less compact heads and are less motile which results in impaired fertility.

molecular biology↗

bioRxiv2022

CiDRE+ M2c macrophages hijacked by SARS-CoV-2 cause COVID-19 severity

Infection of the lungs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin I converting enzyme 2 (ACE2) receptor induces a type of systemic inflammation known as a cytokine storm. However, the precise mechanisms involved in severe coronavirus disease 2019 (COVID-19) pneumonia are unknown. Here, we show that interleukin-10 (IL-10) changed normal alveolar macrophages into ACE2-expressing M2c-type macrophages that functioned as spreading vectors for SARS-CoV-2 infection. The depletion of alveolar macrophages and blockade of IL-10 attenuated SARS-CoV-2 pathogenicity. Furthermore, genome-wide association and quantitative trait locus analyses identified novel mRNA transcripts in human patients, COVID-19 infectivity enhancing dual receptor (CiDRE), which has unique synergistic effects within the IL-10-ACE2 system in M2c-type macrophages. Our results demonstrate that alveolar macrophages stimulated by IL-10 are key players in severe COVID-19. Collectively, CiDRE expression levels are potential risk factors that predict COVID-19 severity, and CiDRE inhibitors might be useful as COVID-19 therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/510331v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1e96c82org.highwire.dtl.DTLVardef@1d2dc32org.highwire.dtl.DTLVardef@7689d1org.highwire.dtl.DTLVardef@520d17_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Onecut1 partially contributes to liver progenitor cell transition and acquisition of metastatic potential in hepatocellular carcinoma.

Metastasis-initiating cells are considered to originate from stem cell-like cancer cells. In hepatocellular carcinoma, liver progenitor-like cells are reported to be derived from hepatocytes, indicating the possible acquisition of metastatic potential during hepatocyte-to-cholangiocyte transdifferentiation. Consistent with the expression pattern observed during ductal plate formation, we revealed an LPC transition with Onecut1 accumulation both during hepatocyte-to-cholangiocyte transdifferentiation and in a cell model. This event may be associated with transient acquisition of metastatic potential.

cancer biology↗