13273 research outputs found
Sort by
OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage
No full textTuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues1. Recent studies have also revealed tuft cell-like human tumors2,3, particularly as a variant form of small cell lung cancer (SCLC). Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F32,4, although the transcriptional mechanisms that generate this cell type are poorly understood. Here we show that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed here OCA-T1 and OCA-T2, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogs of the B cell-specific coactivator OCA-B, which are encoded in a gene cluster and harbor a conserved peptide that binds to class II POU transcription factors and octamer motif DNA in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft cell-like SCLC. In addition, we generated OCA-T1 knockout mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal the POU2F3-OCA-T complex as the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft cell-like SCLC
Transcriptional regulation of primary and specialized metabolism
No full textRegulation of plant development requires intricate communication with both primary and specialized metabolism in order to fuel growth. While transcriptional regulation of metabolism is evident from myriad whole genome-expression analyses, our understanding of which transcriptional regulators are responsible for these changes as well as their underlying mode of action is unclear. I will highlight our efforts on systematic mapping of transcriptional regulators of primary metabolism (nitrogen and central carbon) as well as specialized metabolism (glucosinolates). Network analyses incorporating protein-DNA interaction data, gene expression and connectivity were used to identify critical regulators, most of which were shown to regulate metabolism via developmental- and stress-conditional processes that coordinate across primary and specialized metabolism. These analyses demonstrate distinct design principles responsible for metabolism between microbes and this multicellular eukaryote
Analyzing the impacts of tobacco mosaic virus on the microbial diversity of Nicotiana benthamiana
No full textClinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer
No full textAn adaptive teosinte mexicana introgression modulates phosphatidylcholine levels and is associated with maize flowering time
Get PDFNative Americans domesticated maize (Zea mays ssp. mays) from lowland teosinte parviglumis (Zea mays ssp. parviglumis) in the warm Mexican southwest and brought it to the highlands of Mexico and South America where it was exposed to lower temperatures that imposed strong selection on flowering time. Phospholipids are important metabolites in plant responses to low-temperature and phosphorus availability and have been suggested to influence flowering time. Here, we combined linkage mapping with genome scans to identify High PhosphatidylCholine 1 (HPC1), a gene that encodes a phospholipase A1 enzyme, as a major driver of phospholipid variation in highland maize. Common garden experiments demonstrated strong genotype-by-environment interactions associated with variation at HPC1, with the highland HPC1 allele leading to higher fitness in highlands, possibly by hastening flowering. The highland maize HPC1 variant resulted in impaired function of the encoded protein due to a polymorphism in a highly conserved sequence. A meta-analysis across HPC1 orthologs indicated a strong association between the identity of the amino acid at this position and optimal growth in prokaryotes. Mutagenesis of HPC1 via genome editing validated its role in regulating phospholipid metabolism. Finally, we showed that the highland HPC1 allele entered cultivated maize by introgression from the wild highland teosinte Zea mays ssp. mexicana and has been maintained in maize breeding lines from the Northern United States, Canada, and Europe. Thus, HPC1 introgressed from teosinte mexicana underlies a large metabolic QTL that modulates phosphatidylcholine levels and has an adaptive effect at least in part via induction of early flowering time
Targeted de novo phasing and long-range assembly by template mutagenesis
Get PDFShort-read sequencers provide highly accurate reads at very low cost. Unfortunately, short reads are often inadequate for important applications such as assembly in complex regions or phasing across distant heterozygous sites. In this study, we describe novel bench protocols and algorithms to obtain haplotype-phased sequence assemblies with ultra-low error for regions 10 kb and longer using short reads only. We accomplish this by imprinting each template strand from a target region with a dense and unique mutation pattern. The mutation process randomly and independently converts ∼50% of cytosines to uracils. Sequencing libraries are made from both mutated and unmutated templates. Using de Bruijn graphs and paired-end read information, we assemble each mutated template and use the unmutated library to correct the mutated bases. Templates are partitioned into two or more haplotypes, and the final haplotypes are assembled and corrected for residual template mutations and PCR errors. With sufficient template coverage, the final assemblies have per-base error rates below 10-9. We demonstrate this method on a four-member nuclear family, correctly assembling and phasing three genomic intervals, including the highly polymorphic HLA-B gene
Trafficking and localization of KNOTTED1 related mRNAs in shoot meristems
Get PDFMulticellular organisms use transcripts and proteins as signaling molecules for cell-to-cell communication. Maize KNOTTED1 (KN1) was the first homeodomain transcription factor identified in plants, and functions in maintaining shoot stem cells. KN1 acts non-cell autonomously, and both its messenger RNA (mRNA) and protein traffic between cells through intercellular nanochannels called plasmodesmata. KN1 protein and mRNA trafficking are regulated by a chaperonin subunit and a catalytic subunit of the RNA exosome, respectively. These studies suggest that the function of KN1 in stem cell regulation requires the cell-to-cell transport of both its protein and mRNA. However, in situ hybridization experiments published 25 years ago suggested that KN1 mRNA was missing from the epidermal (L1) layer of shoot meristems, suggesting that only the KN1 protein could traffic. Here, we show evidence that KN1 mRNA is present at a low level in L1 cells of maize meristems, supporting an idea that both KN1 protein and mRNA traffic to the L1 layer. We also summarize mRNA expression patterns of KN1 homologs in diverse angiosperm species, and discuss KN1 trafficking mechanisms
Study of possible molecular states of Ds (∗) Ds (∗) and Bs (∗) Bs (∗)
Get PDFRecently the LHCb Collaboration reported a new exotic state Tcc+ which is conjectured to be a molecular state of D0D∗+ (or D∗0D+) theoretically. Belle Collaboration also searched for tetraquark state Xccss in DsDs (Ds∗Ds∗) final states but no significant signals were observed, which did not rule out the existence of Xccss as a molecular state of DsDs (Ds∗Ds∗). Inspired by these experimental results on double charmed exotic state, in this paper we study whether the molecular bound states of Ds(∗)Ds(∗) and Bs(∗)Bs(∗) can exist with the Bethe-Salpeter (BS) equation approach. We employ heavy meson chiral perturbation theory and one-boson-exchange approximation to calculate the interaction kernels in the BS equations. Our numerical results suggest that two Bs∗ mesons perhaps form a 0+ molecular state. Future experimental search for Xccss and Xbbss states in other decay channels may shed light on the structure of double charmed exotic state
Tumor immunogenicity and plasticity of cancer-associated fibroblasts orchestrate the host immune response to mouse pancreatic cancer
No full textSingle-cell transcriptomics identifies Keap1-Nrf2 regulated collective invasion in a Drosophila tumor model
Get PDFApicobasal cell polarity loss is a founding event in epithelial-mesenchymal transition and epithelial tumorigenesis, yet how pathological polarity loss links to plasticity remains largely unknown. To understand the mechanisms and mediators regulating plasticity upon polarity loss, we performed single-cell RNA sequencing of Drosophila ovaries, where inducing polarity-gene l(2)gl-knockdown (Lgl-KD) causes invasive multilayering of the follicular epithelia. Analyzing the integrated Lgl-KD and wildtype transcriptomes, we discovered the cells specific to the various discernible phenotypes and characterized the underlying gene expression. A genetic requirement of Keap1-Nrf2 signaling in promoting multilayer formation of Lgl-KD cells was further identified. Ectopic expression of Keap1 increased the volume of delaminated follicle cells that showed enhanced invasive behavior with significant changes to the cytoskeleton. Overall, our findings describe the comprehensive transcriptome of cells within the follicle cell tumor model at the single-cell resolution and identify a previously unappreciated link between Keap1-Nrf2 signaling and cell plasticity at early tumorigenesis