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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by extensive intratumoral heterogeneity, high metastasis, and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of these aggressive behaviors remains poorly understood. Using single-cell and spatial transcriptome analysis, here we discovered basal epithelial subpopulations located within the stroma that exhibit chemoresistance characteristics. The subpopulations are defined by distinct signature genes that show a frequent gain in copy number and exhibit an activated epithelial-to-mesenchymal transition program. A subset of these genes can accurately predict chemotherapy response and are associated with poor prognosis. Interestingly, among these genes, elevated ITGB1 participates in enhancing intercellular signaling while ACTN1 confers a survival advantage to foster chemoresistance. Furthermore, by subjecting the transcriptional signatures to drug repurposing analysis, we find that chemoresistant tumors may benefit from distinct inhibitors in treatment-naive versus post-NAC patients. These findings shed light on the mechanistic basis of chemoresistance while providing the best-in-class biomarker to predict chemotherapy response and alternate therapeutic avenues for improved management of TNBC patients resistant to chemotherapy. Synopsis: Chemotherapy resistance is a key challenge in Triple-Negative Breast Cancer (TNBC). Combining single-cell, spatial and bulk transcriptome analysis with machine learning, we uncovered mechanisms of TNBC chemoresistance that provide biomarkers for chemotherapy response and novel avenues for therapy. Basal-epithelial subpopulations underlie chemoresistance in TNBC. Chemoresistance-associated basal-epithelial cells reside in close vicinity to stromal compartments within TNBC tumors and engage in enhanced intercellular communication. These subpopulations are defined by distinct signature genes that provide the best-in-class predictive biomarker of chemotherapy response. Drug repurposing analysis identified existing FDA-approved drugs that may benefit chemoresistant patients. Chemotherapy resistance is a key challenge in Triple-Negative Breast Cancer (TNBC). Combining single-cell, spatial and bulk transcriptome analysis with machine learning, we uncovered mechanisms of TNBC chemoresistance that provide biomarkers for chemotherapy response and novel avenues for therapy. [ABSTRACT FROM AUTHOR]

Up to 80% of children with autism spectrum disorder have at least one other neuropsychiatric comorbidity. The causes of such disorders are highly genetic, yet many studies fail to take analysis further than risk gene discovery to see cellular and mechanistic changes occurring. Therefore, the goal of this study was to unveil novel gene expression signatures involved in important neurodevelopmental processes that, when disrupted, lead to each of the autism comorbidities of interest. We achieved this by analysing a single‐nuclei RNA sequencing dataset with prefrontal cortex samples from autism spectrum disorder plus comorbidities for differentially expressed genes. The highest number of alterations was seen in excitatory neurons, which also showed differential population and cell–cell interactions across disorders and an increase in expression of genes involved in neurodevelopmental pathways. Interestingly, the group without comorbidities displayed an increase in neuron–neuron interactions yet a decrease in population number, suggesting a major rewiring of neuronal connections. Further analysis of the topmost significant genes from this cell type in developing prefrontal cortex datasets revealed interesting expression trajectories corresponding to important time points during corticogenesis. This further identified four novel candidate genes that show a potential link to developmental pathways that may contribute to autism and its comorbidities when dysregulated. The study provides a better understanding of co‐occurring conditions at a transcriptomic and cell‐type level and thereby aid future research in providing earlier diagnosis, care and intervention. [ABSTRACT FROM AUTHOR]

Abstract: Tan spot, caused by a necrotrophic fungus Pyrenophora tritici‐repentis (Ptr), has become an important foliar disease of wheat worldwide. Effective control of tan spot can be achieved by deployment of resistant wheat cultivars. An F2:3 population derived from a cross between synthetic hexaploid wheat (SHW), TA4161‐L1 (moderately resistant) and susceptible winter wheat cultivar, ‘TAM105’ was evaluated with race 1 of Ptr under controlled conditions. The population was genotyped using Diversity Arrays Technology (DArT). Presence of transgressive segregants indicated contribution of positive alleles from both parents. Two major QTLs were located on the short arm of chromosomes 1A and 6A and designated as QTs.ksu‐1A and QTs.ksu‐6A, respectively. Two additional QTLs were identified on chromosome 7A. Resistant alleles of all the QTLs were contributed by TA4161‐L1. Novel QTLs on 6A and 7A can be a valuable addition to known resistance genes and utilized in breeding programmes to produce highly resistant cultivars. [ABSTRACT FROM AUTHOR]

Generating a contiguous, ordered reference sequence of a complex genome such as hexaploid wheat (2n = 6x = 42; approximately 17 GB) is a challenging task due to its large, highly repetitive, and allopolyploid genome. In wheat, ordering of whole-genome or hierarchical shotgun sequencing contigs is primarily based on recombination and comparative genomics-based approaches. However, comparative genomics approaches are limited to syntenic inference and recombination is suppressed within the pericentromeric regions of wheat chromosomes, thus, precise ordering of physical maps and sequenced contigs across the whole-genome using these approaches is nearly impossible. We developed a whole-genome radiation hybrid (WGRH) resource and tested it by genotyping a set of 115 randomly selected lines on a high-density single nucleotide polymorphism ( SNP) array. At the whole-genome level, 26 299 SNP markers were mapped on the RH panel and provided an average mapping resolution of approximately 248 Kb/ cR1500 with a total map length of 6866 cR1500. The 7296 unique mapping bins provided a five- to eight-fold higher resolution than genetic maps used in similar studies. Most strikingly, the RH map had uniform bin resolution across the entire chromosome(s), including pericentromeric regions. Our research provides a valuable and low-cost resource for anchoring and ordering sequenced BAC and next generation sequencing ( NGS) contigs. The WGRH developed for reference wheat line Chinese Spring ( CS- WGRH), will be useful for anchoring and ordering sequenced BAC and NGS based contigs for assembling a high-quality, reference sequence of hexaploid wheat. Additionally, this study provides an excellent model for developing similar resources for other polyploid species. [ABSTRACT FROM AUTHOR]

Cell fate specification relies on the action of critical transcription factors that become available at distinct stages of embryonic development. One such factor is NeuroD1, which is essential for eliciting the neuronal development program and possesses the ability to reprogram other cell types into neurons. Given this capacity, it is important to understand its targets and themechanismunderlying neuronal specification. Here, we show that NeuroD1 directly binds regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms. This targeting is sufficient to initiate events that confer transcriptional competence, including reprogramming of transcription factor landscape, conversion of heterochromatin to euchromatin, and increased chromatin accessibility, indicating potential pioneer factor ability of NeuroD1. The transcriptional induction of neuronal fate genes is maintained via epigenetic memory despite a transient NeuroD1 induction during neurogenesis. NeuroD1 also induces genes involved in the epithelial-to-mesenchymal transition, thereby promoting neuronal migration. Our study not only reveals the NeuroD1-dependent gene regulatory program driving neurogenesis but also increases our understanding of how cell fate specification during development involves a concerted action of transcription factors and epigenetic mechanisms. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) provides a powerful tool for the discovery of important genes and alleles in crop plants and their wild relatives. Despite great advances in NGS technologies, whole-genome shotgun sequencing is cost-prohibitive for species with complex genomes. An attractive option is to reduce genome complexity to a single chromosome prior to sequencing. This work describes a strategy for studying the genomes of distant wild relatives of wheat by isolating single chromosomes from addition or substitution lines, followed by chromosome sorting using flow cytometry and sequencing of chromosomal DNA by NGS technology. We flow-sorted chromosome 5Mg from a wheat/Aegilops geniculata disomic substitution line [DS5Mg (5D)] and sequenced it using an Illumina HiSeq 2000 system at approximately 50 x coverage. Paired-end sequences were assembled and used for structural and functional annotation. A total of 4236 genes were annotated on 5Mg, in close agreement with the predicted number of genes on wheat chromosome 5D (4286). Single-gene FISH indicated no major chromosomal rearrangements between chromosomes 5Mg and 5D. Comparing chromosome 5Mg with model grass genomes identified synteny blocks in Brachy-podium distachyon, rice (Oryza sativa), sorghum (Sorghum bicolor) and barley (Hordeum vulgare). Chromosome 5Mg-specific SNPs and cytogenetic probe-based resources were developed and validated. Deletion bin-mapped and ordered 5Mg SNP markers will be useful to track 5M-specific introgressions and translocations. This study provides a detailed sequence-based analysis of the composition of a chromosome from a distant wild relative of bread wheat, and opens up opportunities to develop genomic resources for wild germplasm to facilitate crop improvement. [ABSTRACT FROM AUTHOR]

The epithelial to mesenchymal transition ( EMT) is a biological process in which cells lose cell-cell contacts and become motile. EMT is used during development, for example, in triggering neural crest migration, and in cancer metastasis. Despite progress, the dynamics of JNK signaling, its role in genomewide transcriptional reprogramming, and involved downstream effectors during EMT remain largely unknown. Here, we show that JNK is not required for initiation, but progression of phenotypic changes associated with EMT. Such dependency resulted from JNK-driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we identified eight novel JNK-induced transcription factors that were required for proper EMT. Three of these factors were also highly expressed in invasive cancer cells where they function in gene regulation to maintain mesenchymal identity. These factors were also induced during neuronal development and function in neuronal migration in vivo. These comprehensive findings uncovered a kinetically distinct role for the JNK pathway in defining the transcriptome that underlies mesenchymal identity and revealed novel transcription factors that mediate these responses during development and disease. [ABSTRACT FROM AUTHOR]

More than 60% of the world population suffers from iron deficiency, and over 30% of the global population has zinc deficiency. Micronutrient deficiency leads to compromised health and economic losses and is prevalent in populations depending on non-diversified plant-based diets. Increasing mineral content of staple food crops through biofortification is the most feasible strategy of combating micronutrient malnutrition. Additionally, it will also enhance the agronomic efficiency of crops on mineral poor soils. A multipronged strategy towards enhancing mineral content of cereal grains should involve increased uptake of minerals from soil, enhanced partitioning towards grain and improved sequestration in the edible tissues of grains. At the same time, it is essential to improve mineral absorption in vivo from cereal-based diets. Both conventional and modern breeding approaches and genetic engineering are being employed for biofortification of crop plants. With increased understanding of mineral uptake and transport mechanisms in plants, it is becoming ever more possible to engineer biofortified crop plants with the ultimate goal of overcoming hidden hunger. [ABSTRACT FROM AUTHOR]

Most of the transcription factors, RNA polymerases and enhancer binding factors are absent from condensed mitotic chromosomes. In contrast, epigenetic marks of active and inactive genes somehow survive mitosis, since the activity status from one cell generation to the next is maintained. For the zinc-finger protein CTCF, a role in interpreting and propagating epigenetic states and in separating expression domains has been documented. To test whether such a domain structure is preserved during mitosis, we examined whether CTCF is bound to mitotic chromatin. Here we show that in contrast to other zinc-finger proteins, CTCF indeed is bound to mitotic chromosomes. Mitotic binding is mediated by a portion of the zinc-finger DNA binding domain and involves sequence specific binding to target sites. Furthermore, the chromatin loop organized by the CTCF-bound, differentially methylated region at the Igf2/H19 locus can be detected in mitosis. In contrast, the enhancer/promoter loop of the same locus is lost in mitosis. This may provide a novel form of epigenetic memory during cell division. [ABSTRACT FROM AUTHOR]