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Nature Neuroscience Mar 2021We used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex. We identified...
We used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex. We identified extensive layer-enriched expression signatures and refined associations to previous laminar markers. We overlaid our laminar expression signatures on large-scale single nucleus RNA-sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions in which morphological architecture is not as well defined as cortical laminae. Last, we created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research ( http://research.libd.org/spatialLIBD ).
Topics: Gene Expression; Gene Regulatory Networks; Humans; Prefrontal Cortex; Transcriptome
PubMed: 33558695
DOI: 10.1038/s41593-020-00787-0 -
Nature Reviews. Genetics Dec 2020Transposable elements (TEs) are insertional mutagens that contribute greatly to the plasticity of eukaryotic genomes, influencing the evolution and adaptation of species... (Review)
Review
Transposable elements (TEs) are insertional mutagens that contribute greatly to the plasticity of eukaryotic genomes, influencing the evolution and adaptation of species as well as physiology or disease in individuals. Measuring TE expression helps to understand not only when and where TE mobilization can occur but also how this process alters gene expression, chromatin accessibility or cellular signalling pathways. Although genome-wide gene expression assays such as RNA sequencing include transposon-derived transcripts, most computational analytical tools discard or misinterpret TE-derived reads. Emerging approaches are improving the identification of expressed TE loci and helping to discriminate TE transcripts that permit TE mobilization from chimeric gene-TE transcripts or pervasive transcription. Here we review the main challenges associated with the detection of TE expression, including mappability, insertional and internal sequence polymorphisms, and the diversity of the TE transcriptional landscape, as well as the different experimental and computational strategies to solve them.
Topics: Animals; DNA Transposable Elements; Gene Expression; Humans; Plants; Polymorphism, Genetic; Transcription, Genetic
PubMed: 32576954
DOI: 10.1038/s41576-020-0251-y -
Trends in Genetics : TIG Jul 2018There is abundant variation in gene expression between individuals, populations, and species. The evolution of gene regulation and expression within and between species... (Review)
Review
There is abundant variation in gene expression between individuals, populations, and species. The evolution of gene regulation and expression within and between species is thought to frequently contribute to adaptation. Yet considerable evidence suggests that the primary evolutionary force acting on variation in gene expression is stabilizing selection. We review here the results of recent studies characterizing the evolution of gene expression occurring in cis (via linked polymorphisms) or in trans (through diffusible products of other genes) and their contribution to adaptation and response to the environment. We review the evidence for buffering of variation in gene expression at the level of both transcription and translation, and the possible mechanisms for this buffering. Lastly, we summarize unresolved questions about the evolution of gene regulation.
Topics: Animals; Evolution, Molecular; Gene Expression; Gene Expression Regulation; Humans; Polymorphism, Genetic
PubMed: 29680748
DOI: 10.1016/j.tig.2018.03.007 -
Cell Oct 2020Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes...
Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from over 12,000 genes across 32 normal human tissues. Tissue-specific or tissue-enriched proteins were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode tissue-specific proteins. Discordance of RNA and protein enrichment revealed potential sites of synthesis and action of secreted proteins. The tissue-specific distribution of proteins also provides an in-depth view of complex biological events that require the interplay of multiple tissues. Most importantly, our study demonstrated that protein tissue-enrichment information can explain phenotypes of genetic diseases, which cannot be obtained by transcript information alone. Overall, our results demonstrate how understanding protein levels can provide insights into regulation, secretome, metabolism, and human diseases.
Topics: Gene Expression; Gene Expression Profiling; Humans; Proteome; Proteomics; RNA; RNA, Messenger; Transcriptome
PubMed: 32916130
DOI: 10.1016/j.cell.2020.08.036 -
Cell May 2021Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand...
Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.
Topics: Adult; Female; Gene Expression; Gene Expression Regulation; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Immune System; Immune System Diseases; Male; Middle Aged; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Transcriptome; Whole Genome Sequencing
PubMed: 33930287
DOI: 10.1016/j.cell.2021.03.056 -
Biomolecules Aug 2021Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in... (Review)
Review
Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in the development and progression of BC. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence that certain phytonutrients are able to modulate gene expression at transcriptional and post-transcriptional levels. Such phytonutrients may also be beneficial to prevent and treat BC. In this review, we will focus on the nutrigenomic effects of various phytochemicals including polyphenols, phytosterols, terpenoids, alkaloids, and other compounds from different sources. Overall, these phytonutrients are found to inhibit BC cell proliferation, differentiation, invasion, metastasis, angiogenesis, and induce apoptotic cell death by targeting various molecular pathways. They also alter epigenetic mechanisms and enhance the chemosensitivity and radiosensitivity of cancer cells. Such phytochemicals may be used for the effective management of BC patients in the clinical setting in the future. The present article aims to summarize the specific molecular pathways involved in the genetic effects of phytochemicals in BC.
Topics: Breast Neoplasms; Epigenesis, Genetic; Female; Gene Expression; Humans; Nutrigenomics; Phytochemicals; Polyphenols
PubMed: 34439842
DOI: 10.3390/biom11081176 -
Current Opinion in Chemical Biology Aug 2019Visualization of transcription in living cells has taught us that genes are often transcribed in bursts, with periods of gene activity interspersed by periods of... (Review)
Review
Visualization of transcription in living cells has taught us that genes are often transcribed in bursts, with periods of gene activity interspersed by periods of inactivity. Recently, technological advances in live-cell imaging have provided a more detailed picture of the characteristics of transcriptional bursts, and have allowed direct visualization of the upstream regulatory steps of bursting at single-molecule resolution. In this review, we highlight the latest insights into transcription dynamics and we discuss recent developments in understanding the regulation of transcriptional bursting through the binding kinetics of transcription factors, enhancer-promoter interactions and clustering/phase separation of the transcriptional machinery.
Topics: Gene Expression; Transcription Factors; Transcription, Genetic
PubMed: 31284216
DOI: 10.1016/j.cbpa.2019.05.031 -
STAR Protocols Dec 2023This overview guides both novices and experienced researchers facing challenging targets to select the most appropriate gene expression system for producing a particular... (Review)
Review
This overview guides both novices and experienced researchers facing challenging targets to select the most appropriate gene expression system for producing a particular protein. By answering four key questions, readers can determine the most suitable gene expression system following a decision scheme. This guide addresses the most commonly used and accessible systems and provides brief descriptions of the main gene expression systems' key characteristics to assist decision making. Additionally, information has been included for selected less frequently used "exotic" gene expression systems.
Topics: Ligands; Databases, Pharmaceutical; Recombinant Proteins; Gene Expression
PubMed: 37917580
DOI: 10.1016/j.xpro.2023.102572 -
Nucleic Acids Research May 2023In situ capturing technologies add tissue context to gene expression data, with the potential of providing a greater understanding of complex biological systems....
In situ capturing technologies add tissue context to gene expression data, with the potential of providing a greater understanding of complex biological systems. However, splicing variants and full-length sequence heterogeneity cannot be characterized at spatial resolution with current transcriptome profiling methods. To that end, we introduce spatial isoform transcriptomics (SiT), an explorative method for characterizing spatial isoform variation and sequence heterogeneity using long-read sequencing. We show in mouse brain how SiT can be used to profile isoform expression and sequence heterogeneity in different areas of the tissue. SiT reveals regional isoform switching of Plp1 gene between different layers of the olfactory bulb, and the use of external single-cell data allows the nomination of cell types expressing each isoform. Furthermore, SiT identifies differential isoform usage for several major genes implicated in brain function (Snap25, Bin1, Gnas) that are independently validated by in situ sequencing. SiT also provides for the first time an in-depth A-to-I RNA editing map of the adult mouse brain. Data exploration can be performed through an online resource (https://www.isomics.eu), where isoform expression and RNA editing can be visualized in a spatial context.
Topics: Animals; Mice; Alternative Splicing; Sequence Analysis, RNA; Protein Isoforms; Gene Expression Profiling; Gene Expression; Transcriptome
PubMed: 36928528
DOI: 10.1093/nar/gkad169 -
Cell Jan 2019Transcriptional regulation in metazoans occurs through long-range genomic contacts between enhancers and promoters, and most genes are transcribed in episodic "bursts"...
Transcriptional regulation in metazoans occurs through long-range genomic contacts between enhancers and promoters, and most genes are transcribed in episodic "bursts" of RNA synthesis. To understand the relationship between these two phenomena and the dynamic regulation of genes in response to upstream signals, we describe the use of live-cell RNA imaging coupled with Hi-C measurements and dissect the endogenous regulation of the estrogen-responsive TFF1 gene. Although TFF1 is highly induced, we observe short active periods and variable inactive periods ranging from minutes to days. The heterogeneity in inactive times gives rise to the widely observed "noise" in human gene expression and explains the distribution of protein levels in human tissue. We derive a mathematical model of regulation that relates transcription, chromosome structure, and the cell's ability to sense changes in estrogen and predicts that hypervariability is largely dynamic and does not reflect a stable biological state.
Topics: Estrogen Receptor alpha; Estrogens; Gene Expression; Gene Expression Regulation; Humans; Models, Theoretical; Promoter Regions, Genetic; RNA, Messenger; Single-Cell Analysis; Transcription, Genetic; Transcriptional Activation; Trefoil Factor-1
PubMed: 30554876
DOI: 10.1016/j.cell.2018.11.026