Anatomy and Neuroscience - Research Publications

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    Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network.
    Grapotte, M ; Saraswat, M ; Bessière, C ; Menichelli, C ; Ramilowski, JA ; Severin, J ; Hayashizaki, Y ; Itoh, M ; Tagami, M ; Murata, M ; Kojima-Ishiyama, M ; Noma, S ; Noguchi, S ; Kasukawa, T ; Hasegawa, A ; Suzuki, H ; Nishiyori-Sueki, H ; Frith, MC ; FANTOM consortium, ; Chatelain, C ; Carninci, P ; de Hoon, MJL ; Wasserman, WW ; Bréhélin, L ; Lecellier, C-H (Springer Science and Business Media LLC, 2021-06-02)
    Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
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    Defining the Role of Nuclear Factor (NF)-?B p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells
    Somma, D ; Kok, FO ; Kerrigan, D ; Wells, CA ; Carmody, RJ (FRONTIERS MEDIA SA, 2021-10-13)
    Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the NFKB1 gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. NFKB1 encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. NFKB1 is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for NFKB1 in the control of the immune system is apparent from Nfkb1-/- mouse studies, we know relatively little of the role of NFKB1 in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of NFKB1-/- human macrophages. Transcriptomic analysis reveals that activated NFKB1-/- macrophages are more pro-inflammatory than wild type controls and express elevated levels of TNF, IL6, and IL1B, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as CD70, CD83 and CD209. NFKB1-/- THP1 macrophages recapitulate key observations in individuals with NFKB1 haploinsufficiency including decreased IL10 expression. These data supporting their utility as an in vitro model for understanding the role of NFKB1 in human monocytes and macrophages and indicate that of loss of function NFKB1 mutations in these cells is an important component in the associated pathology.
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    An integrated analysis of human myeloid cells identifies gaps in in vitro models of in vivo biology
    Rajab, N ; Angel, PW ; Deng, Y ; Gu, J ; Jameson, V ; Kurowska-Stolarska, M ; Milling, S ; Pacheco, CM ; Rutar, M ; Laslett, AL ; Cao, K-AL ; Choi, J ; Wells, CA (CELL PRESS, 2021-06-08)
    The Stemformatics myeloid atlas is an integrated transcriptome atlas of human macrophages and dendritic cells that systematically compares freshly isolated tissue-resident, cultured, and pluripotent stem cell-derived myeloid cells. Three classes of tissue-resident macrophage were identified: Kupffer cells and microglia; monocyte-associated; and tumor-associated macrophages. Culture had a major impact on all primary cell phenotypes. Pluripotent stem cell-derived macrophages were characterized by atypical expression of collagen and a highly efferocytotic phenotype. Myeloid subsets, and phenotypes associated with derivation, were reproducible across experimental series including data projected from single-cell studies, demonstrating that the atlas provides a robust reference for myeloid phenotypes. Implementation in Stemformatics.org allows users to visualize patterns of sample grouping or gene expression for user-selected conditions and supports temporary upload of your own microarray or RNA sequencing samples, including single-cell data, to benchmark against the atlas.
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    Challenges for Computational Stem Cell Biology: A Discussion for the Field
    Rackham, O ; Cahan, P ; Mah, N ; Morris, S ; Ouyang, JF ; Plant, AL ; Tanaka, Y ; Wells, CA (CELL PRESS, 2021-01-12)
    The first meetup for Computational Stem Cell Biologists was held at the 2020 annual meeting of the International Society for Stem Cell Research. The discussions highlighted opportunities and barriers to computational stem cell research that require coordinated action across the stem cell sector.
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    Ten simple rules for navigating the computational aspect of an interdisciplinary PhD
    Islam, S ; Wells, CA ; Schwartz, R (PUBLIC LIBRARY SCIENCE, 2021-02)