| 1. |
- Mold, Jeff E., et al.
(author)
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Clonally heritable gene expression imparts a layer of diversity within cell types
- 2024
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In: Cell systems. - : Elsevier BV. - 2405-4720. ; 15:2, s. 149-
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Journal article (peer-reviewed)abstract
- Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. Using high-coverage single-cell RNA profiling, we asked whether long-term, heritable differences in gene expression can impart diversity within cells of the same type. Studying clonal human lymphocytes and mouse brain cells, we uncovered a vast diversity of heritable gene expression patterns among different clones of cells of the same type in vivo. We combined chromatin accessibility and RNA profiling on different lymphocyte clones to reveal thousands of regulatory regions exhibiting interclonal variation, which could be directly linked to interclonal variation in gene expression. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging, and disease. A record of this paper's transparent peer review process is included in the supplemental information.
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| 2. |
- von Berlin, Leonie, et al.
(author)
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Early fate bias in neuroepithelial progenitors of hippocampal neurogenesis
- 2023
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In: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 33:4, s. 391-401
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Journal article (peer-reviewed)abstract
- Hippocampal adult neural stem cells emerge from progeny of the neuroepithelial lineage during murine brain development. Hippocampus development is increasingly well understood. However, the clonal relationships between early neuroepithelial stem cells and postnatal neurogenic cells remain unclear, especially at the single-cell level. Here we report fate bias and gene expression programs in thousands of clonally related cells in the juvenile hippocampus based on single-cell RNA-seq of barcoded clones. We find evidence for early fate restriction of neuroepithelial stem cells to either neurogenic progenitor cells of the dentate gyrus region or oligodendrogenic, non-neurogenic fate supplying cells for other hippocampal regions including gray matter areas and the Cornu ammonis region 1/3. Our study provides new insights into the phenomenon of early fate restriction guiding the development of postnatal hippocampal neurogenesis.
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| 3. |
- von Berlin, Leonie
(author)
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Simultaneous profiling of cell types and lineages in neuro- and gliogenesis
- 2023
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Doctoral thesis (other academic/artistic)abstract
- The mammalian brain consists of billions of highly specialized cells and trillions of connections between them. This immense complexity arises from a single layer of neuroepithelial progenitor cells. During development each progenitor cell produces many daughter cells which transform, migrate, survive, or die, settle and connect in such a coordinated manner that complicated brain structures such as cortex and hippocampus are formed. In the last decade, great progress in single-cell technologies have led to the identification and description of many of those cells in the central nervous system. However, conventional single-cell transcriptomics does not capture a cell’s location in three-dimensional tissue space as well as its continuous development over time. The developmental and spatial path leading from a neuroepithelial progenitor to a fully differentiated cell remains largely unresolved. Recently, a plethora of methods have emerged to reconstruct cellular lineages at the single-cell level. Single-cell lineage tracing includes marking founder cells with a type of label that is inherited to all daughter cells with each cell division and that can be read out at a later timepoint using single-cell methods. However, due to its complexity and density, in vivo single-cell lineage tracing in the central nervous system has remained challenging. In this work, we developed methods to reconstruct lineages in thousands of murine brain cells in vivo to connect progenitors to their differentiated progeny, their spatial location, and lineage-specific gene expression. In paper I, we establish TREX (= clonal TRacking and gene EXpression profiling using single-cell RNAseq) for in vivo random DNA barcoding of early murine progenitors through lentiviral integration. Integrated barcodes are passed on to the daughter cells and, since they are expressed as mRNA, read out together with the transcriptome of the cell. We combine TREX with spatial transcriptomics, called Space-TREX, to study the spatial distribution of related cells. With the two tools at hand, we uncover lineage relationships between early neuroepithelial and myeloid progenitors and their progeny, respectively. Taking advantage of these data for paper II, we explore in detail the relationship between embryonic neural progenitors and adult neurogenic cells in the hippocampus. Here, we present supporting data for an early fate bias of neuroepithelial progenitors, directing them either toward neurogenic cells within the hippocampal neurogenic region or a nonneurogenic path, where they contribute to other areas within the hippocampus. Finally, in paper III and yet unpublished results, we use our mouse brain lineage tracing data to support a finding initially made in T cells that clonally related cells share gene expression patterns and that those transcriptional patterns can be long-term heritable. With that we identify clonally heritable gene expression as a source of diversity and possibly competition among genetically identical, related cells.
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