Major transcriptome re-organisation and abrupt changes in signalling, cell cycle and chromatin regulation at neural differentiation in vivo

Isabel Olivera-Martinez, Nick Schurch, Roman Li, Junfang Song, Pamela A. Halley, Raman M. Das, Dave W. Burt, Geoffrey J. Barton, Kate G. Storey (Lead / Corresponding author)

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    Abstract

    Here, we exploit the spatial separation of temporal events of neural differentiation in the elongating chick body axis to provide the first analysis of transcriptome change in progressively more differentiated neural cell populations in vivo. Microarray data, validated against direct RNA sequencing, identified: (1) a gene cohort characteristic of the multi-potent stem zone epiblast, which contains neuro-mesodermal progenitors that progressively generate the spinal cord; (2) a major transcriptome re-organisation as cells then adopt a neural fate; and (3) increasing diversity as neural patterning and neuron production begin. Focussing on the transition from multi-potent to neural state cells, we capture changes in major signalling pathways, uncover novel Wnt and Notch signalling dynamics, and implicate new pathways (mevalonate pathway/steroid biogenesis and TGFß). This analysis further predicts changes in cellular processes, cell cycle, RNA-processing and protein turnover as cells acquire neural fate. We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase. This latter step may provide time for epigenetic events to mediate large-scale transcriptome re-organisation; consistent with this, we uncover simultaneous downregulation of major chromatin modifiers as the neural programme is established. We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation. Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation.
    Original languageEnglish
    Pages (from-to)3266-3276
    Number of pages11
    JournalDevelopment
    Volume141
    Issue number16
    DOIs
    Publication statusPublished - Aug 2014

    Fingerprint

    Transcriptome
    Chromatin
    Cell Cycle
    Genetic Epigenesis
    RNA Sequence Analysis
    Germ Layers
    Mevalonic Acid
    Gene Expression Profiling
    Proteasome Endopeptidase Complex
    S Phase
    Epigenomics
    Genes
    Spinal Cord
    Down-Regulation
    Steroids
    RNA
    Neurons
    Population
    Proteins

    Cite this

    Olivera-Martinez, Isabel ; Schurch, Nick ; Li, Roman ; Song, Junfang ; Halley, Pamela A. ; Das, Raman M. ; Burt, Dave W. ; Barton, Geoffrey J. ; Storey, Kate G. / Major transcriptome re-organisation and abrupt changes in signalling, cell cycle and chromatin regulation at neural differentiation in vivo. In: Development. 2014 ; Vol. 141, No. 16. pp. 3266-3276.
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    author = "Isabel Olivera-Martinez and Nick Schurch and Roman Li and Junfang Song and Halley, {Pamela A.} and Das, {Raman M.} and Burt, {Dave W.} and Barton, {Geoffrey J.} and Storey, {Kate G.}",
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    Major transcriptome re-organisation and abrupt changes in signalling, cell cycle and chromatin regulation at neural differentiation in vivo. / Olivera-Martinez, Isabel; Schurch, Nick; Li, Roman; Song, Junfang; Halley, Pamela A.; Das, Raman M.; Burt, Dave W.; Barton, Geoffrey J.; Storey, Kate G. (Lead / Corresponding author).

    In: Development, Vol. 141, No. 16, 08.2014, p. 3266-3276.

    Research output: Contribution to journalArticle

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    AU - Olivera-Martinez, Isabel

    AU - Schurch, Nick

    AU - Li, Roman

    AU - Song, Junfang

    AU - Halley, Pamela A.

    AU - Das, Raman M.

    AU - Burt, Dave W.

    AU - Barton, Geoffrey J.

    AU - Storey, Kate G.

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    N2 - Here, we exploit the spatial separation of temporal events of neural differentiation in the elongating chick body axis to provide the first analysis of transcriptome change in progressively more differentiated neural cell populations in vivo. Microarray data, validated against direct RNA sequencing, identified: (1) a gene cohort characteristic of the multi-potent stem zone epiblast, which contains neuro-mesodermal progenitors that progressively generate the spinal cord; (2) a major transcriptome re-organisation as cells then adopt a neural fate; and (3) increasing diversity as neural patterning and neuron production begin. Focussing on the transition from multi-potent to neural state cells, we capture changes in major signalling pathways, uncover novel Wnt and Notch signalling dynamics, and implicate new pathways (mevalonate pathway/steroid biogenesis and TGFß). This analysis further predicts changes in cellular processes, cell cycle, RNA-processing and protein turnover as cells acquire neural fate. We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase. This latter step may provide time for epigenetic events to mediate large-scale transcriptome re-organisation; consistent with this, we uncover simultaneous downregulation of major chromatin modifiers as the neural programme is established. We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation. Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation.

    AB - Here, we exploit the spatial separation of temporal events of neural differentiation in the elongating chick body axis to provide the first analysis of transcriptome change in progressively more differentiated neural cell populations in vivo. Microarray data, validated against direct RNA sequencing, identified: (1) a gene cohort characteristic of the multi-potent stem zone epiblast, which contains neuro-mesodermal progenitors that progressively generate the spinal cord; (2) a major transcriptome re-organisation as cells then adopt a neural fate; and (3) increasing diversity as neural patterning and neuron production begin. Focussing on the transition from multi-potent to neural state cells, we capture changes in major signalling pathways, uncover novel Wnt and Notch signalling dynamics, and implicate new pathways (mevalonate pathway/steroid biogenesis and TGFß). This analysis further predicts changes in cellular processes, cell cycle, RNA-processing and protein turnover as cells acquire neural fate. We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase. This latter step may provide time for epigenetic events to mediate large-scale transcriptome re-organisation; consistent with this, we uncover simultaneous downregulation of major chromatin modifiers as the neural programme is established. We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation. Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation.

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    JO - Development

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    SN - 0950-1991

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