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Decoding neuronal diversity by single cell Convert-seq

ABSTRACT: The conversion of cell fates is controlled by hierarchical gene regulatory networks (GRNs) that induce remarkable alterations of cellular and transcriptome states. The identification of key regulators within these networks from myriad of candidate genes, however, poses a major research challenge. Here we present Convert-seq, combining single-cell RNA sequencing (scRNA-seq) and pooled (mutiplexed) ectopic gene expression with a new strategy to discriminate sequencing reads derived from exogenous and endogenous transcripts. We demonstrate Convert-seq by associating hundreds of single cells at multiple time-points during direct conversion of human fibroblasts to induced neurons (iN) with exogenous and endogenous transcriptional signatures. Convert-seq simultaneously identified GRNs that modulate the emergence of parallel developmental trajectories during iN conversion and predicted combinatorial interactions of exogenous transcription factors controlling iN subtype specification. Validation of iN subtypes generated by novel combinations of exogenous transcription factors establish Convert-seq as a broadly applicable workflow to rapidly identify key transcription factors and GRNs orchestrating the direct conversion of virtually any cell type.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117075 | GEO | 2019/12/01

REPOSITORIES: GEO

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Project description:Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly specify somatic cell fates in cells such as pancreatic ? cells, contractile cardiomyocytes and neurons. We hypothesized that combinatorial expression of chondrocyte-specific transcription factors could directly convert human amnion cells into chondrosarcoma. Starting from a pool of candidate genes, we identified a combination of only five genes (5F pool), BCL6, T (also called BRACHYURY), c-MYC, MITF and BAF60C (also called SMARCD3) that rapidly and efficiently convert postnatal human amnion into chondrosarcoma. The cells generated expressed multiple cartilage-specific genes such as collagen type II ?1, link protein-1 and aggrecan, and exhibited characteristics of cartilage both in vivo and in vitro. Expression of the endogenous genes for T and MITF was initiated, implying that the cell conversion is due to not only the forced expression of the transgenes, but also the cellular reprogramming by the transgenes. The same set of genes converted human placental artery-derived endothelial (hPAE) cells and menstrual blood-derived cells into chondrosarcoma cells, implying that this conversion is independent of cell types. Direct conversion system from non-cartilage tissue to cartilaginous tissue contributes substantially to a major advance toward cartilage development, oncogenesis of chondrocytes, and cell-based therapy. We hypothesized that combinatorial expression of chondrocyte-specific transcription factors could directly convert human amnion cells into chondrosarcoma. Starting from a pool of candidate genes, we identified a combination of only five genes that rapidly efficiently convert postnatal human amnion into chondrosarcoma.

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Decoding neuronal diversity by single cell Convert-seq

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