학술논문
Single-cell lineage capture across genomic modalities with CellTag-multi reveals fate-specific gene regulatory changes
Document Type
Original Paper
Author
Source
Nature Biotechnology: The Science and Business of Biotechnology. 42(6):946-959
Subject
Language
English
ISSN
1087-0156
1546-1696
1546-1696
Abstract
Complex gene regulatory mechanisms underlie differentiation and reprogramming. Contemporary single-cell lineage-tracing (scLT) methods use expressed, heritable DNA barcodes to combine cell lineage readout with single-cell transcriptomics. However, reliance on transcriptional profiling limits adaptation to other single-cell assays. With CellTag-multi, we present an approach that enables direct capture of heritable random barcodes expressed as polyadenylated transcripts, in both single-cell RNA sequencing and single-cell Assay for Transposase Accessible Chromatin using sequencing assays, allowing for independent clonal tracking of transcriptional and epigenomic cell states. We validate CellTag-multi to characterize progenitor cell lineage priming during mouse hematopoiesis. Additionally, in direct reprogramming of fibroblasts to endoderm progenitors, we identify core regulatory programs underlying on-target and off-target fates. Furthermore, we reveal the transcription factor Zfp281 as a regulator of reprogramming outcome, biasing cells toward an off-target mesenchymal fate. Our results establish CellTag-multi as a lineage-tracing method compatible with multiple single-cell modalities and demonstrate its utility in revealing fate-specifying gene regulatory changes across diverse paradigms of differentiation and reprogramming.
Lineage tracing using both transcriptomics and chromatin accessibility provides mechanistic insights into cell fate.
Lineage tracing using both transcriptomics and chromatin accessibility provides mechanistic insights into cell fate.