Single-cell lineage capture across genomic modalities with CellTag-multi reveals fate-specific gene regulatory changes

Kunal Jindal, Mohd Tayyab Adil, Naoto Yamaguchi, Xue Yang, Helen C. Wang, Kenji Kamimoto, Guillermo C. Rivera-Gonzalez, Samantha A. Morris

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
JournalNature Biotechnology
DOIs
StateAccepted/In press - 2023

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