️ Episode 160: The Long‑Read Leap in Single‑Cell Omics

In this episode of PaperCast Base by Base, we explore how long‑read, single‑molecule sequencing has collided with single‑cell technologies to illuminate “dark” regions and events in the genome, epigenome, and transcriptome that short reads routinely miss.

Study Highlights:
This review maps the rapid maturation of Pacific Biosciences and Oxford Nanopore platforms alongside single‑cell methods, showing how full‑length isoform sequencing reveals complex alternative splicing at single‑cell resolution. It details single‑cell long‑read genome assays such as SMOOTH‑seq and dMDA that sensitively detect structural variants and enable haplotype phasing with tens of cells. It outlines long‑read single‑cell epigenome tools, including scNanoATAC‑seq, scNanoSeq‑CUT&Tag, scNanoCOOL‑seq, and scNanoHi‑C, which recover allele‑specific states, repetitive elements, and higher‑order chromatin contacts. It also highlights computational advances for isoform discovery and quantification as well as open questions around spatial long‑read transcriptomics, native RNA modification detection, and complete per‑cell assemblies.

Conclusion:
Long‑read platforms integrated with single‑cell omics are redefining what can be measured in complex genomic regions, setting the stage for richer mechanistic insights and clinically relevant assays in development, aging, and disease.

Reference:
Wen, L.; Tang, F. Single‑cell omics sequencing technologies: the long‑read generation. Trends in Genetics (2025). https://doi.org/10.1016/j.tig.2025.07.012
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Support:
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Episode Slug: long-read-single-cell-omics
Keywords: single-cell; long-read sequencing; alternative splicing; structural variation; epigenomics