Matched single-cell chromatin, transcriptome, and surface marker profiling captures in vivo epigenomic reprogramming during basal-to-luminal transition in the mammary gland [ChIP-seq]

Yet, the full potential of these approaches remains untapped for rare cell populations, as most methods require thousands of cells and are limited in their ability to capture multiple molecular layers comprehensively within the same cell. Here, we introduce OneCell CUT&Tag a user-friendly method that provides matched high-resolution epigenome, full-transcriptome, and surface marker quantification from every cell, with input as low as one cell.

Using this approach, we uncovered epigenomic priming of basal cells in the mammary gland and captured the dynamics of basal-to-luminal transdifferentiation. We identified a transitional cell population with intermediate epigenomic profiles—absent in reference populations—and demonstrated a continuous epigenomic progression from basal to luminal states, while transcriptomes exhibited a binary switch. Adaptable to diverse samples and tissues, this method also revealed the role of H3K27me3 in shaping zygotic expression programs.