Phospho-seq: integrated, multi-modal profiling of intracellular protein dynamics in single cells

John D. Blair, Austin Hartman, Fides Zenk, Philipp Wahle, Giovanna Brancati, Carol Dalgarno, Barbara Treutlein and Rahul Satija ()
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John D. Blair: New York Genome Center
Austin Hartman: New York Genome Center
Fides Zenk: ETH Zurich
Philipp Wahle: ETH Zurich
Giovanna Brancati: ETH Zurich
Carol Dalgarno: New York Genome Center
Barbara Treutlein: ETH Zurich
Rahul Satija: New York Genome Center

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Cell signaling plays a critical role in neurodevelopment, regulating cellular behavior and fate. While multimodal single-cell sequencing technologies are rapidly advancing, scalable and flexible profiling of cell signaling states alongside other molecular modalities remains challenging. Here we present Phospho-seq, an integrated approach that aims to quantify cytoplasmic and nuclear proteins, including those with post-translational modifications, and to connect their activity with cis-regulatory elements and transcriptional targets. We utilize a simplified benchtop antibody conjugation method to create large custom neuro-focused antibody panels for simultaneous protein and scATAC-seq profiling on whole cells, alongside both experimental and computational strategies to incorporate transcriptomic measurements. We apply our workflow to cell lines, induced pluripotent stem cells, and months-old retinal and brain organoids to demonstrate its broad applicability. We show that Phospho-seq can provide insights into cellular states and trajectories, shed light on gene regulatory relationships, and help explore the causes and effects of diverse cell signaling in neurodevelopment.

Date: 2025
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DOI: 10.1038/s41467-025-56590-7

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