Center for Integrated Cellular Analysis

A single cell is the fundamental unit of life, and the collective actions of individual cells define the behavior of living organisms. To understand cellular identity, it is essential to profile cells individually. In 2020 we launched the Center for Integrated Cellular Analysis as an NIH Center for Excellence in Genomic Science, focused on the measurement and integration of diverse data types at single-cell resolution. Representing a collaborative and synergistic effort across six institutions in New York City, we have pioneered a powerful and broadly impactful suite of methods that have opened the field to the measurement of new and diverse molecular modalities that span the central dogma. In this Renewal application, we aim to continue these efforts while radically advancing and expanding our vision. While our work since 2020 has enabled a breadth of new techniques for high-resolution annotation of cell states, the true potential of single-cell multimodal analysis lies in its ability to not only catalog what cells are doing, but to explain why they are doing it. We propose new technologies that can pinpoint the molecular determinants that establish a cell’s identity, and drive its future behavior and decisions. We aim to tackle four key questions: (i) how are dynamic changes in RNA transcription, splicing and degradation integrated to establish cell state? (ii) how do interactions between transcription factors (TFs) and epigenetic modifications regulate current and future decisions? (iii) how does cellular lineage affect plasticity, differentiation, and growth? (iv) How can perturbations in model systems be used to understand and explain cellular responses in-vivo? While focusing on methods development, we will demonstrate broad generalizability in multiple biological contexts, including the human hematopoietic system, the aging mouse kidney, and pre-malignant patient samples from the esophagus and stomach. To achieve this, we will develop highly scalable, multimodal, and broadly applicable single cell profiling technologies that address key limitations in the field. If successful, our center will unlock the potential of single-cell multi-omics beyond the construction of cell atlases and deliver a powerful and broadly applicable toolkit to understand the determinants of cellular behavior.