Pseudo-spectral angle mapping for automated pixel-level analysis of highly multiplexed tissue image data

IEEE Medical Imaging, 2024

Understanding the cellular constituents captured by highly multiplexed tissue imaging is a major limitation affecting the usability of these novel imaging methods. Many imaging experiments have uniquely designed staining panels, reducing the generalizability of cell classification models to new datasets. We present pseudospectral angle mapping (pSAM), which can compress high-dimensional image data into class representations. We demonstrate that the class representations generated by pSAM can be used to interpret high-plex image data and guide cell classification. Importantly, we also demonstrate that pSAM can generalize to new image datasets—collected with a different staining panel in samples from different tissues—without manual image annotation, subjective intensity gating, or re-training an algorithm.

BRWD1 orchestrates small pre-B cell chromatin topology by converting static to dynamic cohesin

Nature Immunology, 2024

We demonstrate that in small pre-B cells, BRWD1 reorders 3D chromatin topology to affect the transition between proliferative and gene recombination molecular programs by converting chromatin-bound static to dynamic cohesin competent to mediate long-range looping. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be dictated by lineage contextual mechanisms to facilitate specific cell fate transitions into the larger dark zone (DZ) to become differentiating DZ (DZd) cells before re-entering the LZ. We reveal distinct molecular programs in each germinal center population and provide a new three-cell population model of the germinal center.

Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS

Cell, 2023

Loss-of-function approaches in B cell precursors show that IKAROS assembles interactions across megabase distances in preparation for lymphoid development. Interactions emanating from IKAROS-bound enhancers override CTCF-imposed boundaries to assemble lineage-specific regulatory units built on a backbone of smaller invariant topological domains. Gain of function in epithelial cells confirms IKAROS’ ability to reconfigure chromatin architecture at multiple scales. Although the compaction of the Igκ locus required for genome editing represents a function of IKAROS unique to lymphocytes, the more general function of IKAROS is to preconfigure the genome to support lineage-specific gene expression and suppress activation of extra-lineage genes.