Title: FUS-ALS disruption of gene regulation is not rescued by FUS-ASO treatment
Legend: A) UMAP representations of simultaneously measured gene expression and chromatin accessibility of 40,000 individual nuclei, sampled from the lumbar region of a FUS-ALS (left) and FUS-ASO treated (right) adult human spinal cord. The stoichiometric composition of cell types is consistent with known spinal cord cytoarchitecture. B) Schematic representation of the gene regulatory network (GRN). C) Cell type specific GRN of healthy, FUS-ALS, and FUS-ASO treated spinal cords. Transcription factor activity is dysregulated in FUS-ALS across all cell types, with predominant disruption in astrocytes (green), oligodendrocytes (grey), and microglia (orange). FUS-ASO treatment can result in a partial recovery for some transcription factors (NFAT), while the elevated activity for other transcription factors in FUS-ALS is unaffected by ASO treatment (CHOP).
Citation: Kandror, E. K., Wang, A., Carriere, M., Peterson, A., Liao, W., Tjärnberg, A., Fung, J. H., Mahbubani, K. T., Loper, J., Pangburn, W., Xu, Y., Saeb-Parsy, K., Rabadan, R., Maniatis, T., & Rizvi, A. H. (2025). Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord. bioRxiv : the preprint server for biology, 2025.01.10.632483. https://doi.org/10.1101/2025.01.10.632483
Abstract: Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such cryptic enhancers define both stable cell type identity and transitions between cells undergoing differentiation. We also define glial cell gene regulatory networks that reorganize along the rostrocaudal axis, revealing anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular organizations and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state. This study provides fundamental insights into the cellular organization of the healthy human spinal cord.
Investigator: Abbas Rizvi, PhD
About the Lab: The Rizvi research group focuses on studying how patterns of gene regulation, at the level of single cells and spatially resolved, mediate homeostatic function within the central nervous system. They compare these results against neurodegenerative disease states, seeking to understand the molecular and cellular basis for dysfunction.