Biology subjects

Fu, Y. C.

Publications and source records attributed to Fu, Y. C..

4 recordsLinked to original sources

bioRxiv2026

Coordinated inhibition of SOX9 and cell cycle progression by microRNA-200 restricts sebaceous gland fate specification

The microRNA-200 family (miR-200s) is widely recognized for their potent role in inhibiting epithelial-to-mesenchymal transition and cell cycle progression in cancer. However, their functional specificity in normal epithelial development remains poorly understood. Here we show that miR-200s are highly enriched in hair matrix progenitors but conspicuously absent from the upper hair follicle (HF), the anatomical location where sebaceous gland (SG) and HF stem cells are specified. We demonstrate that elevated miR-200 expression in this region abolishes SG fate specification while permitting hair morphogenesis. Genome-wide identification of miR-200 targets reveals that miR-200s regulate multiple negative regulators of WNT signaling, in addition to cell cycle regulators. Single-cell and spatial transcriptomic analyses uncover a mutually exclusive expression patterns between WNT activity and SOX9 in the upper HF, which is disrupted by miR-200 induction, resulting in compromised SOX9 function. Mechanistically, genome-wide identification of SOX9 targets uncovers a broad network of lipid and fatty acid metabolism genes critical for the transition of upper HF progenitors to the SG fate. The coordinated inhibition of the SOX9-dependent lipogenic program and the potent restriction of cell cycle progression, both mediated by miR-200s, collectively blocks SG specification. Taken together, this work reveals an unexpected specificity of miR-200 in restricting epithelial plasticity and elucidates a spatially defined SOX9 regulatory network essential for SG development.

developmental biology↗

bioRxiv2025

Heterochronic myeloid cell replacement reveals the local brain environment as key driver of microglia aging

Aging, the key risk factor for cognitive decline, impacts the brain in a region-specific manner, with microglia among the most affected cell types. However, it remains unclear whether this is intrinsically mediated or driven by age-related changes in neighboring cells. Here, we describe a scalable, genetically modifiable system for in vivo heterochronic myeloid cell replacement. We find reconstituted myeloid cells adopt region-specific transcriptional, morphological and tiling profiles characteristic of resident microglia. Young donor cells in aged brains rapidly acquired aging phenotypes, particularly in the cerebellum, while old cells in young brains adopted youthful profiles. We identified STAT1-mediated signaling as one axis controlling microglia aging, as STAT1-loss prevented aging trajectories in reconstituted cells. Spatial transcriptomics combined with cell ablation models identified rare natural killer cells as necessary drivers of interferon signaling in aged microglia. These findings establish the local environment, rather than cell-autonomous programming, as a primary driver of microglia aging phenotypes.

neuroscience↗

bioRxiv2020

Capybara: A computational tool to measure cell identity and fate transitions

Transitions in cell identity are fundamental to development, reprogramming, and disease. Single-cell technologies enable the dissection of tissue composition on a cell-by-cell basis in complex biological systems. However, highly-sparse single-cell RNA-seq data poses challenges for cell-type identification algorithms based on bulk RNA-seq. Single-cell analytical tools are also limited, where they require prior biological knowledge and typically classify cells in a discrete, categorical manner. Here, we present a computational tool, Capybara, designed to measure cell identity as a continuum, at single-cell resolution. This approach enables the classification of discrete cell entities but also identifies cells harboring multiple identities, supporting a metric to quantify cell fate transition dynamics. We benchmark the performance of Capybara against other existing classifiers and demonstrate its efficacy to annotate cells and identify critical transitions within a well-characterized differentiation hierarchy, hematopoiesis. Our application of Capybara to a range of reprogramming strategies reveals previously uncharacterized regional patterning and identifies a putative in vivo correlate for an engineered cell type that has, to date, remained undefined. These findings prioritize interventions to increase the efficiency and fidelity of cell engineering strategies, showcasing the utility of Capybara to dissect cell identity and fate transitions. Capybara code and documentation are available at https://github.com/morris-lab/Capybara.

genomics↗

bioRxiv2020

High-resolution transcriptional and morphogenetic profiling of cells from micropatterned human embryonic stem cell gastruloid cultures

During mammalian gastrulation, germ layers arise and are shaped into the body plan while extraembryonic layers sustain the embryo. Human embryonic stem cells, cultured with BMP4 on extracellular matrix micro-discs, reproducibly differentiate into gastruloids, expressing markers of germ layers and extraembryonic cells with radial organization. Single-cell RNA sequencing and cross-species comparisons with mouse and cynomolgus monkey gastrulae suggest that gastruloids contain seven major cell types, including epiblast, ectoderm, mesoderm, endoderm, and extraembryonic trophoblast- and amnion-like cells. Upon gastruloid dissociation, single cells reseeded onto micro-discs were motile and aggregated with the same but segregated from distinct cell types. Ectodermal cells segregated from endodermal and extraembryonic cells but mixed with mesodermal cells. Our work demonstrates that the gastruloid system supports primate-specific features of embryogenesis, and that gastruloid cells exhibit evolutionarily conserved sorting behaviors. This work generates a resource for transcriptomes of human extraembryonic and embryonic germ layers differentiated in a stereotyped arrangement.

developmental biology↗