Biology subjects

Gibbs, D.

Publications and source records attributed to Gibbs, D..

6 recordsLinked to original sources

bioRxiv2026

Dynamic reorganization of Developmental to Adult Genome Topology Controls the Initiation and Stabilization of the Human Muscle Stem Cell State

Developmental gene expression is under tight temporal and spatial control. This regulation is imparted by tissue specific enhancers that integrate developmental signals into transcriptional responses to allow for developmental progression. Often species specific, the enhancers that regulate human muscle progenitor and stem cell gene expression are currently unknown. Here, we define the 3D chromatin organization of human muscle development and reveal key changes across the human genome that are associated with multiple layers of 3D genome reorganization during the transition from a more progenitor-like to muscle stem cell state, including a reduction of TAD numbers and an increase in CTCF binding at TAD boundaries and chromatin loops throughout developmental progression. Specifically, we found that increased CTCF occupancy at human enhancers of PAX7 in stem cells holds enhancer-promoter (e-p) loops for timely activation of PAX7 enhancers during early human development. These findings demonstrate that stem cell state acquisition is stabilized earlier than previously known and provide unprecedented insights into the initiation and control of the muscle stem cell state in humans.

developmental biology↗

bioRxiv2025

A fibroblast-centric network drives cold fibrosis in the tumor microenvironment of lung squamous cell carcinoma

The tumor microenvironment (TME) of chronic inflammation-associated cancers (CIACs) is shaped by cycles of injury and maladaptive repair, yet the principles organizing fibrotic stroma in these tumors remain unclear. Here, we applied the concept of hot versus cold fibrosis, originally credentialed in non-cancerous fibrosis of heart and kidney, to lung squamous cell carcinoma (LUSC), a prototypical CIAC. Single-cell transcriptomics of matched tumor and adjacent-normal tissue from 16 treatment-naive LUSC patients identified a cold fibrotic architecture in the LUSC TME: cancer-associated fibroblasts (CAFs) expanded and adopted myofibroblast and stress-response states, while macrophages were depleted. This macrophage-poor, CAF-rich stroma was maintained by CAF autocrine growth factor loops, including TIMP1, INHBA, TGFB1, and GMFB. In parallel, the immune compartment exhibited a hot tumor phenotype with abundant T and B cells, forming spatially distinct but molecularly engaged networks with CAFs. CAF gene programs typifying cold fibrosis in LUSC were conserved in other CIACs, including esophageal and gastric adenocarcinomas. These results redefine desmoplastic regions of tumors through the lens of a non-cancer fibrosis model, demonstrating that conserved stromal circuits constitute therapeutic vulnerabilities in CIACs.

cancer biology↗

bioRxiv2025

Blocking Osteoprotegerin Reprograms Cancer Associated Fibroblast to Promotes Immune Infiltration into the Tumor Microenvironment

AbstractThe stromal compartment of many solid tumors plays a critical role in shaping an immunosuppressive microenvironment that limits the effectiveness of immune-based therapies1. Among stromal constituents, cancer-associated fibroblasts (CAFs) have emerged as key regulators of antitumor immunity2-5. Here, we identify a distinct subset of CAFs in both murine and human stroma-rich cancers that secrete osteoprotegerin (OPG)-- a soluble decoy receptor that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), both of which are involved in T cell function. In vitro, OPG directly impairs CD8 T cell-mediated killing of target cells. In murine models of pancreatic and breast cancer, antibody-mediated blockade of OPG promotes robust immune infiltration into the tumor microenvironment, leading to significant tumor regression. Stromal profiling revealed that OPG blockade induces a shift in CAF cells--reducing immunosuppressive OPG fibroblasts while expanding interferon-responsive fibroblasts, thus recalibrating the tumor stroma toward a pro-immunogenic landscape. These findings uncover a previously unrecognized mechanism of stromal immune suppression and highlight OPG as a stromal immune checkpoint controlling CD8 T cell infiltration. Targeting OPG may offer a novel therapeutic strategy to convert immunologically "cold" tumors into T cell-infiltrated, tumor microenvironment.

cancer biology↗

bioRxiv2023

Light-Guided Rabies Virus Tracing for Neural Circuit Analysis

Neuronal tracing methods are essential tools to understand the fundamental architecture of neural circuits and their connection to the overall functional behavior of the brain. Viral vectors used to map these transsynaptic connections are capable of cell-type-specific and directional-specific labeling of the neuronal connections. Herein, we describe a novel approach to guide the transsynaptic spreading of the Rabies Virus (RV) retrograde tracer using light. We built a Baculovirus (BV) as a helper virus to deliver all the functional components necessary and sufficient for a nontoxic RV to spread from neuron to neuron, with a light-actuated gene switch to control the RV polymerase, the L gene. This design should allow for precisely controlled polysynaptic viral tracing with minimal viral toxicity. To use this system in a highly scalable and automated manner, we built optoelectronics for controlling this system in vitro with a large field of view using an off-the-shelf CMOS sensor, OLED display panel, and microcontrollers. We describe the assembly of these genetic circuits using the uLoop DNA assembly method and a library of genetic parts designed for the uLoop system. Combining these tools provides a framework for increasing the capabilities of nontoxic tracing through multiple synapses and increasing the throughput of neural tracing using viruses.

neuroscience↗

bioRxiv2021

Altered collective mitochondrial dynamics in an Arabidopsis msh1 mutant compromising organelle DNA maintenance

Mitochondria form highly dynamic populations in the cells of plants (and all eukaryotes). The characteristics of this collective behaviour, and how it is influenced by nuclear features, remain to be fully elucidated. Here, we use a recently-developed quantitative approach to reveal and analyse the physical and collective "social" dynamics of mitochondria in an Arabidopsis msh1 mutant where organelle DNA maintenance machinery is compromised. We use a newly-created line combining the msh1 mutant with mitochondrially-targeted GFP, and characterise mitochondrial dynamics with a combination of single-cell timelapse microscopy, computational tracking and network analysis. The collective physical behaviour of msh1 mitochondria is altered from wildtype in several ways: mitochondria become less evenly spread, and networks of inter-mitochondrial encounters become more connected with greater potential efficiency for inter-organelle exchange. We find that these changes are similar to those observed in friendly, where mitochondrial dynamics are altered by a physical perturbation, suggesting that this shift to higher connectivity may reflect a general response to mitochondrial challenges.

plant biology↗

bioRxiv2020

A functional module states framework reveals cell states for drug and target prediction

Cells are complex systems in which many functions are performed by different genetically-defined and encoded functional modules. To systematically understand how these modules respond to drug or genetic perturbations, we developed a Functional Module States framework. Using this framework, we 1) defined the drug induced transcriptional state space for breast cancer cell lines using large public gene expression datasets, and revealed that the transcriptional states are associated with drug concentration and drug targets; 2) identified potential targetable vulnerabilities through integrative analysis of transcriptional states after drug treatment and gene knockdown associated cancer dependency; and 3) used functional module states to predict transcriptional state-dependent drug sensitivity and built prediction models using the functional module states for drug response. This approach demonstrates a similar prediction performance as do approaches using high dimensional gene expression values, with the added advantage of more clearly revealing biologically relevant transcriptional states and key regulators.

systems biology↗