Biology subjects

Rome, K.

Publications and source records attributed to Rome, K..

6 recordsLinked to original sources

bioRxiv2026

Nutrient-sensitive histone propionylation regulates T cell fate and function

Tissue microenvironments differ widely in nutrient composition; yet how local nutrient conditions shape epigenetic programs that direct immune cell fate is poorly understood. We identify histone lysine propionylation (Kpr) as a chromatin mechanism linking nutrient availability to T cell fate decisions. Proteomic analysis reveals that Kpr is broadly reduced in exhausted T cells. H3K18pr is enriched at stemness-associated loci in effector T cells and depleted upon exhaustion. Isoleucine and propionate supply propionyl-CoA in T cells, and restricted nutrient availability within the tumor microenvironment limits histone Kpr, promoting T cell exhaustion. Disrupting isoleucine catabolism in T cells further suppresses Kpr, without altering histone acetylation, and impairs T cell function and antitumor immunity in a manner rescued by propionate. Dietary supplementation of isoleucine and propionate increases Kpr in tumor infiltrating lymphocytes, limits exhaustion, and improves tumor control. These findings establish a microenvironment-chromatin axis crucial for antitumor immunity and amenable to nutritional intervention.

immunology↗

bioRxiv2026

Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch

Mitogenic signals are understood to license cell cycle progression and the metabolic reprogramming required for cell division, with acquired nutrients serving as permissive substrates. Here, we show that nutrient availability instead functions as a mitogen-independent regulatory input that dynamically controls CD8+ T cell proliferative potential. Activating stimuli have been shown to set T cell expansion capacity through their control of c-Myc expression, with the rate of c-Myc decay functioning as a division timer. We demonstrate that nutrient availability is sufficient to control c-Myc expression dynamics and dictates how division potential is stored and later actualized. Glucose-restricted T cells sustain proliferative potential and exhibit high AKT and ERK phosphorylation, despite limited growth. Upon glucose restoration, these cells rapidly increase c-Myc expression, accelerate through the cell cycle, and return to the expansion potential of glucose-replete controls, even after days of enforced restriction. Glucose restriction thus maintains a latent metabolic and mitogenic signaling state that is rapidly realized upon recovery. Mechanistically, mTOR signaling is required for this glucose recovery-driven proliferation, despite c-Myc and pERK remaining elevated following mTOR inhibition, indicating that glucose and mitogen signals operate through parallel rather than hierarchical control points. Altogether, these findings reveal that nutrient availability is not merely rate-limiting for proliferation but dictates the kinetics at which mitogenic signals are dissipated and realized. While mitogenic and nutrient cues converge on a shared anabolic network, they operate through distinct regulatory arms to coordinate the tempo and magnitude of clonal expansion, with implications for protective immunity and immunotherapy. Significance StatementCD8+ T cells rapidly proliferate to fight infections and cancer, often in variable nutrient environments. Activation signals are understood to control T cell expansion potential by setting c-Myc expression and its subsequent decay, with nutrients providing fuel. Here we find that glucose availability functions as an independent regulatory switch. Glucose-restricted T cells remain proliferatively poised for days, keeping pro-growth signaling and metabolic capacity primed. Upon glucose restoration, cells undergo a proliferative burst and catch up to glucose-replete counterparts. Although c-Myc expression rises upon glucose restoration, accelerated division kinetics instead require mTOR activity. These findings reveal that nutrient availability operates in parallel with mitogenic signaling, tuning the rate at which T cells store and realize their expansion potential.

immunology↗

bioRxiv2026

Distinct sensing of BCAAs by mTOR and c-Myc governs T cell proliferation, independent of catabolism

The branched chain amino acids (BCAAs: leucine, isoleucine, valine) are essential amino acids that function as catabolic substrates and signaling molecules via mTORC1. While individual BCAAs have unique roles in organismal and cellular physiology, the mechanisms underlying their individual effects remain poorly understood. We demonstrate that the three BCAAs have distinct roles in T cell biology. We find that isoleucine and valine are necessary and sufficient for quiescence exit and cell division, whereas leucine is dispensable. Mechanistically, these effects are independent of their diverging catabolic fates and instead due to differential sensing of leucine and isoleucine/valine by mTOR and c-Myc. While isoleucine and valine are necessary and sufficient for c-Myc expression, mTORC1 leucine-sensing represses c-Myc and proliferation during BCAA restriction. Together, we find that the discrete sensing of the BCAAs uncouples two major anabolic regulators, mTORC1 and c-Myc, in cell growth. This provides mechanistic insight into the distinct roles of the BCAAs in cell physiology, highlighting divergent BCAA sensing rather than catabolism, and offering a new lens to appreciate their impact on immunity and pathophysiology.

immunology↗

bioRxiv2025

Biosynthetic plasticity enables CD8+ T cell functional resilience under nutrient stress

Summary / AbstractTo maintain lineage-specific functions, cells must acquire and allocate nutrients across diverse cellular processes, even in metabolically-dysregulated environments. The mechanisms allowing CD8+ T cells to maintain immune function in perturbed environments are poorly understood. We find that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reorient translational programming, limiting nutrient demand while prioritizing stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors ATF4 and CEBPG jointly establish an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial anaplerosis. Despite diminished energetic capacity under environmental stress, this program prevents failure of central carbon metabolism, mitigating stress amplification and cellular dysfunction to potentiate anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers functional resilience to immune cells in unfavorable environments, offering novel strategies to enhance immunotherapies.

immunology↗

bioRxiv2024

Malnutrition drives infection susceptibility and dysregulated myelopoiesis that persists after refeeding intervention

Undernutrition is one of the largest persistent global health crises, with nearly 1 billion people facing severe food insecurity. Infectious disease represents the main underlying cause of morbidity and mortality for malnourished individuals, with infection during malnutrition representing the leading cause of childhood mortality worldwide. In the face of this complex challenge, simple refeeding protocols have remained the primary treatment strategy. Although an association between undernutrition and infection susceptibility has been appreciated for over a century, the underlying mechanisms remain poorly understood and the extent to which refeeding intervention is sufficient to reverse nutritionally acquired immunodeficiency is unclear. Here we investigate how malnutrition leads to immune dysfunction and the ability of refeeding to repair it. We find that chronic malnutrition induced through prolonged dietary restriction (40% reduction in food intake) severely impairs the ability of mice to control a sub-lethal Listeria monocytogenes infection. Malnourished mice exhibit blunted immune cell expansion, impaired immune function, and accelerated contraction prior to pathogen clearance. While this defect is global, we find that myelopoiesis is uniquely impacted, resulting in reduced neutrophil and monocyte numbers prior to and post-infection. Upon refeeding, we observe that mice recover body mass, size, cellularity across all major immune organs, the capacity to undergo normal immune cell expansion in response to infection, and a restoration in T cell responses. Despite this broad improvement, refed mice remain susceptible to Listeria infection, uncoupling global lymphoid atrophy from immunodeficiency. We find peripheral neutrophil and monocyte numbers fail to fully recover and refed mice are unable to undergo normal emergency myelopoiesis. Altogether, this work identifies dysregulated myelopoiesis as a link between prior nutritional state and immunocompetency. We believe these findings raise the possibility that exposure to food scarcity should be treated as an immunologic variable, even post-recovery, with considerations for how patient medical history and public health policy.

immunology↗

bioRxiv2019

Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

Chromatin loops enable transcription factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors, such as active forms of Notch, can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3-dimensional (3D) organization of the cancer genome is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B-cell lymphoma, we show that far beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes through establishing new long-range regulatory interactions. Moreover, a large fraction of Notch-promoted regulatory loops forms highly interacting enhancer and promoter spatial clusters, termed "3D cliques". Loss-and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

cancer biology↗