About

Francesca Luca is a Professor at the University of Chicago in the Department of Human Genetics. Her research activities focus on functional genomics, gene regulation, and the genetic and environmental determinants of complex traits. She has been involved in multiple NIH-funded projects, including studies on gene-environment interactions in cardiovascular disease, asthma, and immune responses, as well as the genetic mechanisms underlying complex traits. Her work includes analyzing gene expression changes associated with poverty, immune cell responses to stimuli, and the genetic control of transcriptional responses at single-cell resolution. She has contributed to understanding how genetic variation influences gene regulation across different cell types and environmental conditions, with a particular emphasis on human health and disease.

Research topics

• Genetics
• Biology
• Computer Science
• Computational biology
• Artificial Intelligence
• Machine Learning
• Virology
• Medicine
• Internal medicine
• Immunology
• Neuroscience
• Cell biology

Selected publications

• Tet2-associated inflammatory signaling alters healthy hematopoiesis with clonal expansion

  Blood · 2025-11-03

  articleOpen access

  Abstract Age-related clonal hematopoiesis (CH) is often driven by mutations in epigenetic regulators such as TET2. These mutations in epigenetic regulators predispose individuals to systemic inflammation, immune dysfunction, and the progression of malignant disease. Importantly, CH driven by TET2 mutations is associated with an increased risk of cardiovascular events and leukemia, underscoring its clinical significance. Statistically, individuals with TET2-driven CH have a higher incidence of these severe conditions. This highlights the urgent need to understand mechanisms involved. While much research has focused on how TET2-loss of function cells gain a competitive advantage, it has yet to be appreciated how healthy, non-mutated (mutant-exposed) hematopoietic stem and progenitor cells (HSPCs) are affected by the perturbed environment. Prior work from our group has established that mutant-exposed HSPCs are altered upon exposure to leukemic cells. To address this, we used a competitive transplant model in which TET2 knockout (Tet2KO) cells were intravenously injected into non-irradiated congenic hosts, allowing us to assess the impact of mutant cells on otherwise healthy, non-mutated (mutant-exposed) HSPCs. Unlike irradiated hosts, non-irradiated hosts preserve native niche signals, which are central to our investigation of microenvironmental effects. This approach ensures that the observed influences are a direct result of mutant cellular interactions, rather than artifacts from disrupted environments. Peripheral blood was analyzed monthly using complete blood counts, and flow cytometry to test for engraftment of chimeric mutant cells as well as the percentages of T cells, B cells, and myeloid cells. Mice were sacrificed, bone marrow was analyzed, and further assays were conducted up to 12-months post-transplant. Consistent with prior studies, Tet2KO progenitors were myeloid biased, characterized by increased frequencies of MPP3 (myeloid-biased) cells and reduced MPP4 (lymphoid-biased) populations. Interestingly, frequencies of mutant-exposed MPP3s were also increased compared to controls, while frequencies of mutant-exposed MPP4s were decreased with frequencies being comparable to Tet2KO cells. This signifies that environmental inflammation alone can replicate key phenotypes of Tet2 loss. However, downstream progenitors (GMPs) and mature myeloid cells (Ly6G+ neutrophils, CD11b⁺Ly6G⁻ monocytes) were most significantly expanded in Tet2KO-derived cells only. Suggesting that TET2 loss confers maximal advantage at the point of myeloid commitment, not in upstream HSPCs. To determine potential mechanisms contributing to these effects, we performed single-cell transcriptomics on Lineage⁻Sca-1⁺c-Kit⁺ (LSK, HSPCs) cells from chimeric control and Tet2KO mice. We defined six HSPC clusters. Mutant-exposed MPP3s upregulate genes involved in NFĸB, STAT, and MAPK signaling, highlighting their heightened responsiveness to Tet2KO inflammatory cues. The activation of the MAPK/NFĸB pathways in these MPP3s likely contributes to their reduced fitness, aligning both our biological and transcriptional data. In contrast, Tet2KO MPP3s did not activate these regulatory pathways, implying an inflammatory ignorance that may drive their selective expansion. Functionally, we cultured MPP3 populations from each cohort with Tet2KO serum or cytokines. While all cells exhibited altered differentiation, only Tet2KO MPP3s showed increased myeloid output, reinforcing their unique response to this inflammatory signaling. Collectively, we observed mutant-exposed and Tet2KO cells share similar trends at the primitive progenitor level indicating they're responding similarly to the altered inflammatory environment. However, upon commitment to the myeloid lineage, mutant-exposed healthy cells are lost in favor of Tet2KO cell expansion. Transcriptomic analysis indicates mutant-exposed cells are activating regulatory signaling genes. Therefore, Tet2KO progenitors thrive by ignoring inflammatory constraints, whereas healthy cells are altered by them. These data suggest that the selective advantage of mutant clones may derive not only from cell-intrinsic mutations, but also from an environment that obstructs normal hematopoiesis.

  PublisherOA PDFDOI

• Therapeutic potential of activated donor-derived NK and g/d T cell infusion with haploidentical hematopoietic stem cell transplantation 3753

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Haploidentical hematopoietic stem cell transplantation (hapHSCT) is a vital treatment for hematologic malignancies, but graft-versus-host disease (GvHD) remains a major complication. NK and γ/δ T cells have potent anti-leukemic effects without triggering GvHD. Activated γ/δ T cells upregulate NKG2D on NK cells, enhancing their ability to target resistant tumors. Although NK cell infusions with hapHSCT have been safe in clinical trials, relapse rates remain a concern. We hypothesize that infusing activated NK and γ/δ T cell-enriched donor cells with hapHSCT will enhance anti-leukemic activity through CD137L/CD137 signaling and increased NKG2D expression, improving outcomes. We demonstrate that magnetic depletion of α/β T and B cells enriches NK and γ/δ T cells, with monocytes as the primary remaining cell type. Functional, transcriptomic, and phenotyping analyses reveal the enriched cells not only kill leukemic cells but exhibit unique activation profiles compared to purified NK cells, with potential for improved efficacy in hapHSCT. To investigate the mechanisms, we developed a bi-directional mouse hapHSCT model using MHCb/k donors and MHCb/d recipients, offering a more clinically relevant model. Flow cytometry and histology confirm engraftment and GvHD development after co-transplantation of T cells. Our study provides insights into NK and γ/δ T cell anti-leukemic mechanisms, with potential to improve hapHSCT outcomes by enhancing anti-tumor responses and minimizing GvHD. Funding Sources UAB Division of Hematology/Oncology Topic Categories Transplantation Immunology (TRAN)

  PublisherOA PDFDOI

• Mobilization and homogeneity of healthy hematopoietic stem cells during hematological malignancy 3191

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Hematopoietic stem cells (HSCs) are multipotent and capable of self-renewal, producing all immune cells. HSCs are heterogeneous, showing differences in blood lineage production and responses to stress, such as transient proliferation and migration. Inflammation can disrupt HSC function, but the mechanisms remain unclear; so understanding how inflammation affects HSCs could reveal important aspects of their diversity and behavior. We examined how acute sterile inflammation impacts the HSC biology using a pre-clinical mouse model of acute myeloid leukemia (AML) paired with flow cytometric analysis. Our results showed a rapid decline in marrow-resident HSCs after disease onset, with a corresponding expansion of phenotypically distinct splenic HSCs. These egressed HSCs shared surface markers with those lost from the marrow, suggesting a subset of HSCs that are particularly sensitive to inflammation and mobilization. As disease progressed, remaining marrow HSCs became more quiescent. Interestingly, transcriptomic analysis revealed that these residual HSCs were primed for balanced lineage output and showed increased TGFβ signaling, suggesting that a quiescent, non-biased HSC population has a selective advantage under inflammatory stress. These findings may provide insights into how inflammation compromises HSC function, offering potential explanations for impaired hematopoietic recovery following inflammatory insults and guiding future therapeutic strategies. Funding Sources 1T32GM146611-01A1, Mark Foundation Endeavor Topic Categories Hematopoiesis and Immune System Development (HEM)

  PublisherOA PDFDOI

• Perturbation of iNKT differentiation during clonal hematopoiesis from rewiring of inflammation and lipid presentation

  Blood · 2025-11-03

  articleOpen access1st authorCorresponding

  Abstract Invariant Natural Killer T (iNKT) cells are a rare, non-conventional T cell subset that recognize lipid antigens presented by the MHC class I-like molecule CD1d. Upon activation, iNKTs rapidly produce a wide range of cytokines, enabling them to serve as first responders and modulators of both innate and adaptive immunity. Their roles in inflammation, infection, tumor surveillance, and tissue homeostasis are well documented, but how iNKTs behave in the context of early hematologic transformation remains unclear. Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a common, age-associated premalignant condition characterized by somatic mutations in hematopoietic stem/progenitor cells, most frequently in genes involved in epigenetic regulation such as TET2. CHIP not only predisposes to myeloid malignancies but also promotes systemic inflammation, a hallmark of early disease evolution. While TET2 loss has been shown to promote myeloid skewing and inflammatory signaling, its impact on iNKT biology remains unexplored. We hypothesized that TET2-deficient clonal hematopoiesis alters peripheral iNKT cell homeostasis and function through inflammation and disruption of lipid antigen presentation. To model CHIP, we used a non-irradiated bone marrow chimera system in which wild-type recipients were transplanted with Tet2-deficient (Tet2KO) bone marrow cells. This setup preserves a functional thymus, allowing us to study peripheral effects of clonal hematopoiesis on immune cells in the absence of irradiation-induced artifacts. Tet2KO murine chimeras exhibited a significant and progressive loss of peripheral non-mutated iNKT cells, correlating inversely with the extent of Tet2-deficient hematopoiesis. Thymic iNKT development remained intact, suggesting that peripheral environmental factors, rather than developmental defects, are responsible for the observed phenotype. Single-cell RNA sequencing revealed that Tet2-exposed iNKT cells displayed transcriptional signatures consistent with chronic activation, enhanced TCR signaling, and skewing toward the iNKT17 lineage, while iNKT1-defining transcriptional programs were suppressed. Flow cytometry confirmed a marked reduction in iNKT1 cells and a reciprocal expansion of iNKT17 cells in the spleens of Tet2KO chimeras. The cytokine known to promote iNKT17 differentiation, IL-6, was significantly elevated in the plasma of Tet2KO mice. Transcriptomic data revealed robust enrichment of IL-6–STAT3 target genes in iNKTs exposed to the Tet2-deficient microenvironment, further supporting a mechanistic link. In parallel, ATAC-seq profiling of iNKTs revealed increased chromatin accessibility at NFκB-associated transcription factor motifs and inflammatory response elements, indicating sustained activation.Given that iNKT activation depends on recognition of lipid antigens presented by CD1d, we next examined whether Tet2 loss alters this axis. Tet2KO hematopoietic cells exhibited significantly increased CD1d surface expression on multiple immune cell populations. To assess whether Tet2 deficiency perturbs the composition of lipid antigens available for CD1d presentation, we performed liquid chromatography–mass spectrometry LC-MS lipidomic profiling on Tet2-deficient and WT K562 cells. Notably, Tet2 loss resulted in significant alterations in endogenous glycolipid composition, including the enrichment of several lipid species known to be presented by CD1d to iNKT cells. These findings suggest that Tet2 regulates not only immune signaling but also the antigenic landscape that shapes iNKT activation and differentiation. Our study reveals a novel mechanism by which TET2 mutations in hematopoietic cells reprogram the immune microenvironment and impair the function of iNKT cells. We demonstrate that TET2 loss promotes a dual-hit effect: it generates a pro-inflammatory environment that skews iNKT differentiation toward an iNKT17 fate, and it alters both CD1d expression and lipid antigen composition, potentially reshaping the antigenic context that governs iNKT activation. These findings uncover a previously unrecognized role for TET2 in regulating lipid antigen presentation and iNKT homeostasis. By linking epigenetic dysregulation to innate-like T cell dysfunction, our work provides a mechanistic framework for understanding immune evasion in early clonal hematopoiesis and offers novel immunometabolic targets for therapeutic intervention in CHIP and preleukemic states.

  PublisherOA PDFDOI

• Psychological stress and social support are associated with opposing single-cell pro-inflammatory gene regulatory mechanisms in adults

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Psychological stress is linked to elevated markers of chronic inflammation, whereas social support is associated with lower levels; yet, the molecular mechanisms mediating these effects are poorly understood. We investigated gene regulatory variation in peripheral blood mononuclear cells (PBMCs) from 165 self-reported African American adults (aged 50-89 years) using single-cell RNA sequencing (scRNA-seq) and single-cell chromatin accessibility (scATAC-seq). Self-reported psychological stress and social support were associated with differential expression of 1,956 and 1,296 genes, respectively (10% FDR), primarily in CD4+ T cells and monocytes. Interferon signaling genes showed high expression in individuals with high psychological stress and low expression in those with high social support; this pattern mirrored gene expression in individuals with elevated circulating inflammatory markers (IFN-γ, TNF-α, IL-6). Genome-wide transcription factor (TF) motif analysis identified stress- and social support-associated changes in motif activity for 70 and 116 TFs, respectively, with 87 motifs enriched near differentially expressed genes. In CD4+ T cells, high psychological stress corresponded to increased IRF and STAT TF motif activity (interferon pathway), while social support was associated with reduced activity and expression in these pathways. We used an immune challenge paradigm (i.e., LPS stimulation), which confirmed the biological pathways of these gene regulatory effects. Our results demonstrate that psychological stress and social support modulate immune gene regulation at the single-cell level, revealing mechanistic links between psychosocial factors and inflammation, and suggesting that social support may promote immunological health.

  PublisherOA PDFDOI

• Multi-INTACT: integrative analysis of the genome, transcriptome, and proteome identifies causal mechanisms of complex traits

  Genome biology · 2025-02-03 · 9 citations

  articleOpen access

  We present multi-integration of transcriptome-wide association studies and colocalization (Multi-INTACT), an algorithm that models multiple "gene products" (e.g., encoded RNA transcript and protein levels) to implicate causal genes and relevant gene products. In simulations, Multi-INTACT achieves higher power than existing methods, maintains calibrated false discovery rates, and detects the true causal gene product(s). We apply Multi-INTACT to GWAS on 1408 metabolites, integrating the GTEx expression and UK Biobank protein QTL datasets. Multi-INTACT infers 52 to 109% more metabolite causal genes than protein-alone or expression-alone analyses and indicates both gene products are relevant for most gene nominations.

  PublisherOA PDFDOI

• Living in poverty is associated with gene expression changes in immune cells

  Genetics · 2025-04-11 · 1 citations

  articleOpen accessSenior author

  Social factors influence health outcomes and life expectancy. Individuals living in poverty often have adverse health outcomes related to chronic inflammation that affect the cardiovascular, renal, and pulmonary systems. Negative psychosocial experiences are associated with transcriptional changes in genes associated with complex traits. However, the underlying molecular mechanisms by which poverty increases the risk of disease and health disparities are still not fully understood. To bridge the gap in our understanding of the link between living in poverty and adverse health outcomes, we performed RNA-sequencing of blood immune cells from 204 participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study in Baltimore, Maryland. We identified 138 genes differentially expressed in association with poverty. Genes differentially expressed were enriched in wound healing and coagulation processes. Of the genes differentially expressed in individuals living in poverty, EEF1DP7 and VIL1 are also associated with hypertension in transcriptome-wide association studies. Our results suggest that living in poverty influences inflammation and the risk for cardiovascular disease through gene expression changes in immune cells.

  PublisherOA PDFDOI

• Host transcriptional responses to gut microbiome variation arising from urbanism

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-26

  preprintOpen access

  ABSTRACT Gut microbiomes of urban communities are compositionally different from their rural counterparts, and are associated with immune dysregulation and gastrointestinal disease. However, it is unknown whether these compositional differences impact host physiology, and through what mechanisms. Here, we used human colonic epithelial cells to directly compare host transcriptional changes induced by gut microbiomes from urban versus rural communities. We co-cultured host cells with live, stool-derived gut microbiomes from Rwanda, Ghana, Nigeria, Malaysia, and the United States, and quantified transcriptional responses using RNA-seq. We found that urban microbiomes affected innate immune pathways, including TNF signaling and bacterial antigen recognition. We also found that high-diversity microbiomes elicited a stronger host transcriptional response, while low-diversity microbiomes triggered epithelial restructuring and glycolysis. Finally, specific taxa driving these effects, including Bifidobacterium adolescentis and Bacteroides dorei , correlated with lifestyle factors such as diet. These findings demonstrate that urbanization-associated microbiome changes directly influence host epithelial gene expression.

  PublisherOA PDFDOI

• Nonproteolytic ubiquitination regulates chromatin occupancy by the NCoR/SMRT/HDAC3 corepressor complex in MCF-7 breast cancer cells

  Proceedings of the National Academy of Sciences · 2025-04-30 · 3 citations

  articleOpen access

  Tight regulation of gene expression is achieved through the coordinated action of transcription factors and cofactors that often can act as both repressors and activators in response to regulatory signals, with their activity modulated by context-specific signal transduction pathways that also impinge on their transient and cyclical recruitment to chromatin. However, the mechanisms underlying the intricate interplay between the regulatory strategies controlling cofactors' activity and localization across subcellar domains remain poorly understood. Here, we investigated the role of G-Protein Pathway Suppressor 2 (GPS2), a transcriptional cofactor critical for maintaining cellular homeostasis via regulation of mitochondrial biogenesis, stress response, lipid metabolism, insulin signaling, and inflammation, in MCF-7 breast cancer cells. By integration of biochemical assays with genome-wide RNA sequencing and Chromatin immunoprecipitation-Seq analyses, we show that nuclear GPS2 is required for licensing histone deacetylase 3 recruitment to chromatin via restricted ubiquitination by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase previously shown to regulate the switch from repressive to activating functions of the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex and here unexpectedly found to translocate to the nucleus in response to IL-1β stimulation. Nuclear TRAF6 is recruited to chromatin via direct interaction with the corepressors NCoR/SMRT, and TRAF6-mediated ubiquitination of TGF-beta activated kinase 1 (MAP3K7) binding protein 2 (TAB2), a facultative component of the NCoR/SMRT complex, contributes to corepressor clearance from target regulatory regions. Together, these results reveal an exquisite mechanism for coordinating the local regulation of cofactor activity with proinflammatory signaling pathways.

  PublisherOA PDFDOI

• Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts

  The American Journal of Human Genetics · 2025-01-14 · 7 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• Functional Characterization of the Genetic and Environmental Determinants of Complex Traits

  NIH · $2.9M · 2014–2029

• Functional Characterization of the Genetic and Environmental Determinants of Complex Traits

  NIH · $290k · 2014–2018

Frequent coauthors

• Roger Piqué-Regi

  124 shared

• Xiaoquan Wen

  University of Michigan–Ann Arbor

  77 shared

• Adnan Alazizi

  Wayne State University

  47 shared

• Roberto Romero

  Eunice Kennedy Shriver National Institute of Child Health and Human Development

  24 shared

• Julong Wei

  Wayne State University

  21 shared

• Cynthia A. Kalita

  Wayne State University

  21 shared

• Anthony S Findley

  Wayne State University

  20 shared

• Samuele Zilioli

  Wayne State University

  19 shared

Labs

• Francesca LucaPI

Education

• Ph.D., Human Genetics

  University of Chicago

  2000

• M.S., Human Genetics

  University of Chicago

  1997

• B.S., Human Genetics

  University of Chicago

  1995