About

Quen J. Cheng, MD, PhD, is an infectious diseases physician-scientist whose research is motivated by clinical observations of variable outcomes in infections. His work focuses on understanding how the immune system's context—including factors such as age, sex, chronic diseases, and recent exposure history—affects infection severity. He investigates how innate immune cells like macrophages are reprogrammed through signaling networks and epigenetic states when exposed to cytokines and pathogen-associated molecules, and how this reprogramming influences responses to subsequent infections and post-infectious immune dysfunction. Dr. Cheng's research aims to elucidate the molecular mechanisms of immune reprogramming and its relation to the diverse outcomes observed in human infections.

Research topics

• Biology
• Cell biology
• Genetics
• Immunology
• Computer Science
• Chemistry
• Neuroscience
• Cancer research
• Computational biology
• Physics
• Cognitive psychology
• Psychology

Selected publications

• IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages

  Science Signaling · 2025-01-07 · 13 citations

  articleOpen accessCorresponding

  Macrophages exposed to immune stimuli reprogram their epigenomes to alter their subsequent functions. Exposure to bacterial lipopolysaccharide (LPS) causes widespread nucleosome remodeling and the formation of thousands of de novo enhancers. We dissected the regulatory logic by which the network of interferon regulatory factors (IRFs) induces the opening of chromatin and the formation of de novo enhancers. We found that LPS-activated IRF3 mediated de novo enhancer formation indirectly by activating the type I interferon (IFN)–induced ISGF3. However, ISGF3 was generally needed to collaborate with IRF1, particularly where chromatin was less accessible. At these locations, IRF1 was required for the initial opening of chromatin, with ISGF3 extending accessibility and promoting the deposition of H3K4me1, marking poised enhancers. Because IRF1 expression depends on the transcription factor NF-κB, which is activated in infected but not bystander cells, IRF-regulated enhancers required activation of both the IRF3 and NF-κB branches of the innate immune signaling network. However, type II IFN (IFN-γ), which is typically produced by T cells, may also induce IRF1 expression through the STAT1 homodimer GAF. We showed that, upon IFN-γ stimulation, IRF1 was also responsible for opening inaccessible chromatin sites that could then be exploited by GAF to form de novo enhancers. Together, our results reveal how combinatorial logic gates of IRF1-ISGF3 or IRF1-GAF restrict immune epigenomic memory formation to macrophages exposed to pathogens or IFN-γ–secreting T cells but not bystander macrophages exposed transiently to type I IFN.

  PublisherOA PDFDOI

• IFNγ-induced memory in human macrophages is not sustained by epigenetic changes but the durability of the cytokine itself

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-17 · 1 citations

  preprintOpen access

  Abstract Macrophages, as key sentinel cells of the innate immune system, can retain memory of prior stimulus exposure. Interferon gamma (IFNγ) plays a central role in maintaining trained immunity in vivo and can induce potent memory in macrophages. Such memory is associated with the formation of de novo enhancers that alter gene expression responses to subsequent stimuli. However, how such enhancers are maintained after cytokine exposure remains unclear. We report that durable IFNγ-induced enhancers can last for days after cytokine washout, yet the underlying persistence mechanism is not cell-intrinsic. IFNγ-treated macrophages continue to exhibit JAK/STAT signaling days after cytokine removal. Blocking IFNγ signaling with a JAK inhibitor or anti-IFNγ neutralizing antibodies after cytokine removal is sufficient to reverse IFNγ-induced enhancers and erase the potentiated state of the treated macrophages. Our findings suggest that epigenetic changes in macrophages do not inherently encode innate immune memory or a “potentiated” macrophage state, but in fact are themselves dependent on ongoing cytokine signaling. These findings suggest new possibilities for pharmacologic interventions to reverse aberrantly trained immune states associated with pathology.

  PublisherDOI

• GM-CSF receptor expression determines opposing innate memory phenotypes at different stages of myelopoiesis

  Blood · 2024-04-11 · 14 citations

  articleOpen access

  ABSTRACT: Inflammatory responses must be tightly coordinated with the activation of emergency myelopoiesis to produce potent myeloid cells that fight infection without causing excessive host damage. Here, we show that granulocyte-macrophage colony-stimulating factor (GM-CSF) programs myeloid-committed progenitors to produce trained macrophages (increased cytokine response), but programs the upstream noncommitted LKS+ progenitors (defined as Lin- c-Kit+ Sca-1+ cells) to produce tolerized macrophages (decreased cytokine response). In myeloid progenitors, GM-CSF strongly activates signal transducer and activator of transcription 5 (STAT5), Ras-Raf-extracellular signal regulated kinase (ERK), and Akt-mTOR signaling pathways, which are essential to establish a training program, whereas in LKS+ progenitors, GM-CSF induces NF-κB translocation to the nucleus to establish a tolerization program. These differences arise from higher GM-CSF receptor expression in myeloid progenitors compared with LKS+ cells. We demonstrate that β-catenin regulation of NF-κB nuclear translocation is central in this process. In myeloid progenitors, glycogen synthase kinase 3 (GSK3) inactivation by strong ERK and phosphatidylinositol 3 kinase (PI3K)-Akt signaling increases cytoplasmic β-catenin levels to block NF-κB nuclear translocation. In contrast, when ERK and PI3K-Akt signaling are weak, active GSK3 causes a decrease in β-catenin, allowing NF-κB nuclear translocation in LKS+ progenitors. Finally, GM-CSF-induced LKS+ tolerization takes place in several murine models of trained immunity and in human CD34+ CD38- progenitors. Our study reveals that in addition to activating myelopoiesis, GM-CSF also programs early and immediate myeloid progenitors to produce opposing immune memory phenotypes. We propose that the inflammatory response from immediate myeloid progenitors may be balanced by the tolerized phenotype of early progenitors, thus providing a mechanism for appropriate resolution of inflammation and protection against a prolonged cytokine storm.

  PublisherOA PDFDOI

• Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks

  Scientific Reports · 2024-01-16 · 14 citations

  articleOpen access1st authorCorresponding

  Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. β-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized ligands for inducing innate immune training. However, many Dectin-1 ligands exist, and it is not known whether these all produce the same phenotype. Using a well-established in vitro model of innate immune training, we compared two commercially available Dectin-1 agonists, zymosan and depleted zymosan, with the gold standard β-glucan in the literature. We found that depleted zymosan, a β-glucan purified from Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical effects as C. albicans β-glucan. However, untreated zymosan produced a distinct training effect from β-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of cytokines such as TNF and IL-6. Zymosan activated NFκB and AP-1 transcription factors more strongly than β-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of β-glucans to a phenotype resembling zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1 ligands.

  PublisherOA PDFDOI

• Tonic TNF conditioning of macrophages safeguards stimulus‐specific inflammatory responses

  EMBO Reports · 2023-05-22 · 12 citations

  articleOpen access
  PublisherOA PDFDOI

• A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes

  Molecular Systems Biology · 2023 · 14 citations

  • Computer Science
  • Biology
  • Cell biology

  Type I interferons (IFN) induce powerful antiviral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts, type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common antiviral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis, we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus-specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK-STAT/IRF signaling network that may produce distinct biological responses and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it.

  PublisherOA PDFDOI

• Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-10-01

  preprintOpen access1st authorCorresponding

  Abstract Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. β-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely u:lized and well-characterized ligands for inducing innate immune memory. However, many Dectin-1 agonists exist, and it is not known whether all Dectin-1 ligands produce the same phenotype. Using a well-established in vitro model of trained immunity, we compared two commercially available Dectin-1 agonists, zymosan and depleted zymosan, with the gold standard β-glucan in the literature. We found that depleted zymosan, a β-glucan purified from Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical training effects as C. albicans β-glucan. However, untreated zymosan produced a distinct training effect from β-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of key cytokines such as TNF, IL-12, and IL-6. Zymosan activated NF𝓀B and AP-1 transcription factors more strongly than β-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of β-glucans to a phenotype resembling training with zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1. These findings bring clarity to the specific question of which Dectin-1 agonists produce prototypical training effects and provide broader insight into how signaling networks regulate innate immune training.

  PublisherOA PDFDOI

• A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-08-15

  preprintOpen access

  ABSTRACT Type I interferons (IFN) induce powerful anti-viral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common anti-viral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus-specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK-STAT/IRF signaling network that may produce distinct biological responses, and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it. HIGHLIGHTS High dose IFN-β activates a pro-inflammatory gene program in epithelial cells. IFN-β, but not IFN-λ3, induces a second, potentiated phase in ISGF3 activity. ISGF3 induces its subunits to form a stimulus-contingent positive feedback loop. The positive feedback motif is required for the pro-inflammatory gene program.

  PublisherOA PDFDOI

• Stochastic models of nucleosome dynamics reveal regulatory rules of stimulus-induced epigenome remodeling

  Cell Reports · 2022-07-01 · 8 citations

  articleOpen access

  The genomic positions of nucleosomes are a defining feature of the cell's epigenomic state, but signal-dependent transcription factors (SDTFs), upon activation, bind to specific genomic locations and modify nucleosome positioning. Here we leverage SDTFs as perturbation probes to learn about nucleosome dynamics in living cells. We develop Markov models of nucleosome dynamics and fit them to time course sequencing data of DNA accessibility. We find that (1) the dynamics of DNA unwrapping are significantly slower in cells than reported from cell-free experiments, (2) only models with cooperativity in wrapping and unwrapping fit the available data, (3) SDTF activity produces the highest eviction probability when its binding site is adjacent to but not on the nucleosome dyad, and (4) oscillatory SDTF activity results in high location variability. Our work uncovers the regulatory rules governing SDTF-induced nucleosome dynamics in live cells, which can predict chromatin accessibility alterations during inflammation at single-nucleosome resolution.

  PublisherOA PDFDOI

• NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages

  Science · 2021 · 169 citations

  1st authorCorresponding
  • Cell biology
  • Biology
  • Chemistry

  The epigenome of macrophages can be reprogrammed by extracellular cues, but the extent to which different stimuli achieve this is unclear. Nuclear factor κB (NF-κB) is a transcription factor that is activated by all pathogen-associated stimuli and can reprogram the epigenome by activating latent enhancers. However, we show that NF-κB does so only in response to a subset of stimuli. This stimulus specificity depends on the temporal dynamics of NF-κB activity, in particular whether it is oscillatory or non-oscillatory. Non-oscillatory NF-κB opens chromatin by sustained disruption of nucleosomal histone-DNA interactions, enabling activation of latent enhancers that modulate expression of immune response genes. Thus, temporal dynamics can determine a transcription factor's capacity to reprogram the epigenome in a stimulus-specific manner.

  PublisherOA PDFDOI

Frequent coauthors

• Alexander Hoffmann

  24 shared

• Minh Anh Nguyen

  University of California, Los Angeles

  10 shared

• Kensei Kishimoto

  University of Massachusetts Chan Medical School

  10 shared

• Catera L. Wilder

  University of California, Los Angeles

  9 shared

• Adewunmi Adelaja

  University of California, Los Angeles

  9 shared

• John A. Tainer

  The University of Texas MD Anderson Cancer Center

  7 shared

• Raisa Mathenge

  University of California, San Francisco

  7 shared

• Alma Zuniga Munoz

  University of Southern California

  7 shared

Education

• Ph.D., Molecular Biology

  University of California, Los Angeles

  2000

• M.D.

  University of California, Los Angeles

  1997

• B.S., Microbiology

  University of California, Los Angeles

  1993

Awards & honors

• Infectious Disease, UCLA STAR Program (2019)