About

Christopher Benner is an associate professor in the Department of Medicine at UC San Diego. He holds a PhD in Bioinformatics and a BS in Bioengineering from the University of California, San Diego. Dr. Benner is a bioinformatics and genomics scientist whose research focuses on understanding how cells decode regulatory DNA to orchestrate transcriptional responses. His laboratory develops computational and experimental technologies to study transcription regulation, analyzing the influence of regulatory DNA, epigenetics, and 3D genome structure on gene expression. His work involves profiling transcription initiation using methods such as csRNA-seq and TSS-MPRA, which provide high-resolution measurements of regulatory element activity. These approaches are used to model transcriptional network responses to inflammatory stimuli and pathological conditions, as well as to investigate the impact of non-coding genetic variation. Dr. Benner's lab collaborates on studies related to viral host-pathogen interactions, cellular development, chronic inflammatory diseases, and substance abuse. Additionally, he contributes to the development of genomics software tools like HOMER and Metascape, which aid the scientific community in interpreting genomics data.

Research topics

• Biology
• Internal medicine
• Medicine
• Virology
• Computational biology
• Cell biology
• Computer Science
• Sociology
• Political Science
• Immunology
• Business
• Biochemistry
• Genetics
• Pharmacology
• Engineering ethics
• Regional science
• Endocrinology
• Bioinformatics
• Cancer research
• Engineering
• Evolutionary biology
• Public relations

Selected publications

• <i>Mysm1</i> mutations in <i>meander tail</i> mice cause anterior-selective cerebellum malformation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-26

  articleOpen access

  Abstract Mouse meander tail ( mea ) mutations produce kinked tails and selective malformation of the cerebellum anterior compartment. The anterior cerebellum defects are cell autonomous with respect to granule cell precursors, but the molecular basis has not been known. Myb-like, SWIRM, and MPN domain containing protein 1 (MYSM1) is a chromatin-associated deubiquitinase that promotes gene expression by removing monoubiquitin from histone H2A, among other targets. Loss of MYSM1 function in mice or humans results in bone marrow failure with defective maturation of B cell lineages. Here we show that extant mea alleles have mutations in Mysm1 and cause both neurological and hematological phenotypes, as do new non-complementing endonuclease-mediated mutations. Multimodal single-nucleus assays show Mysm1 effects on gene expression in several lineages and on the proportion of granule cell precursors by E14.5. Intriguingly, Mysm1 orthologs have been independently lost in several animal and fungal lineages, including yeast, flies, and nematodes. These results unite previously disconnected literature and demonstrate a requirement for MYSM1 activity in compartment-specific development of the cerebellum and suggest potential for compensatory pathways. Significance Statement Perturbations to core regulatory machinery often produce pleiotropic effects and even intensively studied systems can have significant phenotypic effects that were not assessed in models developed for a different purpose. Here we show that classical meander tail mice, characterized by ankylosing spondylitis in tail vertebrae and a cerebellum malformation that defined the anterior-posterior compartment boundary, have mutations in Mysm1 , encoding a histone 2A deubiquitinase. We show pigmentation defects and hematopoietic abnormalities that model human disease. While Mysm1 mutations change gene expression patterns in many cerebellar cell types, they selectively decrease the proportion of granule cell lineages. Recurrent loss of Mysm1 orthologs across fungal and animal phylogenies suggests the potential for bypass mechanisms.

  PublisherDOI

• SETD5 dysfunction in human astrocytes drives IL-6-mediated neuronal impairments via the JAK/STAT signaling pathway

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-07 · 1 citations

  articleOpen access

  Abstract Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental conditions marked by lifelong impairments in cognitive, motor, and social functions. Hundreds of genetic variants have been linked to these disorders, including mutations in chromatin regulators such as the SET-domain-containing protein 5 ( SETD5 ) gene. Most studies linking SETD5 loss-of-function to ASD/ID have focused primarily on neurons. However, while SETD5 is highly expressed in astrocytes, its role in glia cells remains poorly understood. Here, we examine how dysfunction of SETD5 in human-induced pluripotent stem cell (hiPSC)-derived astrocytes affects neuronal physiology. We show that SETD5-deficient astrocytes have increased levels of extracellular reactive oxygen species (ROS), glutamate, and interleukins-6 and 8 (IL-6 and (IL-8). Elevated astrocytic IL-6 exerts a non-cell autonomous harmful effect on healthy neurons. Using SETD5-deficient astrocytes as a screening platform, we identify the JAK/STAT pathway as an upstream regulator of abnormal IL-6 accumulation associated with SETD5 dysfunction. Accordingly, pharmacological inhibition of JAK-STAT signaling restores extracellular IL-6 to basal levels and partially rescues astrocyte morphology and neuronal deficits. Collectively, these findings highlight the JAK/STAT pathway as a key regulator of SETD5-mediated astrocytic function and suggest its potential as a therapeutic target for astrocytic-driven neuronal impairments in ASD and ID.

  PublisherOA PDFDOI

• Multiplexed measurements of protein-protein interactions and protein abundance across cellular conditions using Prod&amp;PQ-seq

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-02

  articleOpen access

  Methods to profile protein-protein interactions (PPIs) have limited scalability and can only study a handful of conditions and/or targets. Here, we introduce Prod&PQ-seq, a framework for multiplexed detection and quantification of PPIs and proteins. Our framework uses cross-linked cells, antibody-oligonucleotide conjugates (ab-oligos), and captures PPIs by the DNA-caliper, a specialized oligonucleotide for bidirectional priming of proximal ab-oligos. We benchmarked Prod&PQ-seq using recombinant complexes, titrations and cell mixture experiments and show that our framework is quantitative, reproducible, sensitive and specific. Applying Prod&PQ-seq to study Polycomb Repressive Complex 2 (PRC2) shows that EZH2 inhibition and expression of the oncohistone H3.3K27M weakens both PRC2-H3K27me3 interactions and PPIs within PRC2. Further, H3.1K27M and H3.3K27M variants lead to distinct PPI profiles such as the intensity of H3K27ac-K27M or H3K27ac-EED. Together, Prod&PQ-seq enables detection of changes in PPI composition and intensity and protein quantification across biological conditions, small molecule inhibition and genetic perturbations.

  PublisherDOI

• Profiling active RNA polymerase II transcription start sites from total RNA by capped small RNA sequencing (csRNA-seq)

  Nature Protocols · 2026-01-16

  articleOpen access
  PublisherOA PDFDOI

• Integrative multi-omics analysis in vivo identifies influenza virus host factors

  iScience · 2025-09-24 · 2 citations

  articleOpen access

  Influenza A virus (IAV) infection remodels cellular processes to support viral replication. The modulation of host factors by the virus drives pathogenesis during infection, and these factors may serve as therapeutic targets. Here, we infect mice with two IAV strains, H1N1 and H5N1, and analyze lung tissue with multi-omics. Using network propagation analysis, we identify twenty-four distinct host modules altered by infection, encompassing 2920 genes/proteins. Independently, we develop a computational pipeline, MidTOD, which integrates metabolomic data with other OMICs data-types, linking metabolites to gene/protein alterations. Combining datasets from both approaches reveals alterations in mitochondrial and peroxisomal metabolism in IAV-infected cells and identifies arginine:glycine amidinotransferase (GATM) as a host dependency factor in both human cells and mice. Knockdown of this enzyme reduces IAV-mediated pathology and host inflammatory responses after infection. Collectively, this work provides an integrated systems-level view of host changes during infection and identifies an abundance of IAV-host factors.

  PublisherDOI

• Zika but not Dengue virus infection limits NF-κB activity in human monocyte-derived dendritic cells and suppresses their ability to activate T cells

  Nature Communications · 2025-03-25 · 6 citations

  articleOpen access

  Understanding flavivirus immunity is critical for the development of pan-flavivirus vaccines. Dendritic cells (DC) coordinate antiviral innate and adaptive immune responses, and they can be targeted by flaviviruses as a mechanism of immune evasion. Using an unbiased genome-wide approach designed to specifically identify flavivirus-modulated pathways, we found that, while dengue virus (DENV) robustly activates DCs, Zika virus (ZIKV) causes minimal activation of genes involved in DC activation, maturation, and antigen presentation, reducing cytokine secretion and the stimulation of allogeneic and peptide-specific T cell responses. Mechanistically, ZIKV inhibits DC maturation by suppressing NF-κB p65 recruitment and the subsequent transcription of proinflammatory and DC maturation-related genes. Thus, we identify a divergence in the effects of ZIKV and DENV on the host T cell response, highlighting the need to factor such differences into the design of anti-flavivirus vaccines. Dendritic cells play pivotal roles in the immune response to viral infection but are targeted by flaviviruses resulting in evasion of the host response. Here the authors show Zika but not Dengue virus limits the NF-κB response in monocyte derived dendritic cells diminishing their ability to activate T cells.

  PublisherOA PDFDOI

• Human AUTS2 regulates neurodevelopmental pathways via dual DNA/RNA binding

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-08 · 1 citations

  preprintOpen access

  Abstract The AUTS2 gene is implicated in neurodevelopmental and psychiatric disorders, with patient mutations leading to intellectual disability, microcephaly, and autistic behavior. While AUTS2’s chromatin-and RNA-related functions are recognized, its direct binding to RNA in human neural progenitors has not been previously demonstrated. Here, we used ChIP-seq and eCLIP-seq in human neural progenitor cells (NPCs) to map AUTS2’s chromatin targets and, for the first time, its direct RNA interactome. AUTS2 knockdown in NPCs led to widespread gene expression changes and impaired cell proliferation, migration, and neurite outgrowth. Integrated analysis revealed downregulation of Wnt pathway genes, notably WNT7A , among targets directly bound by AUTS2 at both chromatin and RNA levels. Supplementation with WNT7A rescued cellular phenotypes in AUTS2-deficient NPCs, underscoring the significance of Wnt signaling. These findings highlight AUTS2’s central role in human neurodevelopment and provide mechanistic insight into how its disruption may contribute to the pathology of neurodevelopmental disorders.

  PublisherOA PDFDOI

• Loss of tight junction protein claudin 18 uncovers alveolar epithelial stem cell plasticity and emergence of non-fibrogenic transitional progenitors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-03

  preprintOpen access

  SUMMARY Persistence of senescent alveolar transitional progenitors following lung injury is implicated in the pathogenesis of fibrosis. We identified transitional cells in uninjured Cldn18 knockout (KO) mouse lungs distinct from previously reported damage-associated transitional progenitors (DATPs) with a less fibrogenic transcriptomic profile. Cldn18 KO mice are protected from bleomycin-induced fibrosis, with early restoration of cellular homeostasis. Lineage tracing implicates accelerated differentiation as a mechanism for protection from fibrosis, leading us to name these cells regeneration-associated transitional progenitors (RATPs). Multiome confirms that RATPs and DATPs are epigenetically distinct, with RATPs comprised of RATP2s and RATP1s based on epigenomic proximity to AT2s and AT1s, respectively, and suggests dynamic regulatory remodeling during AT2-to-AT1 differentiation, with NKX2.1 and AP-1 active in early transitions and TEAD factors in later stages. These results reveal an unexpected role for Cldn18 in regulation of AEC plasticity, while identification of RATPs challenges the notion that persistence of transitional alveolar cells is invariably pathologic.

  PublisherOA PDFDOI

• Automated chromatin profiling with spa-ChIP-seq uncovers the impacts of condition variations

  Genome Research · 2025-12-12 · 1 citations

  articleOpen access

  Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is widely used to study the genomic localization of DNA-associated proteins. However, conventional protocols include multiple manual steps that can introduce inconsistency and limit scalability, thereby restricting the inclusion of appropriate replicates and controls. Although the introduction of liquid handling platforms has improved reproducibility, most existing efforts have automated only a subset of the workflow, and extending automation to efficiently map nonhistone proteins, such as chromatin regulators, remains challenging. Here, we present a fully automated implementation of our previously developed single-pot ChIP-seq protocol, named spa-ChIP-seq, which enables scalable processing of eight to 96 ChIP-seq samples from cross-linked cells to a sequencing-ready library in approximately 3 days with an estimated cost of $70 per sample. Benchmarking spa-ChIP-seq against manual ChIP-seq performed in parallel demonstrates a comparable signal-to-noise ratio between the two workflows. Using spa-ChIP-seq, we systematically evaluate multiple parameters including shearing and cross-linking conditions, buffer compositions, and the ratio of antibody to cell number. We find, for the first time to our knowledge, that weaker genomic localization signals are sensitive to changing the antibody-to-cell-number ratio, whereas the stronger signals remain unaffected. This finding underscores the importance of maintaining consistent antibody-to-cell-number ratio for comparative studies, such as treatment responses or chromatin-QTL mapping. The spa-ChIP-seq protocol is publicly available, including deck setups, operational parameters, and scripts. We envision that this robust, cost-efficient protocol will facilitate high-throughput, reproducible ChIP-seq analyses, supporting large-scale studies of antibody validation, compound screening, population genomics, and diagnostic frameworks.

  PublisherOA PDFDOI

• Improved spike-in normalization clarifies the relationship between active histone modifications and transcription

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-26 · 2 citations

  preprintOpen access

  Spike-in normalization enables quantitative analysis of ChIP-sequencing (ChIP-seq) signal. Here we introduce a novel robust dual-spike-in normalization approach for ChIP-seq (ChIP-wrangler). We identify optimal conditions, such as the ratio between the spike-in species and the target, demonstrate the ability of this approach to detect technical artefacts, and use ChIP-wrangler to revisit recent claims that active histone marks are dependent on transcription. Concerned that previous studies improperly used spike-in normalization to arrive at their conclusions, we used ChIP-wrangler to show that acute depletion of RNA polymerase II (RNAPII) has only a modest impact on the levels of H3K4me3 and H3K27ac. In line with other studies, our results provide proof that the maintenance of histone acetylation is not merely a consequence of ongoing transcription. Further, we show that promoters and enhancers are differentially impacted by inhibiting transcription. Specifically, of the 5.9% peaks that showed a decrease in H3K27ac following depletion of RNAPII, 82% are promoter-distal and contain enhancer-related DNA binding motifs. Further, the small subset of regions that gain acetylation (0.35%) were enriched for stress response motifs. Our innovative ChIP-seq normalization approach provides increased rigor and "guardrails" for successful spike-in normalization, and as applied here refines the understanding of the intricate crosstalk between RNAPII activity and histone marks associated with transcription.

  PublisherDOI

Recent grants

• Decoding regulatory functions of genetic variants associated with substance use disorders

  NIH · $435k · 2022–2024

• Uncovering how transcription and chromatin 3D structure impact one another during cellular activation

  NIH · $1.7M · 2019–2024

• NIH Grant U19AI106754

  NIH · $42.3M · 2018

• Decoding the grammar of transcriptional enhancers regulating different stages of opioid use disorder

  NIH · $3.4M · 2020–2026

Frequent coauthors

• Christopher K. Glass

  University of California, San Diego

  52 shared

• Juan Carlos Izpisúa Belmonte

  Altos Labs

  49 shared

• Amanda Schoonover

  Center for Children

  47 shared

• Sven Heinz

  University of California, San Diego

  47 shared

• Tomoaki Hishida

  Wakayama Medical University

  43 shared

• Max W. Chang

  38 shared

• Ignacio Sancho‐Martinez

  37 shared

• Concepción Rodrı́guez Esteban

  Altos Labs

  35 shared

Education

• Ph.D., Environmental Science

  University of California, San Diego

  2002

• M.S., Environmental Science

  University of California, San Diego

  1998

• B.A., Environmental Studies

  University of California, Santa Barbara

  1995