Kameron Rodrigues

All Publications

• Exercise intensity and training alter the innate immune cell type and chromosomal origins of circulating cell-free DNA in humans. Proceedings of the National Academy of Sciences of the United States of America Rodrigues, K. B., Weng, Z., Graham, Z. A., Lavin, K., McAdam, J., Tuggle, S. C., Peoples, B., Seay, R., Yang, S., Bamman, M. M., Broderick, T. J., Montgomery, S. B. 2025; 122 (3): e2406954122

  Abstract

  Exercising regularly promotes health, but these benefits are complicated by acute inflammation induced by exercise. A potential source of inflammation is cell-free DNA (cfDNA), yet the cellular origins, molecular causes, and immune system interactions of exercise-induced cfDNA are unclear. To study these, 10 healthy individuals were randomized to a 12-wk exercise program of either high-intensity tactical training (HITT) or traditional moderate-intensity training (TRAD). Blood plasma was collected pre- and postexercise at weeks 0 and 12 and after 4 wk of detraining upon program completion. Whole-genome enzymatic methylation sequencing (EM-seq) with cell-type proportion deconvolution was applied to cfDNA obtained from the 50 plasma samples and paired to concentration measurements for 90 circulating cytokines. Acute exercise increased the release of cfDNA from neutrophils, dendritic cells (DCs), and macrophages proportional to exercise intensity. Exercise training reduced cfDNA released in HITT participants but not TRAD and from DCs and macrophages but not neutrophils. For most participants, training lowered mitochondrial cfDNA at rest, even after detraining. Using a sequencing analysis approach we developed, we concluded that rapid ETosis, a process of cell death where cells release DNA extracellular traps, was the likely source of cfDNA, demonstrated by enrichment of nuclear DNA. Further, several cytokines were induced by acute exercise, such as IL-6, IL-10, and IL-16, and training attenuated the induction of only IL-6 and IL-17F. Cytokine levels were not associated with cfDNA induction, suggesting that these cytokines are not the main cause of exercise-induced cfDNA. Overall, exercise intensity and training modulated cfDNA release and cytokine responses, contributing to the anti-inflammatory effects of regular exercise.

  View details for DOI 10.1073/pnas.2406954122

  View details for PubMedID 39805013

• Transcriptomics and chromatin accessibility in multiple African population samples. bioRxiv : the preprint server for biology DeGorter, M. K., Goddard, P. C., Karakoc, E., Kundu, S., Yan, S. M., Nachun, D., Abell, N., Aguirre, M., Carstensen, T., Chen, Z., Durrant, M., Dwaracherla, V. R., Feng, K., Gloudemans, M. J., Hunter, N., Moorthy, M. P., Pomilla, C., Rodrigues, K. B., Smith, C. J., Smith, K. S., Ungar, R. A., Balliu, B., Fellay, J., Flicek, P., McLaren, P. J., Henn, B., McCoy, R. C., Sugden, L., Kundaje, A., Sandhu, M. S., Gurdasani, D., Montgomery, S. B. 2023

  Abstract

  Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

  View details for DOI 10.1101/2023.11.04.564839

  View details for PubMedID 37986808

  View details for PubMedCentralID PMC10659267

• Multi- Omic Profiling of Macrophages Lacking Tet2 or Dnmt3a Reveals Mechanisms of Hyper-Inflammation in Clonal Hematopoiesis Rodrigues, K. B., Gopakumar, J., Weng, Z., Mitchell, S., Maurer, M., Nachun, D., Eulalio, T., Estrada, D., Mazumder, T., Ma, L., Montgomery, S., Jaiswal, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187890

  View details for Web of Science ID 001159306704186

• Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes. Nature cardiovascular research Rauch, P. J., Gopakumar, J., Silver, A. J., Nachun, D., Ahmad, H., McConkey, M., Nakao, T., Bosse, M., Rentz, T., Vivanco Gonzalez, N., Greenwald, N. F., McCaffrey, E. F., Khair, Z., Gopakumar, M., Rodrigues, K. B., Lin, A. E., Sinha, E., Fefer, M., Cohen, D. N., Vromman, A., Shvartz, E., Sukhova, G., Bendall, S., Angelo, M., Libby, P., Ebert, B. L., Jaiswal, S. 2023; 2 (9): 805-818

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.

  View details for DOI 10.1038/s44161-023-00326-7

  View details for PubMedID 39196062

  View details for PubMedCentralID 8050831

• Innate immune stimulation of whole blood reveals IFN-1 hyper-responsiveness in type 1 diabetes. Diabetologia Rodrigues, K. B., Dufort, M. J., Llibre, A., Speake, C., Rahman, M. J., Bondet, V., Quiel, J., Linsley, P. S., Greenbaum, C. J., Duffy, D., Tarbell, K. V. 2020

  Abstract

  AIMS/HYPOTHESIS: Self-antigen-specific T cell responses drive type 1 diabetes pathogenesis, but alterations in innate immune responses are also critical and not as well understood. Innate immunity in human type 1 diabetes has primarily been assessed via gene-expression analysis of unstimulated peripheral blood mononuclear cells, without the immune activation that could amplify disease-associated signals. Increased responsiveness in each of the two main innate immune pathways, driven by either type 1 IFN (IFN-1) or IL-1, have been detected in type 1 diabetes, but the dominant innate pathway is still unclear. This study aimed to determine the key innate pathway in type 1 diabetes and assess the whole blood immune stimulation assay as a tool to investigate this.METHODS: The TruCulture whole blood ex vivo stimulation assay, paired with gene expression and cytokine measurements, was used to characterise changes in the stimulated innate immune response in type 1 diabetes. We applied specific cytokine-induced signatures to our data, pre-defined from the same assays measured in a separate cohort of healthy individuals. In addition, NOD mice were stimulated with CpG and monocyte gene expression was measured.RESULTS: Monocytes from NOD mice showed lower baseline vs diabetes-resistant B6.g7 mice, but higher induced IFN-1-associated gene expression. In human participants, ex vivo whole blood stimulation revealed higher induced IFN-1 responses in type 1 diabetes, as compared with healthy control participants. In contrast, neither the IL-1-induced gene signature nor response to the adaptive immune stimulant Staphylococcal enterotoxin B were significantly altered in type 1 diabetes samples vs healthy control participants. Targeted gene-expression analysis showed that this enhanced IFN response was specific to IFN-1, as IFN-gamma-driven responses were not significantly different.CONCLUSIONS/INTERPRETATION: Our study identifies increased responsiveness to IFN-1 as a feature of both the NOD mouse model of autoimmune diabetes and human established type 1 diabetes. A stimulated IFN-1 gene signature may be a potential biomarker for type 1 diabetes and used to evaluate the effects of therapies targeting this pathway.DATA AVAILABILITY: Mouse gene expression data are found in the gene expression omnibus (GEO) repository, accession GSE146452 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE146452). Nanostring count data from the human experiments were deposited in the GEO repository, accession GSE146338 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE146338). Data files and R code for all analyses are available at https://github.com/rodriguesk/T1D_truculture_diabetologia. Graphical abstract.

  View details for DOI 10.1007/s00125-020-05179-4

  View details for PubMedID 32500289