About

Michael Kladde earned his Ph.D. in Cellular and Molecular Biology from the University of Wisconsin-Madison in 1991, working under Dr. Jack Gorski on estrogenic regulation of gene expression. He conducted postdoctoral research on chromatin structure and function in the laboratories of Dr. Robert T. Simpson at the National Institutes of Health and The Pennsylvania State University. In 1998, he joined Texas A&M University, where he was promoted to Associate Professor and continued his studies on epigenetic regulation of gene expression. In 2007, he joined the Department of Biochemistry and Molecular Biology at the University of Florida, where he is a Professor and Director of the Center for Epigenetics. His research focuses on understanding the dynamic interplay in transcription regulation through various layers of epigenetic mechanisms, including nucleosome positioning, histone modifications, and DNA methylation. Dr. Kladde's lab develops innovative epigenetic methods and bioinformatics tools, such as MAPit and MAPit-patch, for mapping DNA methylation and chromatin accessibility at single-molecule resolution. His work involves studying epigenetic alterations in cancers such as colorectal, breast, and brain cancer, aiming to identify molecular steps involved in epigenetic silencing, potential therapeutic targets, and mechanisms of drug resistance. Additionally, his research explores the epigenetic regulation of the infective life cycle of Kaposi’s sarcoma herpesvirus (KSHV), investigating heterogeneity in chromatin accessibility and DNA methylation patterns among viral and cellular genomes, and how these features are established and propagated during infection and latency.

Research topics

• Genetics
• Immunology
• Medicine
• Biology
• Internal medicine
• Endocrinology

Selected publications

• Divergent chromatin remodeling trajectories in CD66b ⁺ MDSCs distinguishes recovery from chronic critical illness after sepsis

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-23

  articleOpen accessSenior authorCorresponding

  ABSTRACT Sepsis remains a leading cause of morbidity and mortality worldwide, with survivors often following divergent trajectories: rapid recovery (RAP) or progression to chronic critical illness (CCI). CCI is characterized by persistent organ dysfunction, recurrent infections, and immune dysregulation. Myeloid-derived suppressor cells (MDSCs), which expand in number after sepsis, are implicated in this maladaptive state, yet their epigenetic regulation remains poorly understood. Here, we applied an Omni-ATAC protocol optimized to profile chromatin accessibility in CD66b + MDSCs from healthy participants (HPs) and sepsis patients across time points (day 4, day 14–21, and 6 months) and clinical outcomes (RAP, CCI, and Deceased). Dimensionality reduction analyses of genome-wide chromatin accessibility showed clear separation of sepsis and HP samples. Furthermore, these analyses revealed distinct trajectories post-sepsis diagnosis: RAP samples progressively regained HP-like chromatin states, whereas CCI samples remained epigenetically “locked” in aberrant states. Differential accessibility analysis identified thousands of promoter regions with altered accessibility, including immune checkpoint and inflammatory genes (e.g., ARG1, CD274, S100A8 / 9 ). Pathway analyses predicted global suppression of immune, metabolic, and chromatin remodeling programs in CCI, contrasting with restoration in RAP. These findings from patient-derived CD66b + MDSCs suggest that epigenetic chromatin remodeling underlies divergent recovery trajectories and highlight chromatin-modifying pathways as potential therapeutic targets to restore immune competence in sepsis patients with CCI.

  PublisherOA PDFDOI

• C-754-01. Burn Injury Drives Biphasic Macrophage Immune Reprogramming Through Locus-Specific Epigenetic Remodeling

  Journal of Burn Care & Research · 2026-03-01

  articleOpen accessSenior author

  Abstract Introduction Severe burn injury is followed by immune dysfunction marked by early hyperinflammation and later immunosuppression. The underlying epigenetic mechanisms remain incompletely understood. We hypothesized that burn injury induces coordinated chromatin remodeling in macrophages that governs this biphasic immune phenotype. Methods Female C57BL/6 mice (n = 6) underwent 20% TBSA full-thickness scald injury or sham procedure. Splenic F4/80+ macrophages were isolated on days 2, 9, and 14 post-injury. Cytokine secretion was measured following TLR2 (peptidoglycan) or TLR4 (LPS) stimulation. Targeted transcriptomic profiling of >1300 immune/metabolic genes was performed by nanoString. Epigenetic remodeling of 180 immune loci was assessed using single-molecule Methyltransferase accessibility protocol for individual templates combined with flap-enabled next-generation capture (MAPit-FENGC) to simultaneously measure DNA methylation and chromatin accessibility. Results Macrophages from burn mice demonstrated a biphasic trajectory. At day 2, TLR-stimulated IL-6, MCP-1, and TNFα secretion were increased versus sham (p<.05). By day 14, MCP-1 and TNFα responses were suppressed, while IL-10 secretion increased (p<.05). Transcriptomic profiling confirmed dynamic regulation of Il10, Socs3, and cell-cycle genes, with persistent repression of Nfkb1, Traf6, and Stat3. MAPit-FENGC revealed early chromatin accessibility gains at proinflammatory loci (Cxcl15, Ccl7) and progressive repression of Stat3, Tgfb1, and Nfkb1 promoters. Nucleosome repositioning at the Il10 promoter preceded transcriptional upregulation, suggesting epigenetic priming for tolerance. Conclusions Burn injury induces temporally coordinated transcriptomic and epigenetic remodeling in macrophages, shifting from hyperinflammation to immune tolerance. Locus-specific chromatin remodeling underlies this transition, highlighting mechanistic drivers of post-burn immune paralysis. Applicability of Research to Practice These findings identify macrophage epigenetic reprogramming as a targetable mechanism of burn-induced immune dysfunction. Therapeutic interventions that recalibrate macrophage chromatin states may restore balanced immunity and reduce infection risk in burn survivors. Funding for the study Supported by NIH NIGMS.

  PublisherOA PDFDOI

• Age- and Sex- Driven Transcriptional and Metabolic Diversity in Myeloid-Derived Suppressor Cells After Mouse Sepsis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-07

  preprintOpen access

  Sepsis induces profound immune dysregulation, often resulting in chronic critical illness characterized by persistent immunosuppression and poor outcomes. Myeloid-derived suppressor cells (MDSCs) are central mediators of this immunosuppressive phenotype, yet the influence of age and sex on their transcriptional and metabolic states remain poorly understood. Here, we employed single-cell RNA sequencing of splenic leukocytes from young (3-4 months) and older (18-24 months) adult male and female mice subjected to a clinically relevant murine sepsis model to define age- and sex-specific MDSC phenotypes. We identified significant differences regarding age and sex in MDSC expansion, transcriptome, canonical pathway activation, RNA velocity, mitochondrial metabolism, and predicted cell-cell communication after sepsis. Using drug2cell analysis of total leukocytes we also identified cohort-specific drug target profiles. These findings underscore the importance of age and sex in shaping sepsis-induced MDSC biology and suggest that personalized immunomodulatory strategies targeting MDSCs could improve sepsis outcomes.

  PublisherOA PDFDOI

• Chromatin Remodeling and Transcriptional Silencing Define the Dynamic Innate Immune Response of Tissue Resident Macrophages After Burn Injury

  Shock · 2025-10-22 · 1 citations

  article

  Severe burn injury induces prolonged immune dysfunction, but the underlying molecular mechanisms remain poorly defined. We hypothesized that burn injury causes epigenetic and transcriptional training of innate immune cells. Splenic F4/80⁺ macrophages were isolated from mice at 2, 9, and 14 days after 20% total body surface area contact burn. Targeted transcriptomics and chromatin profiling revealed a biphasic response: early transcriptional silencing of inflammatory genes (e.g., Stat3 , Traf6 , and Nfkb1 ), followed by increased accessibility and expression of anti-inflammatory loci ( Il-10 and Socs3 ). Metabolic genes showed persistent suppression of mitochondrial and oxidative phosphorylation programs. Canonical pathway analysis indicated early interleukin-10 signaling activation and long-term repression of classical macrophage activation. Chromatin remodeling included nucleosome repositioning events, supporting dynamic, and locus-specific regulation. These findings challenge the notion that burn-induced immune suppression is solely due to systemic inflammation and instead suggest durable, epigenetically programmed alterations in macrophage function.

  PublisherDOI

• Tributyltin chloride alters the structural, genomic, and epigenomic integrity of postejaculatory mammalian sperm

  Epigenetics · 2025-09-15 · 2 citations

  articleOpen access

  ≤ 0.05). Sperm DNA integrity was also negatively affected after 24 h. Whole-genome methyl-seq revealed ~750 differentially methylated regions (DMRs) associated with exposure to TBT. Ingenuity Pathway Analyses and Gene Ontology identified embryo development, cell signaling, and transcriptional regulation as the most relevant bio-functions of TBT altered DMRs. In conclusion, postejaculatory mammalian sperm exposure to TBT negatively affected parameters important for sperm function while altering DNA integrity and the methylation profile of gene promoter regions. Consequences of sperm exposure to TBT included cellular and molecular mechanisms that are important for sperm function but remain undetected by routine clinical analyses. These findings provide new insight into environmental impacts on postejaculatory sperm structure and function.

  PublisherDOI

• Chromatin Remodeling and Transcriptional Silencing Define the Dynamic Innate Immune Response of Tissue Resident Macrophages After Burn Injury

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-20

  preprintOpen access

  Summary Severe burn injury induces long-lasting immune dysfunction, but the molecular mechanisms underlying this phenomenon remain unclear. We hypothesized that burn injury leads to epigenetic and transcriptional reprogramming of innate immune cells. Splenic F4/80⁺ macrophages were isolated from mice at days 2, 9, and 14 days post-20% contact burn injury. Targeted transcriptomics and MAPit single-molecule chromatin profiling were used to assess immune, metabolic, and epigenetic changes. Canonical pathway analysis was performed to infer functional shifts over time. Burn injury induced a biphasic response in macrophages. Early after injury (Day 2), there was broad transcriptional suppression and epigenetic silencing of inflammatory regulators, including Stat3 , Traf6 , and Nfkb1 . Over time (Days 9 and 14), loci associated with anti-inflammatory mediators such as Il-10 and Socs3 exhibited progressive chromatin opening and transcriptional upregulation. Metabolic gene profiles revealed persistent suppression of mitochondrial and oxidative phosphorylation programs. Canonical pathway analysis demonstrated early IL-10 signaling activation with sustained suppression of classical macrophage activation pathways. Chromatin architecture changes included nucleosome sliding and ejection events, consistent with dynamic, locus-specific regulation. This work challenges the classical notion of burn-induced immune suppression as purely a consequence of systemic inflammation. Instead, we reveal a programmed and locus-specific epigenetic architecture that may shape macrophage immune and metabolic function long after the acute phase.

  PublisherOA PDFDOI

• Abstract 226: Methylation specific silencing of miR-9 is associated with an epithelial-mesenchymal transition (EMT) phenotype in laryngeal squamous cell carcinoma

  Cancer Research · 2025-04-21

  article

  Abstract Background: Advanced stage laryngeal squamous cell carcinoma (LSCC) carries one of the highest mortality rates of all head and neck cancers. We previously demonstrated that low miR-9 expression impacts invasiveness and resistance to cisplatin in advanced stage LSCC. Here, we seek to further elucidate how low miR-9 influences LSCC pathogenesis. Methods: Gene expression and clinicopathologic data were obtained for 116 LSCC patients from The Cancer Genome Atlas (TCGA) and used to evaluate predictors of LSCC overall survival. A simple logistic regression combined with a Receiver Operating Characteristic (ROC) curve was used to determine a cutoff for categorizing LSCC patients into low and high miR-9 expression groups. A panel of epithelial-mesenchymal transition (EMT) related genes (MAP1B, DOCK10, FGFR1, FGF1, ZEB1, VCAN, WNT5A, SRGN, THEM30B, CDH1 and EGFR) and methylated miR-9 transcripts were assessed between low and high miR-9 expressing LSCC patients via Principal Component Analysis. In vitro validation of an EMT phenotype and miR-9 promoter hypermethylation was performed using four advanced stage LSCC cell lines with variable miR-9 expression. Cell line EMT gene expression was evaluated via RNA sequencing and validated by qPCR. Methylation and chromatin accessibility of the three miR-9 promoter regions were quantified in each LSCC cell line through PacBio sequencing. Low miR-9 expressing cell lines were treated with the global demethylating agent, 5-Azacytidine (0μM, 0.1μM, 0.5μM and 1μM), and differences in EMT-related gene expression were assessed via qPCR. Results: Low miR-9 and methylation of miR-9 were found to be significant predictors of poor LSCC survival (p < 0.05). Gene signatures representing a high EMT phenotype and high methylated miR-9 status were identified as unique classifiers of low compared with high miR-9 expressing LSCC patients. Differential expression of EMT related genes was detected in low compared with high miR-9 expressing cell lines; low miR-9 cell lines had significantly higher baseline expression of MAP1B, DOCK10, FGFR1, FGF1, and ZEB1 (>2-fold, p < 0.0001) and significantly lower baseline expression of CDH1 and EGFR (>2-fold, p < 0.0001). Low miR-9 expressing cell lines also had significantly greater methylation of miR-9 promoter regions (p < 0.0001) as well as significantly fewer chromatin accessibility sites open for miR-9 transcription (p < 0.0001). Global demethylation treatment of the low miR-9 expressing cell lines dose dependently restored miR-9 expression (>2-fold, p < 0.0001) and resulted in inverse expression of MAP1B, DOCK10, FGFR1, FGF1, ZEB1, CDH1 and EGFR at the 1μM dose (>2-fold, p < 0.0001). Conclusion: Our findings indicate that methylation specific silencing of miR-9 may be a mechanism that yields a high EMT phenotype, predictive of poor overall survival in LSCC. Citation Format: Christina Gobin, Matthew Chang, Marie Gauthier, Chayil C. Lattimore, Michael Kladde, Kristianna Fredenburg. Methylation specific silencing of miR-9 is associated with an epithelial-mesenchymal transition (EMT) phenotype in laryngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 226.

  PublisherDOI

• Sepsis Induces Age- and Sex-Specific Chromatin Remodeling in Myeloid-Derived Suppressor Cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-30

  preprintOpen accessSenior author

  Sepsis survivors frequently develop long-term immune dysfunction, but the epigenetic mechanisms underlying persistent myeloid suppression remain unclear. Myeloid-derived suppressor cells (MDSCs), whose function is shaped by host age and sex, are key contributors to post-sepsis immune dysregulation. Here, we present a high-resolution epigenetic map targeting gene promoters of MDSCs after sepsis using MAPit-FENGC, a single-molecule assay that simultaneously profiles DNA methylation and chromatin accessibility. In a clinically relevant murine model including young and older adult male and female mice, splenic MDSCs were isolated for MAPit-FENGC and single-cell RNA sequencing. Unsupervised clustering identified nine promoter classes reflecting chromatin dynamics: age- and sex-dependent sepsis-induced opening (Classes 1-4), persistent closure with varying levels of DNA methylation (Classes 5-7), and constitutive openness post-sepsis (Classes 8, 9). Transcriptomic profiling corroborated these promoter states, linking accessibility with gene expression. These findings establish how epigenetic reprogramming of MDSCs may shape age- and sex-specific immune trajectories in sepsis survivors.

  PublisherOA PDFDOI

• Unique lymphocyte transcriptomic profiles in septic patients with chronic critical illness

  Frontiers in Immunology · 2024-12-03 · 4 citations

  articleOpen access

  Introduction Despite continued improvement in post-sepsis survival, long term morbidity and mortality remain high. Chronic critical illness (CCI), defined as persistent inflammation and organ injury requiring prolonged intensive care, is a harbinger of poor long-term outcomes in sepsis survivors. Current dogma states that sepsis survivors are immunosuppressed, particularly in CCI. Investigation of this immune suppression in heterogeneous immune populations across distinct clinical trajectories and outcomes, along with limited sampling access, is accessible via single-cell RNA sequencing (scRNA-seq). Methods scRNA-seq analysis was performed on healthy subjects (n=12), acutely septic patients at day 4 ± 1 (n=4), and those defined as rapid recovery (n=4) or CCI (n=5) at day 14-21. Differential gene expression and pathway analyses were performed on peripheral blood lymphocytes at both a population and annotated cell subset level. Cellular function was assessed via enzyme-linked immunosorbent spot (ELISpot), cytokine production analysis, and T-cell proliferation assays on an additional cohort of septic patients (19 healthy, 68 acutely septic, 27 rapid recovery and 20 classified as CCI 14-21 days after sepsis onset). Results Sepsis survivors that developed CCI exhibited proportional shifts within lymphoid cell populations, with expanded frequency of CD8 + and NK cells. Differential expression and pathway analyses revealed continued activation in T cells and NK cells, with generalized suppression of B-cell function. Both T and NK cell subsets displayed transcriptomic profiles of exhaustion and immunosuppression in CCI, particularly in CD8 + T effector memory (TEM) cells and NK cells. Functional validation of T-cell behavior in an independent cohort demonstrated T cells maintained proliferative responses in vitro yet exhibited a marked loss of cytokine production. IFN-γ production at the acute phase (day 4 ± 1) was significantly reduced in subjects later classified as CCI. Discussion Sepsis patients exhibit unique T-, B-, and NK-cell transcriptional patterns that are both time- and clinical trajectory-dependent. These transcriptomic and pathway differences in sepsis patients that develop CCI are associated with exhaustion in CD8 + TEM cells and NK cells. Understanding the specific immune system patterns of different cell subsets after sepsis at a molecular level will be key to the development of personalized immunotherapy and drug-targeting intervention. Clinical trial registration https://clinicaltrials.gov/ , identifier NCT02276417.

  PublisherOA PDFDOI

• TRANSCRIPTOMIC DIFFERENCES IN PERIPHERAL MONOCYTE POPULATIONS IN SEPTIC PATIENTS BASED ON OUTCOME

  Shock · 2024-05-02 · 6 citations

  articleOpen access

  ABSTRACT: Postsepsis early mortality is being replaced by survivors who experience either a rapid recovery and favorable hospital discharge or the development of chronic critical illness with suboptimal outcomes. The underlying immunological response that determines these clinical trajectories remains poorly defined at the transcriptomic level. As classical and nonclassical monocytes are key leukocytes in both the innate and adaptive immune systems, we sought to delineate the transcriptomic response of these cell types. Using single-cell RNA sequencing and pathway analyses, we identified gene expression patterns between these two groups that are consistent with differences in TNF-α production based on clinical outcome. This may provide therapeutic targets for those at risk for chronic critical illness in order to improve their phenotype/endotype, morbidity, and long-term mortality.

  PublisherOA PDFDOI

Recent grants

• Interplay of Epigenetic Mechanisms in Gene Silencing

  NIH · $1.5M · 2011–2017

• NIH Grant R01CA095525

  NIH · $1.3M · 2010

Frequent coauthors

• Carolina Pardo‐Díaz

  Universidad del Rosario

  89 shared

• Nancy H. Nabilsi

  TScan Therapeutics (United States)

  76 shared

• Santhi Pondugula

  57 shared

• Russell P. Darst

  Cellecta (United States)

  38 shared

• Philip A. Efron

  University of Florida

  32 shared

• Dijoia B. Darden

  Florida College

  31 shared

• Alicia M. Mohr

  University of Florida

  31 shared

• Jaimar C. Rincon

  University of Florida

  31 shared

Education

• Postdoctoral with Robert T. Simpson, MD, PhD, Biochemistry & Molecular Biology

  Pennsylvania State University

  1998

• Postdoctoral with Robert T. Simpson, MD, PhD, Laboratory of Cell & Developmental Biology

  National Institutes of Health

  1993

• PhD, Cellular and Molecular Biology

  University of Wisconsin–Madison

  1991

• BA

  University of California, San Diego

  1984