Biology subjects

Mohr, A. M.

Publications and source records attributed to Mohr, A. M..

3 recordsLinked to original sources

bioRxiv2026

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

Sepsis survivors exhibit divergent clinical trajectories, including rapid recovery (RAP) or progression to chronic critical illness (CCI), yet how these outcomes are linked to epigenetic repression remains poorly defined. Here, we applied an optimized Omni-ATAC approach to profile chromatin accessibility in CD66b myeloid-derived suppressor cells (MDSCs) from healthy participants and longitudinally sampled sepsis cohorts stratified by outcome. RAP samples progressively restored healthy chromatin states, whereas CCI samples remained epigenetically fixed in aberrant configurations. Chromatin remodeling exhibited strong pathway specificity: promoters associated with MHC class II antigen presentation were coordinately repressed in CCI, while MHC class I antigen processing and presentation machinery remained preserved. Genome-wide analyses revealed extensive promoter remodeling during recovery in RAP, including immune regulatory loci such as ARG1, CD274, and S100A8/A9, contrasted with broad suppression of immune, metabolic, and chromatin regulatory programs in CCI. These findings define divergent epigenetic trajectories in post-sepsis MDSCs and implicate selective failure of antigen presentation as a mechanism of sepsis-induced immunoparalysis in CCI.

immunology↗

bioRxiv2023

Cholangiocyte primary cilia transduce a fluid shear signal to increase KLF2 via the actin cytoskeleton

Cholangiocarcinoma is an aggressive solid tumor formed in the bile duct epithelium. Often this tumor obstructs bile flow, known as cholestasis. Normal cholangiocytes detect bile flow in the ductal lumen with an extension of the apical membrane called the primary cilium. However, these sensory organelles are often lost in malignant cells. Kruppel-like factor 2 (KLF2) is an important flow-sensitive transcription factor involved in shear stress response in endothelial cells, and has anti-proliferative, anti-inflammatory, and anti-angiogenic effects. The potential role of KLF2 in cholangiocyte flow detection and in cholangiocarcinoma is unknown. We hypothesized that reduced bile flow contributes to malignant features in cholangiocarcinoma through regulation of KLF2 signaling. We observed that primary cilia were expressed in normal cholangiocytes but were absent in malignant cells. KLF2 expression was higher in normal cells compared to malignant. Depletion of cilia in normal cells led to a decrease in KLF2 expression and increased cilia number was associated with increased KLF2. Enforced KLF2 expression inhibited cell proliferation, migration, and also decreased cell death induction in malignant cells. Applied media flow over cholangiocytes increased KLF2 and cilia depletion completely blocked flow-induced KLF2 expression. Disruption of filamentous actin decreased KLF2 expression, suggesting the cilium may communicate through a cytoskeletal mechanotransduction pathway. Our studies demonstrate that cilia positively regulated KLF2 protein levels and increased fluid flow induced KLF2 expression for the first time in cholangiocytes, emphasizing the importance of reestablishing bile flow in cholestatic cholangiocarcinoma.

cancer biology↗

bioRxiv2016

miR-106b-responsive gene landscape identifies regulation of Kruppel-like factor family

MicroRNA dysregulation is a common feature of cancer and due to the promiscuity of microRNA binding this can result in a wide array of genes whose expression is altered. miR-106b is an oncomiR overexpressed in cholangiocarcinoma and its upregulation in this and other cancers often leads to repression of anti-tumorigenic targets. The goal of this study was to identify the miR-106b-regulated gene landscape in cholangiocarcinoma cells using a genome-wide, unbiased mRNA analysis. Through RNA-Seq we found 112 mRNAs significantly repressed by miR-106b. The majority of these genes contain the specific miR-106b seed-binding site. We have validated 11 genes from this set at the mRNA level and demonstrated regulation by miR-106b of five proteins. Combined analysis of our miR-106b-regulated mRNA data set plus published reports indicate that miR-106b binding is anchored by G:C pairing in and near the seed. Novel targets Kruppel-like factor 2 (KLF2) and KLF6 were verified both at the mRNA and at the protein level. Further investigation showed regulation of four other KLF family members by miR-106b. We have discovered coordinated repression of several members of the KLF family by miR-106b that may play a role in cholangiocarcinoma tumor biology.

molecular biology↗