Biology subjects

Abrahante, J. E.

Publications and source records attributed to Abrahante, J. E..

7 recordsLinked to original sources

bioRxiv2026

Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver

ObjectivesPrior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. MethodsMice with or without hepatocyte cyclin D1 (D1fl/fl or D1{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. ResultsCyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. ConclusionsCyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging. HighlightsO_LICyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression. C_LIO_LIAcute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1. C_LIO_LIHepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation. C_LIO_LICyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition in C. elegans. C_LI

physiology↗

bioRxiv2025

Cholangiocytes' Primary Cilia Regulate DNA Damage Response and Repair

Primary cilia have been considered as tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary cilia affects DNA damage response (DDR) and DNA repair processes in CCA. Human cholangiocyte cell lines were used to examine the colocalization of DNA repair proteins at the cilia and assess the impact of experimental deciliation on DNA repair pathways. Deciliation was induced using shRNA knockdown or CRISPR knockout of IFT20, IFT88, and KIF3A, followed by exposure to genotoxic agents such as cisplatin, methyl methanesulfonate (MMS), and irradiation. Cell survival, cell cycle progression, and apoptosis rates were evaluated, while DNA damage was assessed using comet assays and {gamma}H2AX quantification. An in vivo liver-specific knockout model of IFT88 was generated using the Cre/Lox recombination system. Results showed that RAD51 localized at the cilia base, while ATR, PARP1, CHK1 and CHK2 were found within the cilia. Deciliated cells displayed dysregulation in critical DDR pathways. These cells also showed reduced survival and increased S-phase arrest after genotoxic challenges. Enhanced DNA damage was observed via increased {gamma}H2AX signals and comet assay results. An increase in {gamma}H2AX expression was observed in our in vivo model, indicating elevated DNA damage. Additionally, key DDR proteins, such as ATM, p53, and p21, were downregulated in deciliated cells after irradiation. This study underscores the crucial role of primary cilia in regulating DNA repair, suggesting that targeting cilia-related mechanisms could present a novel therapeutic approach for CCA. Key PointsThe results presented delineate the following critical observations: O_LIDNA Damage Response (DDR) and DNA repair proteins localized to primary cilia structures C_LIO_LIDeciliated cells exhibited dysregulated DDR pathways, reduced survival, and S-phase arrest under genotoxic stress C_LIO_LIElevated DNA damage was evident in deciliated cells, with increased {gamma}H2AX signals and comet assay results C_LIO_LIIn vivo IFT88 knockout mice also showed increased {gamma}H2AX expression, indicating heightened DNA damage C_LIO_LIKey DDR proteins (ATM, p53, p21) were downregulated in deciliated cells after irradiation. C_LI

pathology↗

bioRxiv2023

The oral pathogen Porphyromonas gingivalis resists the antimicrobial peptide LGL13K and evades the D-enantiomer by synonymous mutations in hagA

Porphyromonas gingivalis is a keystone pathogen for periodontal disease. The bacteria are black-pigmented and require heme for growth. P. gingivalis exhibit resistance to many antimicrobial peptides, including the L-enantiomer of the antimicrobial peptide GL13K, which contributes to their success in the oral cavity. P. gingivalis W50 was resistant to LGL13K but susceptible to the stereo-isomer DGL13K. Upon prolonged exposure to DGL13K, a novel non-pigmented mutant was isolated that showed a low minimum inhibitory concentration and two-fold extended minimum duration for killing by DGL13K, consistent with tolerance to this peptide. The DGL13K tolerant bacteria exhibited synonymous mutations in the hagA gene. The mutations did not prevent mRNA expression but were predicted to alter mRNA structure. The non-pigmented bacteria were deficient in hemagglutination and hemoglobin binding, suggesting that the HagA protein was not expressed. This was supported by whole cell ELISA and gingipain activity assays, which suggested the absence of HagA but not two closely related gingipains. In vivo virulence was similar for wild-type and non-pigmented bacteria in the Galleria mellonella model. Loss of the hemagglutinin HagA may allow bacteria to escape from a biofilm that is under attack by antimicrobial peptides.

microbiology↗

bioRxiv2022

The HH-GLI2-CKS1B network regulates the proliferation-to-maturation transition of human cardiomyocytes

Cardiomyocyte (CM) proliferation and maturation are highly linked processes, however, the extent to which these processes are controlled by a single signaling axis is unclear. Here, we find the Hedgehog (HH)-GLI2-CKS1B cascade regulates the transition between proliferation and maturation in hiPSC-CMs. Initially, we found a significant enrichment of GLI2-signaling in CMs from patients with ischemic heart failure (HF) or dilated-cardiomyopathy (DCM), indicating initiation of fetal programs in the stressed heart. Developmentally, we showed downregulation of GLI-signaling in adult human CM, adult murine CM, and in late-stage hiPSC-CM. In early-stage, proliferative hiPSC-CM, inhibition of Hh- or GLI-proteins enhanced CM maturation. Mechanistically, we identified CKS1B, a new effector of GLI2 and showed that GLI2 binds the CKS1B promoter to regulate its expression. CKS1B overexpression in late-stage hiPSC-CMs led to increased proliferation with loss of maturation. Thus, the Hh-GLI2-CKS1B axis regulates the proliferation-maturation transition and provides targets to enhance cardiac tissue engineering and regenerative therapies.

developmental biology↗

bioRxiv2021

Self-organized emergence of hyaline cartilage in hiPSC-derived multi-tissue organoids

Despite holding great therapeutic potential, existing protocols for in vitro chondrogenesis and hyaline cartilage production from human induced pluripotent stem cells (hiPSC) are laborious and complex with unclear long-term consequences. Here, we developed a simple xeno- and feeder-free protocol for human hyaline cartilage production in vitro using hydrogel-cultured multi-tissue organoids (MTOs). We investigate gene regulatory networks during spontaneous hiPSC-MTO differentiation using RNA sequencing and bioinformatic analyses. We find the interplays between BMPs and neural FGF pathways are associated with the phenotype transition of MTOs. We recognize TGF-beta/BMP and Wnt signaling likely contribute to the long-term maintenance of MTO cartilage growth and further adoption of articular cartilage development. By comparing the MTO transcriptome with human lower limb chondrocytes, we observe that the expression of chondrocyte-specific genes in MTO shows a strong correlation with fetal lower limb chondrocytes. Collectively, our findings describe the self-organized emergence of hyaline cartilage in MTO, its associated molecular pathways, and its spontaneous adoption of articular cartilage development trajectory.

cell biology↗

bioRxiv2019

The Genome of the Zebra Mussel, Dreissena polymorpha: A Resource for Invasive Species Research

The zebra mussel, Dreissena polymorpha, continues to spread from its native range in Eurasia to Europe and North America, causing billions of dollars in damage and dramatically altering invaded aquatic ecosystems. Despite these impacts, there are few genomic resources for Dreissena or related bivalves, with nearly 450 million years of divergence between zebra mussels and its closest sequenced relative. Although the D. polymorpha genome is highly repetitive, we have used a combination of long-read sequencing and Hi-C-based scaffolding to generate the highest quality molluscan assembly to date. Through comparative analysis and transcriptomics experiments we have gained insights into processes that likely control the invasive success of zebra mussels, including shell formation, synthesis of byssal threads, and thermal tolerance. We identified multiple intact Steamer-Like Elements, a retrotransposon that has been linked to transmissible cancer in marine clams. We also found that D. polymorpha have an unusual 67 kb mitochondrial genome containing numerous tandem repeats, making it the largest observed in Eumetazoa. Together these findings create a rich resource for invasive species research and control efforts.

genomics↗

bioRxiv2018

A Cell Proliferation and Inflammatory Signature is Induced by Lawsonia intracellularis Infection in Swine

Lawsonia intracellularis causes porcine proliferative enteropathy. This is an enteric disease characterized by thickening of the wall of the ileum that leads to decreased growth and diarrhea of animals. In this study, we investigated the host response to L. intracellularis infection by performing transcriptomic and pathway analysis of intestinal tissue in groups of infected and non-infected animals at 14, 21 and 28 days post challenge. At the peak of infection, when animals developed most severe lesions, infected animals expressed higher levels of several genes involved in cellular proliferation and inflammation including matrix metalloproteinase-7 (MMP7), transglutaminase-2 (TGM2) and Oncostatin M (OSM). Histomorphology also revealed general features of intestinal inflammation. This study identified important pathways associated with the host response in developing and resolving lesions due to L. intracellularis infection.\n\nImportanceLawsonia intracellularis is among the most important enteric pathogens of swine and it can also infect other mammalian species. Much is still unknown regarding its pathogenesis and the host response, especially at the site of infection. In this study we uncovered several novel genes and pathways associated with infection. These differentially expressed genes, in addition to histological changes in infected tissue, revealed striking similarities between L. intracellularis infection and cellular proliferation mechanisms described in some cancers and inflammatory diseases of the gastrointestinal tract. This research sheds important light into the pathogenesis of L. intracellularis and the host response associated with the lesions caused by infection.

microbiology↗