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PubMed2006

Acquisition and extinction of gene expression programs are separable events in heterokaryon reprogramming.

Although differentiated cells normally retain cell-type-specific gene expression patterns throughout their lifetime, cell identity can sometimes be modified or reversed in vivo by transdifferentiation, or experimentally through cell fusion or by nuclear transfer. To examine the epigenetic changes that are required for the dominant conversion of lymphocytes to muscle, we generated heterokaryons between human B lymphocytes and mouse C2C12 myotubes. We show that within 2 days of heterokaryon formation lymphocyte nuclei adopt an architecture resembling that of muscle and then initiate the expression of muscle-specific genes in the same temporal order as developing muscle. The establishment of this muscle-specific program is coordinated with the shutdown of several lymphocyte-associated genes. Interestingly, erasing lymphocyte identity in reprogrammed cells requires histone deacetylase (HDAC) activity. Inhibition of HDAC activity during reprogramming selectively blocks the silencing of lymphocyte-specific genes but does not prevent the establishment of muscle-specific gene expression. Successful reprogramming is therefore shown to be a multi-step process in which the acquisition and extinction of lineage-specific gene programs are separable events.

Animals↗
PubMed2004

HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells.

A T-cell subset, defined as CD4(+)CD25(hi) (regulatory T-cells [Treg cells]), was recently shown to suppress T-cell activation. We demonstrate that human Treg cells isolated from healthy donors express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication. Because Treg cells are present in very few numbers and are difficult to expand in vitro, we genetically modified conventional human T-cells to generate Treg cells in vitro by ectopic expression of FoxP3, a transcription factor associated with reprogramming T-cells into a Treg subset. Overexpression of FoxP3 in naïve human CD4(+) T-cells recapitulated the hyporesponsiveness and suppressive function of naturally occurring Treg cells. However, FoxP3 was less efficient in reprogramming memory T-cell subset into regulatory cells. In addition, FoxP3-transduced T-cells also became more susceptible to HIV infection. Remarkably, a portion of HIV-positive individuals with a low percentage of CD4(+) and higher levels of activated T-cells have greatly reduced levels of FoxP3(+)CD4(+)CD25(hi) T-cells, suggesting disruption of the Treg cells during HIV infection. Targeting and disruption of the T-cell regulatory system by HIV may contribute to hyperactivation of conventional T-cells, a characteristic of HIV disease progression. Moreover, the ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.

CD4-Positive T-Lymphocytes↗
PubMed2006

Human natural killer T cells are heterogeneous in their capacity to reprogram their effector functions.

BACKGROUND: Natural killer T (NKT) cells are a subset of T cells that help potentiate and regulate immune responses. Although human NKT cell subsets with distinct effector functions have been identified, it is unclear whether the effector functions of these subsets are imprinted during development or can be selectively reprogrammed in the periphery. RESULTS: We found that neonatal NKT cells are predominantly CD4+ and express higher levels of CCR7 and CD62L and lower levels of CD94 and CD161 than adult CD4+ or CD4- NKT cell subsets. Accordingly, neonatal NKT cells were more flexible than adult CD4+ NKT cells in their capacity to acquire Th1- or Th2-like functions upon either cytokine-mediated polarization or ectopic expression of the Th1 or Th2 transcription factors T-bet and GATA-3, respectively. Consistent with their more differentiated phenotype, CD4- NKT cells were predominantly resistant to functional reprogramming and displayed higher cytotoxic function. In contrast to conventional T cells, neither the expression of CXCR3 nor the cytotoxic capacity of neonatal NKT cells could be reprogrammed. CONCLUSIONS AND SIGNIFICANCE: Together, these results suggest that neonatal CD4+, adult CD4+, and adult CD4- NKT may represent unique states of maturation and that some functions of human NKT cells may be developmentally imprinted, while others are acquired similar to conventional T cell subsets during peripheral maturation and differentiation. Given the potent immuno-regulatory functions of NKT cells, these findings have important implications for the development of novel NKT cell-based therapeutics and vaccines.

Adult↗
PubMed2006

Epigenetic reprogramming of somatic genomes by electrofusion with embryonic stem cells.

Cell fusion is an approach for combining genetic and epigenetic information between two different types of cells. Electrofusion for generating hybrid cells between mouse embryonic stem cells and somatic cells, which is a type of nonchemically induced and nonvirus-mediated cell fusion, is introduced here as a highly effective, reproducible, and biomedically safe in vitro system. Under optimized electrofusion conditions, cells are ligned and form pearl chains between electrodes in response to AC pulse stimulation, and subsequently adjacent cytoplasmic membranes are fused by DC pulse stimulation. Hybrid cells survive as drug-resistant colonies in selection medium. Cell fusion is a technique that is applied widely in the life sciences. A recent topic of great interest in the field of stem cell research is the successful production of cloned animals via epigenetic reprogramming of somatic nuclei. Interestingly, nuclear reprogramming for conferring pluripotency on somatic nuclei also occurs via cell fusion between pluripotential stem cells and somatic cells. Furthermore, it has been shown that spontaneous cell fusion contributes to generating the intrinsic plasticity of tissue stem cells. Cell fusion technology may make important contributions to the fields of regenerative medicine and epigenetic reprogramming.

Animals↗
PubMed2006

Nuclear reprogramming: an overview.

Nuclear reprogramming is an intriguing phenomenon, in which specialized somatic cells reacquire pluripotency through the global resetting of epigenetic modifications without changes occurring to their nuclear DNA information. The nuclear reprogramming activity retained by unfertilized eggs and embryonic stem cells is readily observable through the techniques of nuclear transplantation and cell fusion, respectively. Furthermore, researches involving somatic stem cells have provided evidence that spontaneous cell fusion functions, at least in part, in maintaining the homeostasis of various tissues through the generation of replacement cells in vivo. Novel approaches by application of the nuclear reprogramming activity may open new avenues producing genetically matched personalized pluripotential stem cells derived from patient somatic cells.

Animals↗
PubMed2005

Human embryonic stem cells reprogram myeloid precursors following cell-cell fusion.

Here, we examine the ability of undifferentiated human embryonic stem cells (hESCs) to reprogram the nuclei of hESC-derived myeloid precursors following cell-cell fusion. Using an OP9 coculture system, we produced CD45+ CD33+ myeloperoxidase+ myeloid precursors from an Oct4-enhanced green fluorescent protein (EGFP) knock-in hESC line and demonstrated that Oct4-EGFP expression was extinguished in these precursors. Upon fusion with undifferentiated hESCs, EGFP expression from the endogenous Oct4 promoter/regulatory region was re-established, ESC-specific surface antigens and marker genes were expressed, and myeloid precursor-specific antigens were no longer detectable. When the hybrid cells were formed into embryoid bodies, upregulation of genes characteristic of the three germ layers and extraembryonic tissues occurred, indicating that the hybrid cells had the potential to differentiate into multiple lineages. Interestingly, the hybrid cells were capable of redifferentiating into myeloid precursors with efficiency comparable with that of diploid hESCs despite their neartetraploid chromosome complement. These results indicate that hESCs are capable of reprogramming nuclei from differentiated cells and that hESC hybrid cells provide a new model system for studying the mechanisms of nuclear reprogramming.

Animals↗
PubMed2006

Reprogramming efficiency following somatic cell nuclear transfer is influenced by the differentiation and methylation state of the donor nucleus.

Reprogramming of a differentiated cell nucleus by somatic cell nuclear transplantation is an inefficient process. Following nuclear transfer, the donor nucleus often fails to express early embryonic genes and establish a normal embryonic pattern of chromatin modifications. These defects correlate with the low number of cloned embryos able to produce embryonic stem cells or develop into adult animals. Here, we show that the differentiation and methylation state of the donor cell influence the efficiency of genomic reprogramming. First, neural stem cells, when used as donors for nuclear transplantation, produce embryonic stem cells at a higher efficiency than blastocysts derived from terminally differentiated neuronal donor cells, demonstrating a correlation between the state of differentiation and cloning efficiency. Second, using a hypomorphic allele of DNA methyltransferase-1, we found that global hypomethylation of a differentiated cell genome improved cloning efficiency. Our results provide functional evidence that the differentiation and epigenetic state of the donor nucleus influences reprogramming efficiency.

Animals↗
PubMed2006

Reprogramming of interceptive actions: time course of temporal corrections for unexpected target velocity change.

The authors investigated the time course of reprogramming of the temporal dimension of motor acts in a task requiring interception of a moving target. The target moved at a constant velocity on a monitor screen; in part of the trials, target velocity was unexpectedly increased or decreased. Those modifications were produced at different moments during target displacement, leaving periods of time from 100 to 800 ms for movement timing correction. The authors assessed the effects of probability of target velocity change (25% vs. 50%), uncertainty about direction of velocity change (unidirectional vs. bidirectional), and direction of velocity change (increase vs. decrease). Analysis of 24 participants' arm acceleration showed that fast adjustments took place between 100 and 200 ms after target velocity change similarly for all uncertainty conditions. Analysis of temporal error indicated that the combination of high probability of target velocity change and certainty on direction of target velocity change led to the most successful movement timing reprogramming. For the other experimental conditions, temporal accuracy was still poor when a period of 800 ms was available for correction. Movement reprogramming was a continuous process that was more efficient for target velocity increase than for target velocity decrease.

Adult↗
PubMed2001

IFN-gamma-independent autocrine cytokine regulatory mechanism in reprogramming of macrophage responses to bacterial lipopolysaccharide.

Macrophages are now well recognized to have a critical role in both innate and acquired immunity. The sentinel macrophage function is highly regulated and serves to allow for intrinsic plasticity of the innate immune responses to potential environmental signals. However, the mechanisms underlying the dynamic properties of the cellular arm of innate immunity are poorly understood. Therefore, we have conducted a series of in vitro studies to evaluate the contribution of immunoregulatory cytokines, such as IFN-gamma, IL-10, and IL-12, in modulation of macrophage responses. We found that macrophages from IFN-gamma knockout (IFN-gamma(-/-)) mice exhibit only marginal LPS-induced TNF-alpha, IL-12, and NO responses, all of which can be fully restored in the presence of rIFN-gamma. Pretreatment with substimulatory LPS concentrations led to reprogramming of IFN-gamma(-/-) macrophage responses in a dose-dependent manner that manifested by an increased TNF-alpha and IL-12, but not NO, production upon the subsequent LPS challenge. These reprogramming effects were substantially attenuated and profoundly enhanced in macrophages from IL-12(-/-) and IL-10(-/-) mice, respectively, as compared with those modulated in macrophages from the congenic wild-type mice. LPS-dependent reprogramming was also fully reproduced in macrophages isolated from SCID mice after immunodepletion of NK cells. Our data strongly imply that cytokine (TNF-alpha and IL-12), but not NO, responses in macrophages may, at least in part, be governed by an autocrine IFN-gamma-independent regulatory mechanism reciprocally controlled by IL-10 and IL-12. This mechanism may serve as an alternative/coherent pathway to the canonical IFN-gamma-dependent induction of antimicrobial and tumoricidal activity in macrophages.

Adjuvants, Immunologic↗
PubMed2005

Changing cell fate by nuclear reprogramming.

The differentiated state of somatic cells is remarkably stable, but nuclear transfer can efficiently override the stability of cell differentiation by nuclear reprogramming. Genes that were silent in the differentiated state are activated, whereas genes specific for the differentiated state are switched off during the reprogramming process. The epigenetic changes that occur after nuclear transfer to Xenopus oocytes involve chromatin remodelling and DNA demethylation. In particular, we have reported that reactivation of the mouse stem cell specific gene oct-4 depends on demethylation of CpG:s in the proximal oct-4 promoter. Here we discuss molecular mechanisms of nuclear reprogramming, with special emphasis on DNA demethylation.

Animals↗
PubMedDate not supplied

Nuclear transplantation: reprogramming of transplanted nuclei.

Recent results in animal cloning have demonstrated that the events of cell differentiation can be reversed. This reversal necessarily requires genetic reprogramming of the transplanted nucleus. It has emerged from review articles that synthesis of nuclear and ribosomal RNA is blocked after fusion independently of cell cycle stage of the transferred nucleus, and that the cytoplasm condition of the cytoplast controls the speed of this inhibition. Transcription of the embryonic genome in nuclear transplant embryos begins either at the same stage as in normal development or even earlier. Expression analysis of individual genes showed up differences between nuclear transplant and normal embryos at the blastocyst stage. A certain degree of nuclear reprogramming after fusion is necessary, but exact timing and the qualitative sequence of the processes are probably not necessary for the successful embryonic development of the cloned embryo. In the future, observation of the expression of individual genes will bring more exact information about nucleus reprogramming.

Animals↗
PubMedDate not supplied

[The effect of serum starvation on the efficacy of the nuclear reprogramming of rabbit embryonic fibroblasts].

Successful transplantation of mammalian nuclei from differentiated cells has become possible after the application of original methods directed at the synchronization of cell cycles of the donor cell and recipient cytoplasm. We obtained a line of rabbit fetal fibroblasts which was used to study factors affecting the success of reprogramming. The nuclei of fetal fibroblasts (up to the 10th passage inclusive) proved to be capable of reprogramming and ensuring development of the cloned embryos until the preimplantation stages. The influence of synchronization of the cell cycles of the nucleus donor and recipient on the efficiency of reprogramming was studied. The rate of development of the cloned rabbit embryos to the morula-blastocyst stage reached 67% when the nuclei used were from stationary culture cells (G0-phase).

Animals↗
PubMed2000

[Cloning and reprogramming of the nucleus in the preimplantation embryo].

In mammals, nuclear transfer (or cloning) consists of introducing the nucleus which is generally transcriptionally active into a new cytoplasmic environment, usually that of a transcriptionally inactive metaphase II oocyte. Following the transfer, intense nucleocytoplasmic exchange takes place, and is responsible for remodeling of the nuclear structure and gene reprogramming. The original development program of the donor nucleus is effaced, and the reconstructed embryo adopts that of the recipient oocyte. Both remodeling and reprogramming are regulated by maternal cytoplasmic factors. Overall transcriptional activity, splicing and translational functions as well as the specific expression of certain genes are fairly similar to corresponding activity in normal embryos. However, the development program seems to be read some hours in advance by the reconstructed embryos, and some basic information is lacking. It is particularly important to study these reprogramming abnormalities during the early stages of development in the context of specific abnormalities in fetal and neonatal development observed after transfer of somatic cells.

Animals↗
PubMed1996

Reprogramming pacemakers enhances longevity and is cost-effective.

BACKGROUND: Historically, the majority of pulse generators implanted in the United States remain at the nominal programmed settings from the time of implant. While these nominal settings typically allow a sufficient safety margin to prevent later loss of capture with potential chronic threshold rise, the pulse generator with significant use would not be expected to last longer than that predicted by the manufacturer. However, improvements in lead technology have resulted in significantly lower chronic capture thresholds, which would permit lower programmable output settings while still allowing acceptable safety margins. Such changes could result in a significant reduction in long-term battery drain and translate into longer generator life. METHODS AND RESULTS: One hundred eighty consecutive patients undergoing implantation of permanent pacemakers at our institution were studied to determine the impact of reprogramming on pulse generator longevity and cost. Of these patients, 122 completed 6 months of follow-up at our institution and had pulse generators implanted that were capable of measuring battery current. We compared the estimated longevity based on battery current at nominal settings with that based on settings achieved in follow-up. The final settings were determined by the patient's physician using standard safety margins. The predicted longevity was 6.95 +/- 1.59 years at nominal implant settings and 11.16 +/- 2.71 years at final programmed settings (P < .001). Therefore, reprogramming extends the estimated pulse generator longevity by 4.25 +/- 2.14 years (64%) at a mean cost of $110 per patient (+37 per year extended). CONCLUSIONS: Reprogramming of permanent pacemakers is efficacious and cost-effective.

Cost-Benefit Analysis↗
PubMed2026

Metabolic convergence of diabetes and prostate cancer: from dysglycemia to tumor microenvironment reprogramming.

The relationship between diabetes mellitus and prostate cancer (PC) represents one of the most intriguing paradoxes in cancer epidemiology, with diabetic individuals exhibiting a reduced incidence of PC yet poorer prognosis following diagnosis. This apparent contradiction underscores the need for an integrated understanding of how systemic metabolic dysfunction influences prostate carcinogenesis and disease progression. The present review critically synthesizes contemporary epidemiological, mechanistic, and translational evidence to establish metabolic convergence as a unifying framework linking diabetes-associated metabolic abnormalities with PC biology. Current evidence indicates that chronic dysglycemia, hyperinsulinemia, insulin resistance, and endocrine perturbations orchestrate interconnected intracellular signaling networks involving PI3K-AKT-mTOR, AMPK, AGE-RAGE signaling, oxidative stress, mitochondrial dysfunction, and epigenetic reprogramming, collectively driving metabolic adaptation and tumor evolution. Beyond tumor-intrinsic mechanisms, diabetes profoundly remodels the prostate tumor microenvironment through alterations in stromal metabolism, cancer-associated fibroblast activation, adipocyte-tumor crosstalk, extracellular matrix (ECM) remodeling, hypoxic adaptation, and vascular dysfunction, while simultaneously promoting immunometabolic reprogramming characterized by macrophage polarization, T-cell dysfunction, immune checkpoint activation, and immune evasion. The review further examines the bidirectional interactions between antidiabetic therapies and PC treatment, critically evaluating the translational potential of metformin and emerging glucose-lowering agents within the context of precision metabolic therapeutics. Finally, future directions encompassing biomarker-guided patient stratification, longitudinal metabolic profiling, multi-omics integration, artificial intelligence, and clinically relevant mechanistic validation are discussed as essential components of next-generation precision oncology. Collectively, this review reframes diabetes as an active metabolic determinant of PC rather than a coincidental comorbidity and highlights metabolism-centered precision strategies as promising avenues for improving risk stratification, therapeutic decision-making, and clinical outcomes in diabetes-associated PC.

Humans↗
PubMed2026

Molecular determinants of AR-enhancer interaction and cistrome reprogramming in prostate cancer progression.

The androgen receptor (AR) is a key transcription factor in prostate cancer (PCa), whose enhanced and altered functions are known drivers of cancer progression. A key aspect of this is reprogramming of the AR cistrome, which consists of genome-wide enhancer-binding sites through which AR regulates gene expression. The magnitude and biological impact of the AR cistrome are impacted by the AR itself, including the responses to ligand, as well as the organization of the associated DNA response elements, and availability of pioneer factors, cofactors, and noncoding RNAs, all of which contribute to a functional transcription complex. In this review, we will examine, in the context of PCa progression, the factors that affect the binding of AR and its interacting partners at enhancers, with a focus on AR cistrome reprogramming. We also discuss the clinical utility of targeting the AR-enhancer nucleoprotein complex and the potential of using the AR cistrome as a prognostic tool.

Humans↗
PubMed2026

Metabolic reprogramming and taxonomic drivers in bacterial vaginosis: A large-scale metagenomic meta-analysis.

OBJECTIVE: Bacterial vaginosis (BV) represents a profound ecological shift from a Lactobacillus-dominated microbiota to a diverse polymicrobial biofilm associated with adverse outcomes. While taxonomic signatures are well-documented, the functional mechanisms driving this transition remain obscured. This study elucidates the genomic potential for metabolic reprogramming and the putative "functional handover" underpinning the stability of the dysbiotic state. METHODS: A computational meta-analysis of 3557 vaginal microbiomes from diverse global cohorts was performed using the standardized MGnify pipeline. A high-resolution subset of 187 whole-genome shotgun (WGS) metagenomes was stratified to compare functional potential across demographic groups. Taxon-function interaction networks were constructed, utilizing a dual-filter statistical approach (p&#x202f;<&#x202f;0.05 and effect size ranking), to map the shift from homeostatic maintenance to dysbiotic metabolic potential. RESULTS: BV was characterized by a fundamental shift from "maintenance" pathways to high-turnover "growth-oriented" genomic repertoires. While ABC transporter-like domains were present in healthy communities, dysbiosis was marked by a quantitative expansion and diversification of these systems alongside P-loop NTPases. Network analysis revealed a putative "functional handover": while Gardnerella serves as the adherent structural scaffold, the metabolic burden appears to be associated with secondary anaerobes, specifically BVAB1 and Sneathia, which exhibit strong genomic correlations with nutrient transport and stress response pathways. Crucially, microbiomes from women of African ancestry (Black cohort) exhibited a distinct functional profile with genomic signatures consistent with functions previously associated with resistome expansion (e.g., tetracycline/macrolide resistance), contrasting with Asian cohorts. CONCLUSION: BV is a state of metabolic reprogramming where genomic functional dominance is transferred from Lactobacillus to a cooperative network of anaerobic opportunists. Identifying BVAB1 and Sneathia as candidate metabolic engines, supported by a Gardnerella scaffold, challenges current therapeutic paradigms and highlights the potential for precision medicine targeting specific functional drivers and resistome profiles across diverse populations.

Humans↗
PubMed2026

Loss of PBRM1 accelerates pancreatic cancer progression by inducing acquisition of mesenchymal phenotype and inflammatory cancer-associated fibroblasts reprogramming.

BACKGROUND: PBRM1 is an important subunit of the SWI/SNF complex, which broadly regulates gene transcription by chromatin remodeling. Genomic alterations of PBRM1 have been found in patients with pancreatic ductal adenocarcinoma (PDAC), but its molecular functions remain unclear. METHODS: Clinical relevance of PBRM1 was analyzed by using human PDAC samples and public genomic datasets. Mice with concomitant pancreas-specific Pbrm1 deletion in Kras-driven genetic PDAC models were generated. Single-cell transcriptomics were performed to determine tumor phenotype and microenvironment reprogramming. RESULTS: Reduction of PBRM1 expression was observed in human PDAC tissues and correlated with poor prognosis and metastasis. Pbrm1 loss promoted ductal metaplasia and delayed epithelial recovery in mice with caerulein-induced pancreatic injury. In PDAC model with either mutant Kras alone or in combination with Trp53 mutation, lack of Pbrm1 markedly accelerated tumor development and progression. Bulk transcriptomics and scRNA-seq identified reprogramming of both tumor compartment with mesenchymal phenotype acquisition and stroma compartment with inflammatory cancer-associated fibroblasts (iCAFs) transformation. Mechanistically, Pbrm1 deletion induced Zeb1 upregulation through epigenetic chromatin remodeling, thereby enhancing epithelial-mesenchymal and basal-like subtype transition. CONCLUSIONS: These findings indicated a tumor-suppressing role of PBRM1 in PDAC. PBRM1-deficient PDAC constitutes a specific subgroup of patients with aggressive phenotype and prognostic significance.

Animals↗