Yeast Nat4 regulates DNA damage checkpoint signaling through its N-terminal acetyltransferase activity on histone H4.

The DNA damage response (DDR) constitutes a vital cellular process that safeguards genome integrity. This biological process involves substantial alterations in chromatin structure, commonly orchestrated by epigenetic enzymes. Here, we show that the epigenetic modifier N-terminal acetyltransferase 4 (Nat4), known to acetylate the alpha-amino group of serine 1 on histones H4 and H2A, is implicated in the response to DNA damage in S.

Oct4 is a gatekeeper of epithelial identity by regulating cytoskeletal organization in skin keratinocytes.

Oct4 is a pioneer transcription factor regulating pluripotency. However, it is not well known whether Oct4 has an impact on epidermal cells. We generated OCT4 knockout clonal cell lines using immortalized human skin keratinocytes to identify a functional role for the protein.

Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.

Histone modifications commonly integrate environmental cues with cellular metabolic outputs by affecting gene expression. However, chromatin modifications such as acetylation do not always correlate with transcription, pointing towards an alternative role of histone modifications in cellular metabolism. Using an approach that integrates mass spectrometry-based histone modification mapping and metabolomics with stable isotope tracers, we demonstrate that elevated lipids in acetyltransferase-depleted hepatocytes result from carbon atoms derived from deacetylation of hyperacetylated histone H4 flowing towards fatty acids.

A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer.

The Octamer-binding transcription factor-4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post-embryonic re-expression is inadequately understood. In cervical cancer, Oct4 expression is higher in human papillomavirus (HPV)-related than HPV-unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4-transcriptional output and Oct4-related phenotypes in cervical cancer, however, the underlying mechanism remains elusive.

A calibration and uncertainty quantification analysis of classical, fractional and multiscale logistic models of tumour growth.

Background And Objective: The validation of mathematical models of tumour growth is frequently hampered by the lack of sufficient experimental data, resulting in qualitative rather than quantitative studies. Recent approaches to this problem have attempted to extract information about tumour growth by integrating multiscale experimental measurements, such as longitudinal cell counts and gene expression data. In the present study, we investigated the performance of several mathematical models of tumour growth, including classical logistic, fractional and novel multiscale models, in terms of quantifying in-vitro tumour growth in the presence and absence of therapy.

Special Issue "New Frontiers in Small DNA Virus Research".

Scientific progress in understanding, preventing, treating, and managing viral infections and associated diseases exemplifies the extent to which research on small DNA tumor viruses has impacted human health [...

Protocol for in vivo lineage tracing of the mouse-papillomavirus-type 1-infected cells in mice.

Here, we present a protocol to create an in vivo lineage-tracing mouse model for mouse-papillomavirus-type 1 (MmuPV1)-infected cells. We describe the steps to generate and deliver the MmuPV1 lox-Cre-lox plasmid for the infection of mice, followed by skin tissue extraction and processing. We then detail how to use flow cytometry to trace, quantify, and analyze MmuPV1-harboring cells and their progeny.

Decitabine Treatment Induces a Viral Mimicry Response in Cervical Cancer Cells and Further Sensitizes Cells to Chemotherapy.

Purpose: To investigate the anti-cancer, chemosensitizing and/or immunomodulating effects of decitabine (DAC) to be used as a potential therapeutic agent for the treatment of cervical cancer (CC).

Methods: Cervical cancer cell lines were treated with low doses of DAC treatment used as a single agent or in combination with chemotherapy. End-point in vitro assays were developed as indicators of the anti-cancer and/or immunomodulating effects of DAC treatment in CC cells.

A novel lineage-tracing mouse model for studying early MmuPV1 infections.

Human papillomaviruses are DNA viruses that ubiquitously infect humans and have been associated with hyperproliferative lesions. The recently discovered mouse specific papillomavirus (MmuPV1) provides the opportunity to study papillomavirus infections in vivo in the context of a common laboratory mouse model (). To date, a major challenge in the field has been the lack of tools to identify, observe, and characterize individually the papillomavirus hosting cells and also trace the progeny of these cells over time.

Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.

Background: Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown.

Resveratrol loaded polymeric micelles for theranostic targeting of breast cancer cells.

Treatment of breast cancer underwent extensive progress in recent years with molecularly targeted therapies. However, non-specific pharmaceutical approaches (chemotherapy) persist, inducing severe side-effects. Phytochemicals provide a promising alternative for breast cancer prevention and treatment.

Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers.

Octamer binding transcription factor-4 (Oct4), is highly expressed in stem cells and has indispensable roles in pluripotency and cellular reprogramming. In contrast to other factors used for cellular reprogramming, a role for Oct4 outside embryonic stem cells has been elusive and highly controversial. Emerging evidence implicates Oct4 in the carcinogenic process, but the mechanism through which Oct4 may be functioning in cancers is not fully appreciated.

Individualized growth prediction of mice skin tumors with maximum likelihood estimators.

Background & Objective: In this work, we focus on estimating the parameters of the Gompertz model in order to predict tumor growth. The estimation is based on measurements from mice skin tumors of de novo carcinogenesis. The main objective is to compare the Maximum Likelihood estimator with the best performance from our previous work with the Non-linear Least Squares estimator which is commonly used in the literature to estimate the growth parameters of the Gompertz model.

Whole transcriptome sequence data of 5-FU sensitive and 5-FU resistant tumors generated in a mouse model of de novo carcinogenesis.

We have performed whole transcriptome sequencing of 5-FU resistant and 5-FU sensitive tumors generated in a mouse model of de novo carcinogenesis that closely recapitulates tumor initiation, progression and maintenance in vivo. Tumors were generated using the DMBA/TPA model of chemically induced carcinogenesis [1], tumor-bearing mice were subsequently treated with 5-FU, and tumor growth as well as response to treatment was monitored by measuring tumor volume twice a week. Based on these measurements, we selected two 5-FU resistant and two 5-FU sensitive tumors and performed whole transcriptome sequencing and in order to identify differentially expressed transcripts between the two sets.

Terc is dispensable for most of the short-term HPV16 oncogene-mediated phenotypes in mice.

High-risk human papillomaviruses (HPVs) have been shown in vitro to impinge on telomere homeostasis in a number of ways. However, the in vivo interaction of viruses with the telomere homeostasis apparatus has not been previously explored. Since E6 and E7 are the main viral oncogenes and key for viral replication, we have explored here the short-term phenotypes of the genes in the context of defective telomere homeostasis.

Changing Stem Cell Dynamics during Papillomavirus Infection: Potential Roles for Cellular Plasticity in the Viral Lifecycle and Disease.

Stem cells and cellular plasticity are likely important components of tissue response to infection. There is emerging evidence that stem cells harbor receptors for common pathogen motifs and that they are receptive to local inflammatory signals in ways suggesting that they are critical responders that determine the balance between health and disease. In the field of papillomaviruses stem cells have been speculated to play roles during the viral life cycle, particularly during maintenance, and virus-promoted carcinogenesis but little has been conclusively determined.

Inflammation Shapes Stem Cells and Stemness during Infection and Beyond.

The outcome of an inflammatory incident can hang in the balance between restoring health and tissue integrity on the one hand, and promoting aberrant tissue homeostasis and adverse outcomes on the other. Both microbial-related and sterile inflammation is a complex response characterized by a range of innate immune cell types, which produce and respond to cytokine mediators and other inflammatory signals. In turn, cells native to the tissue in question can sense these mediators and respond by migrating, proliferating and regenerating the tissue.

Direct conversion of mouse embryonic fibroblasts into functional keratinocytes through transient expression of pluripotency-related genes.

The insufficient ability of specialized cells such as neurons, cardiac myocytes, and epidermal cells to regenerate after tissue damage poses a great challenge to treat devastating injuries and ailments. Recent studies demonstrated that a diverse array of cell types can be directly derived from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or somatic cells by combinations of specific factors. The use of iPSCs and direct somatic cell fate conversion, or transdifferentiation, holds great promise for regenerative medicine as these techniques may circumvent obstacles related to immunological rejection and ethical considerations.

Model-Based Tumor Growth Dynamics and Therapy Response in a Mouse Model of De Novo Carcinogenesis.

Tumorigenesis is a complex, multistep process that depends on numerous alterations within the cell and contribution from the surrounding stroma. The ability to model macroscopic tumor evolution with high fidelity may contribute to better predictive tools for designing tumor therapy in the clinic. However, attempts to model tumor growth have mainly been developed and validated using data from xenograft mouse models, which fail to capture important aspects of tumorigenesis including tumor-initiating events and interactions with the immune system.

Shared mechanisms in stemness and carcinogenesis: lessons from oncogenic viruses.

A rise in technologies for epigenetic reprogramming of cells to pluripotency, highlights the potential of understanding and manipulating cellular plasticity in unprecedented ways. Increasing evidence points to shared mechanisms between cellular reprogramming and the carcinogenic process, with the emerging possibility to harness these parallels in future therapeutics. In this review, we present a synopsis of recent work from oncogenic viruses which contributes to this body of knowledge, establishing a nexus between infection, cancer, and stemness.

The HPV16 oncogenes cause aberrant stem cell mobilization.

Human Papilloma Virus related epithelial cancers have been speculated to derive from virus-infected tissue stem cells. Stem cells also are thought to provide a reservoir of latently infected cells that can persist for long periods. In this study we have examined the effects of HPV16 E6 and E7 oncogenes on multipotent epithelial stem cells, using in vivo systems.

Deficiencies in the Fanconi anemia DNA damage response pathway increase sensitivity to HPV-associated head and neck cancer.

Patients with the rare genetic disease, Fanconi anemia (FA), are highly susceptible to squamous cell carcinomas arising at multiple anatomic sites including the head and neck region. Human papillomaviruses (HPVs), particularly HPV16, are associated with ∼20% of head and neck squamous cell carcinomas (HNSCCs) in the general population. Some but not other investigators have reported that HNSCCs in FA patients are much more frequently positive for HPV.

Human papillomavirus type 16 E6 and E7 oncoproteins act synergistically to cause head and neck cancer in mice.

High-risk human papillomaviruses (HPVs) contribute to cervical and other anogenital cancers, and they are also linked etiologically to a subset of head and neck squamous cell carcinomas (HNSCC). We previously established a model for HPV-associated HNSCC in which we treated transgenic mice expressing the papillomaviral oncoproteins with the chemical carcinogen 4-nitroquinoline-1-oxide (4-NQO). We found that the HPV-16 E7 oncoprotein was highly potent in causing HNSCC, and its dominance masked any potential oncogenic contribution of E6, a second papillomaviral oncoprotein commonly expressed in human cancers.