The Bivalent Genome: Characterization, Structure, and Regulation.

An intricate molecular machinery is at the core of gene expression regulation in every cell. During the initial stages of organismal development, the coordinated activation of diverse transcriptional programs is crucial and must be carefully executed to shape every organ and tissue. Bivalent promoters and poised enhancers are regulatory regions decorated with histone marks that are associated with both positive and negative transcriptional outcomes. These apparently contradictory signals are important for setting bivalent genes in a poised state, which is subsequently resolved during differentiation into either active or repressive states. We discuss the origins of bivalent promoters and the mechanisms implicated in their acquisition and maintenance. We further review how the presence of bivalent marks influences genome architecture. Finally, we highlight the potential link between bivalency and cancer which could drive biomedical research in disease etiology and treatment.

Differential contribution to gene expression prediction of histone modifications at enhancers or promoters.

The ChIP-seq signal of histone modifications at promoters is a good predictor of gene expression in different cellular contexts, but whether this is also true at enhancers is not clear. To address this issue, we develop quantitative models to characterize the relationship of gene expression with histone modifications at enhancers or promoters. We use embryonic stem cells (ESCs), which contain a full spectrum of active and repressed (poised) enhancers, to train predictive models. As many poised enhancers in ESCs switch towards an active state during differentiation, predictive models can also be trained on poised enhancers throughout differentiation and in development. Remarkably, we determine that histone modifications at enhancers, as well as promoters, are predictive of gene expression in ESCs and throughout differentiation and development. Importantly, we demonstrate that their contribution to the predictive models varies depending on their location in enhancers or promoters. Moreover, we use a local regression (LOESS) to normalize sequencing data from different sources, which allows us to apply predictive models trained in a specific cellular context to a different one. We conclude that the relationship between gene expression and histone modifications at enhancers is universal and different from promoters. Our study provides new insight into how histone modifications relate to gene expression based on their location in enhancers or promoters.

Inflammatory myofibroblastic tumour of an unusual presentation in the uterine cervix: a case report.

BACKGROUND: Inflammatory myofibroblastic tumour is an infrequent mesenchymal neoplasia of unknown aetiology and variable behaviour, ranging from rather benign lesions to locally aggressive and even metastatic disease. Its presence has been described in almost all organs; however, its location in the female genital tract has rarely been reported. CASE PRESENTATION: We present the case of a 47-year-old female, who was studied in our institution for a recent medical history of several weeks of dyspareunia and abdominal pain. She underwent pertinent studies including ultrasonography and CT scan. Under suspicion of degenerated leiomyoma, a total hysterectomy was performed. Unexpectedly, the pathological study of the surgical specimen showed very few tumour cells with focal fusiform morphology surrounded by an abundant inflammatory infiltrate; a thorough immunohistochemistry study lead to myofibroblastic tumour of the cervix diagnosis. A PET-CT scan did not show metastatic disease. The patient did not undergo any adjuvant treatment, and she is currently on surveillance with no evidence of disease relapse. CONCLUSIONS: Inflammatory myofibroblastic tumour remains a rare entity yet to be fully elucidated. The diagnosis is based on pathological study due to the lack of typical clinical manifestations and typical radiological images. Surgical resection is the most frequent treatment, whereas chemotherapy and radiotherapy are restricted to locally advanced or metastatic disease. Tirosine kinase inhibitor crizotinib has shown promising results especially in tumours harbouring ALK mutation.

Mpox (Monkeypox) Presenting as Cervical and Vulvar Disease.

BACKGROUND: Since the beginning of the current mpox (formerly "monkeypox") outbreak in May 2022, 23,465 confirmed cases of monkeypox virus infection have been reported in Europe; women represent less than 1% of these cases. Mpox lesions are found with greater frequency in the genital area, and, in women, have been described primarily in the vulva. CASE: We present a case of monkeypox virus infection in a 28-year-old woman confirmed by polymerase chain reaction testing, in which the only clinical manifestation was the appearance of concomitant lesions in the cervix and the vulva, with no other clinical features. No other sexual transmitted diseases were found. The lesions disappeared spontaneously in 2 weeks. CONCLUSION: Mpox lesions can affect the cervix; thus, recognition by gynecologists is important. Given the current epidemic outbreak, correct identification is essential to help control disease transmission.

A computational pipeline to learn gene expression predictive models from epigenetic information at enhancers or promoters.

Here, we present a computational pipeline to obtain quantitative models that characterize the relationship of gene expression with the epigenetic marking at enhancers or promoters in mouse embryonic stem cells. Our protocol consists of (i) generating predictive models of gene expression from epigenetic information (such as histone modification ChIP-seq) at enhancers or promoters and (ii) assessing the performance of these predictive models. This protocol could be applied to other biological scenarios or other types of epigenetic data. For complete details on the use and execution of this protocol, please refer to Gonzalez-Ramirez et al. (2021).1.

HPV vaccination coverage in women between 15 and 55 years old in Spain: Temporal trend during the period 2007-2020.

OBJECTIVE: The objective of this study was to analyse the temporal trend of HPV vaccination coverage (VC) in Spain in women aged 15-55 years not included in systematic vaccination programmes during the period 2007-2020. METHODS: We assessed the vaccine coverage rate in this population based on three estimations: 1) annual vaccination coverage with at least one dose (VCR ≥ 1d), 2) annual VC for the full schedule (VCR3d), and 3) cumulative VC for the full schedule (aVCR). RESULTS: Annual VCR ≥ 1d and VCR3d were highest in 2008 (2.40% and 0.66% respectively) and subsequently decreased drastically in 2011 (0.55% and 0.15%). From 2017 to 2019 there was an increase from 1.4-fold to 1.6-fold, respectively, which decreased in 2020. In relation to aVCR, there was an increasing trend throughout the study period with approximately 4.03% of the study population having been vaccinated against HPV in 2020. CONCLUSION: In Spain, the cumulative vaccination coverage against HPV in women between 15-55 years old not included in current vaccination programmes remains very low. Nonetheless, the temporal trend has shown a slight increase in recent years. Despite the COVID-19 pandemic in 2020, no significant negative impact on vaccination coverage has been observed in this population.

Glucocorticoid-induced Fingerprints on Visceral Adipose Tissue Transcriptome and Epigenome.

CONTEXT: Chronic glucocorticoid (GC) overexposure, resulting from endogenous Cushing's syndrome (CS) or exogenous GC therapy, causes several adverse outcomes, including persistent central fat accumulation associated with a low-grade inflammation. However, no previous multiomics studies in visceral adipose tissue (VAT) from patients exposed to high levels of unsuppressed GC during active CS or after remission are available yet. OBJECTIVE: To determine the persistent VAT transcriptomic alterations and epigenetic fingerprints induced by chronic hypercortisolism. METHODS: We employed a translational approach combining high-throughput data on endogenous CS patients and a reversible CS mouse model. We performed RNA sequencing and chromatin immunoprecipitation sequencing on histone modifications (H3K4me3, H3K27ac, and H3K27me3) to identify persistent transcriptional and epigenetic signatures in VAT produced during active CS and maintained after remission. RESULTS: VAT dysfunction was associated with low-grade proinflammatory status, macrophage infiltration, and extracellular matrix remodeling. Most notably, chronic hypercortisolism caused a persistent circadian rhythm disruption in VAT through core clock genes modulation. Importantly, changes in the levels of 2 histone modifications associated to gene transcriptional activation (H3K4me3 and H3K27ac) correlated with the observed differences in gene expression during active CS and after CS remission. CONCLUSION: We identified for the first time the persistent transcriptional and epigenetic signatures induced by hypercortisolism in VAT, providing a novel integrated view of molecular components driving the long-term VAT impairment associated with CS.

Productive visualization of high-throughput sequencing data using the SeqCode open portable platform.

Large-scale sequencing techniques to chart genomes are entirely consolidated. Stable computational methods to perform primary tasks such as quality control, read mapping, peak calling, and counting are likewise available. However, there is a lack of uniform standards for graphical data mining, which is also of central importance. To fill this gap, we developed SeqCode, an open suite of applications that analyzes sequencing data in an elegant but efficient manner. Our software is a portable resource written in ANSI C that can be expected to work for almost all genomes in any computational configuration. Furthermore, we offer a user-friendly front-end web server that integrates SeqCode functions with other graphical analysis tools. Our analysis and visualization toolkit represents a significant improvement in terms of performance and usability as compare to other existing programs. Thus, SeqCode has the potential to become a key multipurpose instrument for high-throughput professional analysis; further, it provides an extremely useful open educational platform for the world-wide scientific community. SeqCode website is hosted at http://ldicrocelab.crg.eu , and the source code is freely distributed at https://github.com/eblancoga/seqcode .

Value of robotic surgery in endometrial cancer by body mass index.

OBJECTIVE: To compare perioperative outcomes and complications in robotically assisted laparoscopy (RAL) and standard laparoscopy (SLP) approaches in the treatment of endometrial cancer by body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters). METHODS: A comparative study was carried out of women treated for endometrial cancer at the Hospital Clinico San Carlos from January 2012 to December 2016: 133 patients were operated by RAL and 101 by SLP. Demographic characteristics of the patients, perioperative outcomes and complications were compared in both approaches. RESULTS: Hospital stay was significantly lower in patients with BMI ≤30 operated with RAL (2 days RAL vs 4 days SLP; P=0.002). Estimated blood loss was significantly lower in the group with BMI<25 (60 mL RAL vs 100 mL SLP; P=0.004) and in the group with BMI ≥30 (87.5 mL RAL vs 180 SLP; P=0.003) operated with RAL. RAL significantly reduced the conversion rate in patients with BMI ≥30 (2 [3.4%] patients RAL vs 6 [27.3%] patients SLP; P=0.004). CONCLUSIONS: RAL has demonstrated advantages in treating obese women with endometrial cancer by reducing blood loss and conversion to laparotomy.