Departamento de Medicina Preventiva y Salud Públicahttps://hdl.handle.net/10481/310602024-03-29T13:15:53Z2024-03-29T13:15:53ZLocus-resolution analysis of L1 regulation and retrotransposition potential in mouse embryonic developmentGerdes, PatriciaSánchez Luque, Francisco Joséhttps://hdl.handle.net/10481/860422023-12-05T13:41:17ZLocus-resolution analysis of L1 regulation and retrotransposition potential in mouse embryonic development
Gerdes, Patricia; Sánchez Luque, Francisco José
Mice harbor similar to 2800 intact copies of the retrotransposon Long Interspersed Element 1 (L1). The in vivo retrotransposition capacity of an L1 copy is defined by both its sequence integrity and epigenetic status, including DNA methylation of the monomeric units constituting young mouse L1 promoters. Locus-specific L1 methylation dynamics during development may therefore elucidate and explain spatiotemporal niches of endogenous retrotransposition but remain unresolved. Here, we interrogate the retrotransposition efficiency and epigenetic fate of source (donor) L1s, identified as mobile in vivo. We show that promoter monomer loss consistently attenuates the relative retrotransposition potential of their offspring (daughter) L1 insertions. We also observe that most donor/daughter L1 pairs are efficiently methylated upon differentiation in vivo and in vitro. We use Oxford Nanopore Technologies (ONT) long-read sequencing to resolve L1 methylation genome-wide and at individual L1 loci, revealing a distinctive "smile" pattern in methylation levels across the L1 promoter region. Using Pacific Biosciences (PacBio) SMRT sequencing of L1 5 ' RACE products, we then examine DNA methylation dynamics at the mouse L1 promoter in parallel with transcription start site (TSS) distribution at locus-specific resolution. Together, our results offer a novel perspective on the interplay between epigenetic repression, L1 evolution, and genome stability.
The authors thank Dr. John V. Moran, Dr. Ian R. Adams and members of the Richardson and Faulkner labs for helpful advice and discussion. HeLa-JVM cells were a gift from Dr. John V. Moran. The L1SM and L1SMmut2 constructs were a gift from Dr. Jef D. Boeke, and the L1spa construct was a gift from Dr. Haig Kazazian. This research was supported by an Australian Government Research Training Program Scholarship and a Mater Research Frank Clair Scholarship awarded to P.G., a University of Queensland Research Training Program Scholarship and Commonwealth Scientific and Industrial Research Organisation Postgraduate Top-Up Scholarship awarded to M.L., the People Programme (Marie Sk & lstrok;odowska-Curie Actions) of the European Union Seventh Framework Program (FP7/2007-2013) under REA grant agreement PIOF-GA-2013-623324 awarded to F.J.S.-L. and the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Development Fellowship GNT1108258 awarded to G.O.B. This study was funded by the Australian NHMRC (GNT1125645, GNT1138795, and GNT1173711 to G.J.F.; GNT1173476 to S.R.R.), The ARC (DP200102919 to G.J.F. and S.R.R.), an Australian Department of Health Medical Frontiers Future Fund (MRFF) (MRF1175457) grant awarded to A.D.E., a CSL Centenary Fellowship to G.J.F., an Advance Queensland Women's Academic Fund Maternity Funding award to S.R.R., the Mater Research Strategic Grant for Outstanding Women to S.R.R, and the Mater Foundation (Equity Trustees / AE Hingeley, QFC Thomas George and KC BM Thomson Trusts). We acknowledge the TRI flow cytometry core for technical assistance and equipment. We acknowledge QBI Advanced Microscopy Facility for technical assistance and equipment, supported by ARC LIEF grant LE130100078.
Persistent organic pollutant exposure as a risk factor of gestational diabetes mellitus: A systematic review and meta-analysisKouiti, MalakCastillo-Hermoso, María ÁngelesYoulyouz-Marfak, IbtissamSaeed Khan, KhalidThangaratinam, ShakilaOlmedo-Requena, RocíoZamora, JavierJiménez-Moléon, José Juanhttps://hdl.handle.net/10481/860322023-12-05T09:26:09ZPersistent organic pollutant exposure as a risk factor of gestational diabetes mellitus: A systematic review and meta-analysis
Kouiti, Malak; Castillo-Hermoso, María Ángeles; Youlyouz-Marfak, Ibtissam; Saeed Khan, Khalid; Thangaratinam, Shakila; Olmedo-Requena, Rocío; Zamora, Javier; Jiménez-Moléon, José Juan
Background: Findings related to the association between persistent organic pollut-
ants (POPs) and gestational diabetes mellitus (GDM) are inconclusive.
Objectives: To estimate the strength of the association between POP exposure and
GDM in a systematic review with meta-analysis.
Search strategy: MEDLINE, Scopus and Web of Science were searched until July
2023.
Selection criteria: Cohort and case–control studies analysing the association be-
tween POPs and GDM.
Data collection and analysis: We assessed the risk of bias using the Quality in
Prognosis Studies scale (QUIPS). Standardised mean differences were pooled using
random-effect models.
Main results: Sixteen articles including 12 216 participants were selected. The risk of
bias was high in four articles (25%), moderate in 11 (68.75%) and low in one (6.25%).
Small mean difference between GDM cases and controls was observed for PFHpA
(0.26, 95% confidence interval [CI] 0.1–0.35, I2 = 0.0%), PCB180 (0.37, 95% CI 0.19–0.56;
I2 = 25.3%), BDE47 (0.23, 95% CI 0.0–0.45, I2 = 0%), BDE99 (0.36, 95% CI 0.14–0.59;
I2 = 0%), BDE100 (0.42, 95% CI 0.19–0.64; I2 = 0%) and HCB (0.22, 95% CI 0.01–0.42,
I2 = 39.6%). No considerable difference was observed for the rest of POPs.
Conclusion: Small mean differences between GDM cases and controls were ob-
served for some POPs. However, evidence shows mostly moderate quality and results
were heterogeneous. Improved research methodology is needed to assess POPs and
GDM risk.
Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylationCheng, Kevin C. L.Sánchez Luque, Francisco JoséGarcía Cañadas, MartaGarcía Pérez, José Luishttps://hdl.handle.net/10481/859142023-11-29T08:41:44ZVitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation
Cheng, Kevin C. L.; Sánchez Luque, Francisco José; García Cañadas, Marta; García Pérez, José Luis
Background
Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells.
Results
Here we show that vitC increases the expression of several TE families, including evolutionarily young LINE-1 (L1) elements, in mouse ESCs. We find that TET activity is dispensable for L1 upregulation, and that instead it occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we did not detect increased somatic insertion rates in vitC-treated cells. Notably, treatment of human ESCs with vitC also increases L1 protein levels, albeit through a distinct, post-transcriptional mechanism.
Conclusion
VitC directly modulates the expression of mouse L1s and other TEs through epigenetic mechanisms, with potential for downstream effects related to the multiple emerging roles of L1s in cellular function.
This work was supported by grants from the Wellcome Trust/Royal Soci‑
ety (101225/Z/13/Z) and MRC (MR/X008487/1) to M.R.B.; and BBSRC (BB/
T000031/1) to M.R.B. and J.M.F.
Healthcare-associated infections by multidrug-resistant bacteria in Andalusia, Spain, 2014 to 2021Fernández-Martínez, Nicolás FranciscoRivera Izquierdo, MarioMartínez Ruiz, Virginia AnaLardelli Claret, PabloValero Ubierna, María del Carmenhttps://hdl.handle.net/10481/855542023-11-09T12:00:28ZHealthcare-associated infections by multidrug-resistant bacteria in Andalusia, Spain, 2014 to 2021
Fernández-Martínez, Nicolás Francisco; Rivera Izquierdo, Mario; Martínez Ruiz, Virginia Ana; Lardelli Claret, Pablo; Valero Ubierna, María del Carmen
Background: Multidrug-resistant (MDR) bacteria are
among chief causes of healthcare-associated infections
(HAIs). In Spain, studies addressing multidrug
resistance based on epidemiological surveillance
systems are lacking. Aim: In this observational study,
cases of HAIs by MDR bacteria notified to the epidemiological
surveillance system of Andalusia, Spain,
between 2014−2021, were investigated. Notified cases
and their spatiotemporal distribution were described,
with a focus on social determinants of health (SDoH).
Methods: New cases during the study period of
HAIs caused by extended-spectrum β-lactamase
(ESBL)-/carbapenemase-producing Enterobacterales,
MDR Acinectobacter baumannii, MDR Pseudomonas
aeruginosa or meticillin resistant Staphylococcus
aureus were considered. Among others, notification
variables included sex and age, while socio-economic
variables comprised several SDoH. Cases’ spatial
distribution across municipalities was assessed.
The smooth standardised incidence ratio (sSIR)
was obtained using a Bayesian spatial model.
Association between municipalities’ sSIR level and
SDoH was evaluated by bivariate analysis. Results:
In total, 6,389 cases with a median age of 68 years
were notified; 61.4% were men (n = 3,921). The
most frequent MDR bacteria were ESBL-producing
Enterobacterales (2,812/6,389; 44.0%); the main
agent was Klebsiella spp. (2,956/6,389; 46.3%).
Between 2014 and 2021 case numbers appeared to
increase. Overall, up to 15-fold differences in sSIR
between municipalities were observed. In bivariate
analysis, there appeared to be an association between
municipalities’ sSIR level and deprivation (p = 0.003).
Conclusion: This study indicates that social factors
should be considered when investigating HAIs by MDR
bacteria. The case incidence heterogeneity between
Andalusian municipalities might be explained by SDoH,
but also possibly by under-notification. Automatising
reporting may address the latter
Prediagnostic serum calcium concentrations and risk of colorectal cancer development in 2 large European prospective cohortsKaravasiloglou, NenaSánchez Pérez, María Joséhttps://hdl.handle.net/10481/855332023-11-08T12:27:14ZPrediagnostic serum calcium concentrations and risk of colorectal cancer development in 2 large European prospective cohorts
Karavasiloglou, Nena; Sánchez Pérez, María José
Background
Higher dietary calcium consumption is associated with lower colorectal cancer (CRC) risk. However, little data are available on the association between circulating calcium concentrations and CRC risk.
Objectives
To explore the association between circulating calcium concentrations and CRC risk using data from 2 large European prospective cohort studies.
Methods
Conditional logistic regression models were used to calculate multivariable-adjusted ORs and 95% CIs in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC; n-cases = 947, n-controls = 947) and the UK Biobank (UK-BB; n-cases = 2759, n-controls = 12,021) cohorts.
Results
In EPIC, nonalbumin-adjusted total serum calcium (a proxy of free calcium) was not associated with CRC (OR: 0.94; 95% CI: 0.85, 1.03; modeled as continuous variable, per 1 mg/dL increase), colon cancer (OR: 0.93; 95% CI: 0.82, 1.05) or rectal cancer (OR: 1.01; 95% CI: 0.84, 1.20) risk in the multivariable adjusted model. In the UK-BB, serum ionized calcium (free calcium, most active form) was inversely associated with the risk of CRC (OR: 0.85; 95% CI: 0.76, 0.95; per 1 mg/dL) and colon cancer (OR: 0.78; 95% CI: 0.68, 0.90), but not rectal cancer (OR: 1.02; 95% CI: 0.83, 1.24) in multivariable adjusted models. Meta-analysis of EPIC and UK-BB CRC risk estimates showed an inverse risk association for CRC in the multivariable adjusted model (OR: 0.90; 95%CI: 0.84, 0.97). In analyses by quintiles, in both cohorts, higher levels of serum calcium were associated with reduced CRC risk (EPIC: ORQ5vs.Q1: 0.69; 95% CI: 0.47, 1.00; P-trend = 0.03; UK-BB: ORQ5vs.Q1: 0.82; 95% CI: 0.72, 0.94; P-trend < 0.01). Analyses by anatomical subsite showed an inverse cancer risk association in the colon (EPIC: ORQ5vs.Q1: 0.63, 95% CI: 0.39, 1.02; P-trend = 0.05; UK-BB: ORQ5vs.Q1: 0.75; 95% CI: 0.64, 0.88; P-trend < 0.01) but not the rectum.
Conclusions
In UK-BB, higher serum ionized calcium levels were inversely associated with CRC, but the risk was restricted to the colon. Total serum calcium showed a null association in EPIC. Additional prospective studies in other populations are needed to better investigate these associations.