Cellular fate and gene expression patterns are modulated by different epigenetic factors including non-coding RNAs (ncRNAs) and chromatin organization. Both factors are dynamic throughout male germ cell differentiation on the seminiferous tubule, despite the transcriptional inactivation in the last stages of spermatogenesis. Sperm maturation during the caput-to-cauda transit on the epididymis involves changes in chromatin organization and the soma-to-germ line transference of ncRNAs that are essential to obtain a functional sperm for fertilization and embryo development. Here, the male environment (diseases, drugs, mental stress) is crucial to modulate these epigenetic factors throughout sperm maturation, affecting the corresponding offspring. Paternal transgenerational inheritance has been directly related to sperm epigenetic changes, most of them associated with variations in the ncRNA content and chromatin marks. Our aim is to give an overview about how epigenetics, focused on ncRNAs and chromatin, is pivotal to understand spermatogenesis and sperm maturation, and how the male environment impacts the sperm epigenome modulating the offspring gene expression pattern.

Long non-coding RNAs (lncRNAs) have been shown to modulate gene expression and are involved in the initiation and progression of various cancer types. Despite the wealth of studies describing transcriptome changes upon lncRNA knockdown, there is limited information describing lncRNA-mediated effects on regulatory elements (REs) modulating gene expression. In this study, we investigated how the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA regulates primary target genes using time-resolved MALAT1 knockdown followed by parallel RNA-seq and ATAC-seq assays. The results revealed that MALAT1 primarily regulates specific protein-coding genes and a substantial decrease in the accessibility downstream of the NR4A1 gene that was associated with a decreased NR4A1 expression. Moreover, the presence of an NR4A1-downstream RE was demonstrated by CRISPR-i assays to define a functional MALAT1/NR4A1 axis. By analyzing TCGA data, we identified a positive correlation between NR4A1 expression and NR4A1-downstream RE accessibility in breast cancer but not in pancreatic cancer. Accordingly, this regulatory mechanism was experimentally validated in breast cancer cells (MCF7) but not in pancreatic duct epithelial carcinoma (PANC1) cells. Therefore, our results demonstrated that MALAT1 is involved in a molecular mechanism that fine-tunes NR4A1 expression by modulating the accessibility of a downstream RE in a cell type-specific manner.

Background: Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide, with metabolic syndrome and its risk factors contributing substantially to cases in Latin America. In southern Chile, obesity, dyslipidemia, and sedentary behavior are highly prevalent, yet comprehensive baseline data on these factors are scarce. Establishing regional cardiometabolic profiles is crucial to inform prevention strategies. Objective: To describe the RIO-Study protocol and characterize the baseline cardiometabolic profile of adults from Valdivia, southern Chile. Methods: The RIO-Study is a randomized, double-blind, placebo-controlled, crossover clinical trial evaluating the effects of nutritional doses of seaweed-derived omega-3 fatty acids on lipid metabolism, inflammation, and molecular lipid regulators in adults with overweight/obesity. The protocol includes a standardized high-fat breakfast challenge and repeated postprandial blood sampling to assess dynamic lipid responses. Screening procedures comprised blood pressure measurement, fasting blood sampling, body composition by bioelectrical impedance, and health and lifestyle questionnaires. Results: Among screened participants, 91% presented overweight/obesity and 55% presented central adiposity, exceeding regional cardiometabolic risk thresholds (waist circumference ≥ 90 cm in men, ≥80 cm in women). Men exhibited higher waist circumference (100 ± 10.8 vs. 91.6 ± 11.9 cm), waist-to-hip ratio (0.99 ± 0.08 vs. 0.92 ± 0.07), systolic blood pressure (130 ± 12.0 vs. 122 ± 13.4 mmHg), triglycerides (168 ± 84.7 vs. 122 ± 64.9 mg/dL), VLDL-C (33.7 ± 17.2 vs. 24.4 ± 13.0 mg/dL), and sedentary time (8.1 ± 2.3 vs. 6.8 ± 2.3 h/day). Women had greater total body fat (39.7 ± 4.75% vs. 31.1 ± 5.30%), higher HDL-C (56.6 ± 13.3 vs. 46.9 ± 9.39 mg/dL), and more often had normal weight (13% vs. 0%). Conclusions: The RIO-Study provides novel insights into cardiometabolic risk and will elucidate the effects of nutritional omega-3 supplementation in a high-risk Chilean population.

TRPV1, a member of the transient receptor potential (TRP) family, is a non-selective cation channel primarily known for its role in pain perception, inflammation, and thermosensation. In mammals, it responds to noxious heat (>43°C) and chemical stimuli such as capsaicin and protons. It is widely expressed in sensory neurons, notably in the dorsal root and trigeminal ganglia. However, it is also found in some non-neuronal tissues, like the skin and bladder. The human canonical variant of TRPV1 renders a protein with 839 residues. Different splice variants have been described, and some display a dominant negative effect, partially or totally inhibiting the activity of the canonical counterpart. Here, we characterize a splice variant that encodes for a channel of 850 amino acids (TRPV1 ₈₅₀ ). This variant is an evolutionary novelty of catarrhine (Old World monkeys and apes) primates, incorporating an exon of 33 bp long. Both imaging of membrane expression and electrophysiological recordings suggest that TRPV1 ₈₅₀ alone does not reach the plasma membrane. However, in cells co-expressing the canonical and TRPV1 ₈₅₀ variants, the latter would act as a dominant negative, preventing the canonical variant from reaching the plasma membrane and rendering smaller macroscopic currents in response to capsaicin. Thus, this new isoform of the TRPV1 ion channel represents a novel form of functional regulation only present in apes and Old World monkeys. Significance: We identified a novel isoform of the TRPV1 ion channel, a protein essential for detecting pain and heat stimuli unique to apes and Old World monkeys. This isoform contains an additional exonic sequence encoding eleven amino acids, which originated in the common ancestor of apes and Old World monkeys. This additional exonic sequence disrupts a specific domain in the N-terminal region of the protein, resulting in functional differences. Unlike the canonical TRPV1 isoform, this variant cannot reach the plasma membrane independently. Instead, it exerts a dominant-negative effect by interfering with the canonical TRPV1 protein, reducing its ability to localize to the cell surface and diminishing its responsiveness to capsaicin, a well-known TRPV1 activator.

Hydroxycarboxylic acid receptors (HCARs) are class A G-protein-coupled receptors that function as metabolic sensors. This receptor family includes three members (HCAR1, HCAR2, and HCAR3) expressed in metabolically active tissues and immune cells, where they link cellular metabolic status to physiological responses. This study aims to elucidate the evolutionary history of the most recently originated members of the HCAR gene family, namely HCAR2 and HCAR3, in primates. According to our phylogenetic analyses, the duplicative history of these genes involved multiple independent duplication events during ape evolution. Thus, most ape lineages possess independently originated duplicated copies, while non-ape primates retain the ancestral condition of a single-copy gene (HCAR2/3). Our analyses further indicate that this single-copy gene in non-ape primates is functionally equivalent to HCAR2, suggesting that the primary functional innovation in apes is associated with the physiological roles of HCAR3. Finally, gene expression analyses reveal that major divergence in tissue expression occurred after the initial duplication event that generated HCAR1 and the HCAR2/3 lineage, whereas HCAR2 and HCAR3 exhibit substantial overlap in their expression profiles. Thus, the more refined and context-dependent regulation of lipid metabolism that provides the HCAR3 receptor seems to have originated multiple times during the evolutionary history of apes.

Hydroxycarboxylic acid receptors are class A G-protein-coupled receptors that act as metabolic sensors linking cellular metabolic status to physiological and immune responses. This family comprises three members (HCAR1, HCAR2, and HCAR3), expressed in metabolically active tissues and immune cells. Here, we investigate the evolutionary history of the most recently derived members, HCAR2 and HCAR3, in primates. Phylogenetic analyses reveal a complex duplicative history involving multiple independent duplication events during ape evolution. As a result, most ape lineages harbor independently originated duplicated copies, whereas non-ape primates retain the ancestral single-copy condition (HCAR2/3). Functional inference indicates that this single-copy gene may be functionally similar to HCAR2, suggesting that the major functional innovation in apes is associated with the emergence of HCAR3. Gene expression analyses further show that major divergence in tissue expression occurred early, following the duplication that generated HCAR1 and the HCAR2/3 lineage, while HCAR2 and HCAR3 retain largely overlapping expression profiles. Together, our results suggest that HCAR3 receptors may have evolved repeatedly in apes, potentially contributing to refined lipid-sensing.