Tissue-specific Gene Expression Research Articles

The H2Bub1-deposition complex is required for human and mouse cardiogenesis.

De novo variants affecting monoubiquitylation of histone H2B (H2Bub1) are enriched in human congenital heart disease. H2Bub1 is required in stem cell differentiation, cilia function, post-natal cardiomyocyte maturation and transcriptional elongation. However, how H2Bub1 affects cardiogenesis is unknown. We show that the H2Bub1-deposition complex (RNF20-RNF40-UBE2B) is required for mouse cardiogenesis and for differentiation of human iPSCs into cardiomyocytes. Mice with cardiac-specific Rnf20 deletion are embryonic lethal and have abnormal myocardium. We then analyzed H2Bub1 marks during differentiation of human iPSCs into cardiomyocytes. H2Bub1 is erased from most genes at the transition from cardiac mesoderm to cardiac progenitor cells but is preserved on a subset of long cardiac-specific genes. When H2Bub1 is reduced in iPSC-derived cardiomyocytes, long cardiac-specific genes have fewer full-length transcripts. This correlates with H2Bub1 accumulation near the center of these genes. H2Bub1 accumulation near the center of tissue-specific genes was also observed in embryonic fibroblasts and fetal osteoblasts. In summary, we show that normal H2Bub1 distribution is required for cardiogenesis and cardiomyocyte differentiation, and suggest that H2Bub1 regulates tissue-specific gene expression by increasing the amount of full-length transcripts.

Comparative RNA-Seq Analysis Revealed Tissue-Specific Splicing Variations during the Generation of the PDX Model

Tissue-specific gene expression generates fundamental differences in the function of each tissue and affects the characteristics of the tumors that are created as a result. However, it is unclear how much the tissue specificity is conserved during grafting of the primary tumor into an immune-compromised mouse model. Here, we performed a comparative RNA-seq analysis of four different primary-patient derived xenograft (PDX) tumors. The analysis revealed a conserved RNA biotype distribution of primary−PDX pairs, as revealed by previous works. Interestingly, we detected significant changes in the splicing pattern of PDX, which was mainly comprised of skipped exons. This was confirmed by splicing variant-specific RT-PCR analysis. On the other hand, the correlation analysis for the tissue-specific genes indicated overall strong positive correlations between the primary and PDX tumor pairs, with the exception of gastric cancer cases, which showed an inverse correlation. These data propose a tissue-specific change in splicing events during PDX formation as a variable factor that affects primary−PDX integrity.

Identification of a Novel Gene Regulatory Element in Human Erythroid Progenitor Cells

Early erythropoiesis involves commitment of multi-lineage progenitors to erythroid progenitor cells and differentiation into erythroid burst-forming unit (BFU-E) cells, then erythroid colony-forming unit (CFU-E) cells. In contrast to terminal erythroid differentiation, regulation of gene expression in early erythropoiesis is poorly defined. To address this knowledge gap, we identified active enhancers in erythroid progenitor cells linked to known disease genes and genes associated with erythrocyte traits in genome wide association studies. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) isolated from mobilized peripheral blood were cultured towards the erythroid lineage. From these cultures, FACS-based methods were utilized to purify four stages of erythroid progenitor cells, termed EP1 to EP4, and five populations of terminally differentiated erythroblasts, from proerythroblasts to orthochromatic erythroblasts. ChIP-seq was performed using antibodies to H3K4me1, H3K27Ac, H3K27me3, and H3K9me2/3. Chromatin accessibility was determined by ATAC-seq. Patterns of gene expression were determined by RNA-seq. Active enhancers were identified using the ModHMM algorithm. Numerous erythroid progenitor cell-specific active enhancers were identified near genes linked to known disease genes and GWAS-associated erythrocyte traits. rs162375, a single nucleotide polymorphism (SNP) linked to mean corpuscular hemoglobin, was in a 475bp Long Terminal Repeat Retrotransposon (LTR) element upstream of the RRP1B gene. The LTR enhancer near the RRP1B gene is a member of the LTR15 family. Transposable elements are a source of novelty in primate gene regulation when they acquire binding sites for critical tissue-specific transcription factors, and then these tissue-specific regulatory regions direct tissue-specific expression of nearby genes. The SNP-containing LTR15 erythroid progenitor-specific enhancer upstream of RRP1B contains 2 conserved GATA motifs and a conserved RUNX motif. The enhancer region had a peak of open chromatin determined by ATAC-seq, and H3K27 acetylation and strong GATA1 binding determined by ChIP-seq. These findings were present only in erythroid progenitor cells, not in earlier hematopoietic cells, terminally differentiating erythroid cells, or other non-erythroid cells. CRISPR-based gene editing was utilized to delete the LTR15 enhancer in CD34+ HSPCs cultured towards the erythroid lineage into erythroid progenitor cells. mRNA expression of RRP1B was decreased to 70.2% of wild type. Luciferase-based reporter gene studies demonstrated the enhancer increased expression of a minimal promoter 3.2-fold over background. Mutation of the GATA and RUNX sites individually or together decreased reporter gene activity to background levels. Bioinformatic analyses identified 291 additional erythroid progenitor cell specific LTR15 element active enhancers, with most containing two GATA motifs and a RUNX motif. The majority of the novel enhancer regions were also marked by progenitor cell-specific ATAC peaks and strong GATA1 binding in ChIP-seq. GATA1 and RUNX, both present in early erythropoiesis, are required to activate the regulatory elements in erythroid progenitor cells. Decreasing levels of RUNX in terminal erythroid differentiation parallels loss of enhancer activity. Since LTR15 first appeared in Catarrhine, old-world monkeys, these data indicate this novel regulatory element has recently evolved to contribute to regulation of gene expression in early erythropoiesis in primates.

SUMOylation of Bonus, the Drosophila homolog of Transcription Intermediary Factor 1, safeguards germline identity by recruiting repressive chromatin complexes to silence tissue-specific genes.

The conserved family of Transcription Intermediary Factors (TIF1) proteins consists of key transcriptional regulators that control transcription of target genes by modulating chromatin state. Unlike mammals that have four TIF1 members, Drosophila only encodes one member of the family, Bonus. Bonus has been implicated in embryonic development and organogenesis and shown to regulate several signaling pathways, however, its targets and mechanism of action remained poorly understood. We found that knockdown of Bonus in early oogenesis results in severe defects in ovarian development and in ectopic expression of genes that are normally repressed in the germline, demonstrating its essential function in the ovary. Recruitment of Bonus to chromatin leads to silencing associated with accumulation of the repressive H3K9me3 mark. We show that Bonus associates with the histone methyltransferase SetDB1 and the chromatin remodeler NuRD and depletion of either component releases Bonus-induced repression. We further established that Bonus is SUMOylated at a single site at its N-terminus that is conserved among insects and this modification is indispensable for Bonus's repressive activity. SUMOylation influences Bonus's subnuclear localization, its association with chromatin and interaction with SetDB1. Finally, we showed that Bonus SUMOylation is mediated by the SUMO E3-ligase Su(var)2-10, revealing that although SUMOylation of TIF1 proteins is conserved between insects and mammals, both the mechanism and specific site of modification is different in the two taxa. Together, our work identified Bonus as a regulator of tissue-specific gene expression and revealed the importance of SUMOylation as a regulator of complex formation in the context of transcriptional repression.

Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes (n = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in C3 rs2230199 and CFH rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for CFH rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. STAT1, validated between the iAMD vs. normal comparison, and AGTPBP1, BBS5, CERKL, FGFBP2, KIFC3, RORα, and ZNF292, validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes C3 and CFH suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.

Chromatin priming elements direct tissue-specific gene activity before hematopoietic specification.

Tissue-specific gene regulation during development involves the interplay between transcription factors and epigenetic regulators binding to enhancer and promoter elements. The pattern of active enhancers defines the cellular differentiation state. However, developmental gene activation involves a previous step called chromatin priming which is not fully understood. We recently developed a genome-wide functional assay that allowed us to functionally identify enhancer elements integrated in chromatin regulating five stages spanning the in vitro differentiation of embryonic stem cells to blood. We also measured global chromatin accessibility, histone modifications, and transcription factor binding. The integration of these data identified and characterised cis-regulatory elements which become activated before the onset of gene expression, some of which are primed in a signalling-dependent fashion. Deletion of such a priming element leads to a delay in the up-regulation of its associated gene in development. Our work uncovers the details of a complex network of regulatory interactions with the dynamics of early chromatin opening being at the heart of dynamic tissue-specific gene expression control.

Allelic variations of WAK106-E2Fa-DPb1-UGT74E2 module regulate fibre properties in Populus tomentosa.

Wood formation, intricately linked to the carbohydrate metabolism pathway, underpins the capacity of trees to produce renewable resources and offer vital ecosystem services. Despite their importance, the genetic regulatory mechanisms governing wood fibre properties in woody plants remain enigmatic. In this study, we identified a pivotal module comprising 158 high-priority core genes implicated in wood formation, drawing upon tissue-specific gene expression profiles from 22 Populus samples. Initially, we conducted a module-based association study in a natural population of 435 Populus tomentosa, pinpointing PtoDPb1 as the key gene contributing to wood formation through the carbohydrate metabolic pathway. Overexpressing PtoDPb1 led to a 52.91% surge in cellulose content, a reduction of 14.34% in fibre length, and an increment of 38.21% in fibre width in transgenic poplar. Moreover, by integrating co-expression patterns, RNA-sequencing analysis, and expression quantitative trait nucleotide (eQTN) mapping, we identified a PtoDPb1-mediated genetic module of PtoWAK106-PtoDPb1-PtoE2Fa-PtoUGT74E2 responsible for fibre properties in Populus. Additionally, we discovered the two PtoDPb1 haplotypes that influenced protein interaction efficiency between PtoE2Fa-PtoDPb1 and PtoDPb1-PtoWAK106, respectively. The transcriptional activation activity of the PtoE2Fa-PtoDPb1 haplotype-1 complex on the promoter of PtoUGT74E2 surpassed that of the PtoE2Fa-PtoDPb1 haplotype-2 complex. Taken together, our findings provide novel insights into the regulatory mechanisms of fibre properties in Populus, orchestrated by PtoDPb1, and offer a practical module for expediting genetic breeding in woody plants via molecular design.

Atypical Modes of CTCF Binding Facilitate Tissue-Specific and Neuronal Activity-Dependent Gene Expression States.

Multivalent binding of CTCF to variable DNA sequences is thought to underlie its ability to mediate diverse cellular functions. CTCF typically binds a 20 base-pair consensus DNA sequence, but the full diversity of CTCF binding sites (CBS) within the genome has not been interrogated. We assessed CTCF occupancy in cultured cortical neurons and observed surprisingly that ~ 22% of CBS lack the consensus CTCF motif. We report here that sequence diversity at most of these atypical CBS involves degeneracy at specific nucleotide positions within the consensus CTCF motif, which likely affect the binding of CTCF zinc fingers 6 and 7. This mode of atypical CTCF binding defines most CBS at gene promoters, as well as CBS that are dynamically altered during neural differentiation and following neuronal stimulation, revealing how atypical CTCF binding could influence gene activity. Dynamic CBS are distributed both within and outside loop anchors and TAD boundaries, suggesting both looping-dependent and independent roles for CTCF. Finally, we describe a second mode of atypical CTCF binding to DNA sequences that are completely unrelated to the consensus CTCF motif, which are enriched within the bodies of tissue-specific genes. These tissue-specific atypical CBS are also enriched in H3K27ac, which marks cis-regulatory elements within chromatin, including enhancers. Overall, these results indicate how atypical CBS could dynamically regulate gene activity patterns during differentiation, development, and in response to environmental cues.

Gene communities in co-expression networks across different tissues.

With the recent availability of tissue-specific gene expression data, e.g., provided by the GTEx Consortium, there is interest in comparing gene co-expression patterns across tissues. One promising approach to this problem is to use a multilayer network analysis framework and perform multilayer community detection. Communities in gene co-expression networks reveal groups of genes similarly expressed across individuals, potentially involved in related biological processes responding to specific environmental stimuli or sharing common regulatory variations. We construct a multilayer network in which each of the four layers is an exocrine gland tissue-specific gene co-expression network. We develop methods for multilayer community detection with correlation matrix input and an appropriate null model. Our correlation matrix input method identifies five groups of genes that are similarly co-expressed in multiple tissues (a community that spans multiple layers, which we call a generalist community) and two groups of genes that are co-expressed in just one tissue (a community that lies primarily within just one layer, which we call a specialist community). We further found gene co-expression communities where the genes physically cluster across the genome significantly more than expected by chance (on chromosomes 1 and 11). This clustering hints at underlying regulatory elements determining similar expression patterns across individuals and cell types. We suggest that KRTAP3-1, KRTAP3-3, and KRTAP3-5 share regulatory elements in skin and pancreas. Furthermore, we find that CELA3A and CELA3B share associated expression quantitative trait loci in the pancreas. The results indicate that our multilayer community detection method for correlation matrix input extracts biologically interesting communities of genes.

Interferon stimulated immune profile changes in a humanized mouse model of HBV infection

The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg and/or young ages, is still unresolved due to the lack of surrogate models. Here, we generate a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrate that human IFN stimulates gene expression profiles in huIFNAR peripheral blood mononuclear cells (PBMCs) are similar to those in human PBMCs, supporting the representativeness of this mouse model for functionally analyzing human IFN in vivo. Next, we reveal the tissue-specific gene expression atlas across multiple organs in response to human IFN treatment; this pattern has not been reported in healthy humans in vivo. Finally, by using the AAV-HBV model, we test the antiviral effects of human interferon. Fifteen weeks of human PEG-IFNα2 treatment significantly reduces HBsAg and HBeAg and even achieves HBsAg seroconversion. We observe that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon may be critical for HBsAg suppression. Our huIFNAR mouse can authentically respond to human interferon stimulation, providing a platform to study interferon function in vivo. PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion.

TE-TSS: an integrated data resource of human and mouse transposable element (TE)-derived transcription start site (TSS).

Transposable elements (TEs) are abundant in the genome and serve as crucial regulatory elements. Some TEs function as epigenetically regulated promoters, and these TE-derived transcription start sites (TSSs) play a crucial role in regulating genes associated with specific functions, such as cancer and embryogenesis. However, the lack of an accessible database that systematically gathers TE-derived TSS data is a current research gap. To address this, we established TE-TSS, an integrated data resource of human and mouse TE-derived TSSs (http://xozhanglab.com/TETSS). TE-TSS has compiled 2681 RNA sequencing datasets, spanning various tissues, cell linesand developmental stages. From these, we identified 5768 human TE-derived TSSs and 2797 mouse TE-derived TSSs, with 47% and 38% being experimentally validated, respectively. TE-TSS enables comprehensive exploration of TSS usage in diverse samples, providing insights into tissue-specific gene expression patterns and transcriptional regulatory elements. Furthermore, TE-TSS compares TE-derived TSS regions across 15 mammalian species, enhancing our understanding of their evolutionary and functional aspects. The establishment of TE-TSS facilitates further investigations into the roles of TEs in shaping the transcriptomic landscape and offers valuable resources for comprehending their involvement in diverse biological processes.

Plant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis

Plants synthesize numerous alkaloids that mimic animal neurotransmitters1. The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds2,3, yet many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids4, we identified an unexpected enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) proteins are required in the biosynthetic route to a key precursor of the Lycopodium alkaloids by catalysing a stereospecific Mannich-like condensation and subsequent bicyclic scaffold generation. Also, we describe a series of scaffold tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A5. Our findings suggest a broader involvement of CAH-like enzymes in specialized metabolism and demonstrate how successive scaffold tailoring can drive potency against a neurological protein target.

Genome-wide analysis of the SPL transcription factor family and its response to water stress in sunflower (Helianthus annuus).

SPL (SQUAMOSA promoter binding proteins-like) are plant-specific transcription factors that play essential roles in a variety of developmental processes as well as the ability to withstand biotic and abiotic stresses. To date, numerous species have been investigated for the SPL gene family, but so far, no SPL family genes have been thoroughly identified and characterized in the sunflower (Helianthus annuus). In this study, 25 SPL genes were identified in the sunflower genome and were unevenly distributed on 11 chromosomes. According to phylogeny analysis, 59 SPL genes from H. annuus, O. sativa, and A. thaliana were clustered into seven groups. Furthermore, the SPL genes in groups-I and II were demonstrated to be potential targets of miR156. Synteny analysis showed that 7 paralogous gene pairs exist in HaSPL genes and 26 orthologous gene pairs exist between sunflower and rice, whereas 21 orthologous gene pairs were found between sunflower and Arabidopsis. Segmental duplication appears to have played a vital role in the expansion processes of sunflower SPL genes, and because of selection pressure, all duplicated genes have undergone purifying selection. Tissue-specific gene expression analysis of the HaSBP genes proved their diverse spatiotemporal expression patterns, which were predominantly expressed in floral organs and differentially expressed in stem, axil, and root tissues. The expression pattern of HaSPL genes under water stress showed broad involvement of HaSPLs in the response to flood and drought stresses. This genome-wide identification investigation provides detailed information on the sunflower SPL transcription factor gene family and establishes a strong platform for future research on sunflower responses to abiotic stress tolerance.

The Eukaryotic Cell Nucleus: Custodian of Genetic Information and Key to Understanding Nuclear Envelope Diseases

The eukaryotic cell nucleus, discovered over 300 years ago, remains at the heart of scientific concerns. In-depth studies, including those carried out recently, confirm its central role in the control of cellular activities and genetic transmission across generations. Morphofunctionally, the nucleus consists of the nuclear envelope, the nucleoplasm and the nucleolus, each playing a crucial role. The nuclear envelope, often underestimated, is a dynamic structure that protects the genome, regulates its organization and responds to epigenetic changes. Abnormalities of this envelope, such as invagination, are diagnostic criteria for pathologies including cancer. Recently, the micronucleus has attracted particular interest due to its role in mechanisms triggering immune responses and contributing to chromosomal instability. Another study highlights the association between abnormalities in nuclear envelope proteins and various human diseases. Mutations in lamin A are linked to laminopathies, including the serious disease progeria. Emerin or lamin A/C, among other proteins, can lead to disorders such as Emery-Dreifuss muscular dystrophy. The study also reveals the importance of the lamin B receptor (LBR) in conditions such as Pelger-Huët anomaly. Although the underlying mechanisms of the mutations remain unknown, two general hypotheses are put forward: "mechanical stress" making cells vulnerable to physical strain, and "gene expression" altering the regulation of tissue-specific gene expression. In short, the cell nucleus is essential to cellular life, and abnormalities in its nuclear envelope are associated with devastating diseases. Research in this field offers promising prospects for understanding pathological mechanisms and developing treatments, particularly in the context of cancer.

A comprehensive AI-driven analysis of large-scale omic datasets reveals novel dual-purpose targets for the treatment of cancer and aging.

As aging and tumorigenesis are tightly interconnected biological processes, targeting their common underlying driving pathways may induce dual-purpose anti-aging and anti-cancer effects. Our transcriptomic analyses of 16,740 healthy samples demonstrated tissue-specific age-associated gene expression, with most tumor suppressor genes downregulated during aging. Furthermore, a large-scale pan-cancer analysis of 11 solid tumor types (11,303 cases and 4431 control samples) revealed that many cellular processes, such as protein localization, DNA replication, DNA repair, cell cycle, and RNA metabolism, were upregulated in cancer but downregulated in healthy aging tissues, whereas pathways regulating cellular senescence were upregulated in both aging and cancer. Common cancer targets were identified by the AI-driven target discovery platform-PandaOmics. Age-associated cancer targets were selected and further classified into four groups based on their reported roles in lifespan. Among the 51 identified age-associated cancer targets with anti-aging experimental evidence, 22 were proposed as dual-purpose targets for anti-aging and anti-cancer treatment with the same therapeutic direction. Among age-associated cancer targets without known lifespan-regulating activity, 23 genes were selected based on predicted dual-purpose properties. Knockdown of histone demethylase KDM1A, one of these unexplored candidates, significantly extended lifespan in Caenorhabditis elegans. Given KDM1A's anti-cancer activities reported in both preclinical and clinical studies, our findings propose KDM1A as a promising dual-purpose target. This is the first study utilizing an innovative AI-driven approach to identify dual-purpose target candidates for anti-aging and anti-cancer treatment, supporting the value of AI-assisted target identification for drug discovery.

Exploring the Molecular and Developmental Dynamics of Endothelial Cell Differentiation.

The development and differentiation of endothelial cells (ECs) are fundamental processes with significant implications for both health and disease. ECs, which are found in all organs and blood vessels, play a crucial role in facilitating nutrient and waste exchange and maintaining proper vessel function. Understanding the intricate signaling pathways involved in EC development holds great promise for enhancing vascularization, tissue engineering, and vascular regeneration. Hematopoietic stem cells originating from hemogenic ECs, give rise to diverse immune cell populations, and the interaction between ECs and immune cells is vital for maintaining vascular integrity and regulating immune responses. Dysregulation of vascular development pathways can lead to various diseases, including cancer, where tumor-specific ECs promote tumor growth through angiogenesis. Recent advancements in single-cell genomics and in vivo genetic labeling have shed light on EC development, plasticity, and heterogeneity, uncovering tissue-specific gene expression and crucial signaling pathways. This review explores the potential of ECs in various applications, presenting novel opportunities for advancing vascular medicine and treatment strategies.

Human endogenous retroviruses of the HERV-K (HML-2) family are expressed in the brain of healthy individuals and modify the composition of the brain-infiltrating immune cells

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the human genome. RNA expression of individual HERVs has frequently been observed in various pathologic conditions, but some activity can also be seen in healthy individuals, e.g. in the blood. To quantitate the basal expression levels of HERVs in the brain, we now used high-throughput sequencing-based metagenomic analysis to characterize the expression profiles of the HERV-K (HML-2) family proviruses in different brain regions of healthy brain tissue. To this end, RNA-seq data from the Genotype-Tissue Expression (GTEx) project was used. The GTEx project is a public resource to study tissue-specific gene expression and regulation, consisting of a large selection of sequenced samples from different tissues. The GTEx data used in this study consisted of 378 samples taken from 13 brain regions from 55 individuals. The data demonstrated that out of 99 intact proviruses in the family 58 were expressed, but the expression profiles were highly divergent and there were no significant differences in the expression profiles between the various anatomic regions of the brain. It is known that the brain contains a variety of infiltrating immune cells, which are probably of great importance both in the normal defense mechanisms as well as in the various pathogenic processes. Digital cytometry (CIBERSORTx) was used to quantify the proportions of the infiltrating immune cells in the same brain samples. Six most abundant (>5 % of the total population) cell types were observed to be CD4 memory resting T cells, M0 macrophages, plasma cells, CD8 T cells, CD4 memory activated T cells, and monocytes. Analysis of the correlations between the individual HERVs and infiltrating cell types indicated that a cluster of 6 HERVs had a notable correlation signature between T cell type infiltrating cell proportions and HERV RNA expression intensity. The correlations between inflammatory type infiltrating cells were negative or weak. Taken together, these data indicate that the expression of HERVs is associated with a T cell type immunity.

Thyroid dysfunction alters gene expression of proteins related to iron homeostasis and metabolomics in male rats

Thyroid hormones (THs) are crucial in bodily functions, while iron is essential for processes like oxygen transport. Specialized proteins maintain iron balance, including ferritin, transferrin, ferroportin, and hepcidin. Research suggests that THs can influence iron homeostasis by affecting mRNA and protein expression, such as ferritin and transferrin. Our study focused on male rats to assess mRNA expression of iron homeostasis-related proteins and metabolomics in thyroid dysfunction. We found altered gene expression across various tissues (liver, duodenum, spleen, and kidney) and identified disrupted metabolite patterns in thyroid dysfunction. These findings highlight tissue-specific effects of thyroid dysfunction on essential iron homeostasis proteins and provide insights into associated metabolic changes. Our research contributes to understanding the intricate interplay between thyroid hormones and iron balance. By unveiling tissue-specific gene expression alterations and metabolic disruptions caused by thyroid dysfunction, our work lays a foundation for future investigations to explore underlying mechanisms and develop targeted strategies for managing iron-related complications in thyroid disorders.

Influence of silver nanoparticles on mRNA expression of thyroid hormone-related genes in the thyroid gland and liver of laying hens

The widespread use of silver nanoparticles (AgNPs) in consumer products and animal husbandry raises the need to study their impact on living organisms. This study was conducted on Hy-Line Brown hens at the age of 25 weeks with an average weight of 1.58 kg. Hens for 2 weeks received a solution of 50 nm AgNPs at a concentration of 100 pm (experimental group; n = 6) or a solution in which the nanoparticles were suspended (control group; n = 6). Thyroid hormones (thyroxine – T4, triiodothyronine – T3) were evaluated in the blood plasma and expression profiles of genes involved in thyroid hormone (TH) synthesis (TSHR, NIS, TPO, TG), metabolism (DIO1, DIO2, DIO3) and transport (MCT8, MCT10, LAT1) were determined in the chicken thyroid gland. Furthermore, iodothyronine deiodinase, TH transporter and TH receptor (THRA, THRB) mRNA expressions were evaluated in the livers isolated from the same chickens. AgNPs did not affect serum T4 levels but elevated serum T3 concentration. The results showed that AgNPs increased DIO3 mRNA in the thyroid gland. In turn, in the liver AgNPs administration significantly upregulated DIO2 and downregulated MCT10 mRNA levels. These results indicate that exposure to AgNPs leads to a tissue-specific alternative expression of genes engaged in TH metabolism. Moreover, the mRNA expression of DIO2 in the liver showed a positive correlation with plasma T3 levels. In conclusion, AgNPs may have an impact on TH metabolism by affecting deiodinases and TH transporter MCT10 mRNA expression.

Epigenome-Wide Meta-analysis Reveals Associations Between Dietary Glycemic Index and Glycemic Load and DNA Methylation in Children and Adolescents of Different Body Sizes.

Dietary glycemic index (GI) and glycemic load (GL) are associated with cardiometabolic health in children and adolescents, with potential distinct effects in people with increased BMI. DNA methylation (DNAm) may mediate these effects. Thus, we conducted meta-analyses of epigenome-wide association studies (EWAS) between dietary GI and GL and blood DNAm of children and adolescents. We calculated dietary GI and GL and performed EWAS in children and adolescents (age range: 4.5-17 years) from six cohorts (N = 1,187). We performed stratified analyses of participants with normal weight (n = 801) or overweight or obesity (n = 386). We performed look-ups for the identified cytosine-phosphate-guanine (CpG) sites (false discovery rate [FDR] <0.05) with tissue-specific gene expression of 832 blood and 223 subcutaneous adipose tissue samples from children and adolescents. Dietary GL was positively associated with DNAm of cg20274553 (FDR <0.05), annotated to WDR27. Several CpGs were identified in the normal-weight (GI: 85; GL: 17) and overweight or obese (GI: 136; GL: 298; FDR <0.05) strata, and none overlapped between strata. In participants with overweight or obesity, identified CpGs were related to RNA expression of genes associated with impaired metabolism (e.g., FRAT1, CSF3). We identified 537 associations between dietary GI and GL and blood DNAm, mainly in children and adolescents with overweight or obesity. High-GI and/or -GL diets may influence epigenetic gene regulation and thereby promote metabolic derangements in young people with increased BMI.