Tissue-specific Processes Research Articles

SpatialLIBD: an R/Bioconductor package to visualize spatially-resolved transcriptomics data

BackgroundSpatially-resolved transcriptomics has now enabled the quantification of high-throughput and transcriptome-wide gene expression in intact tissue while also retaining the spatial coordinates. Incorporating the precise spatial mapping of gene activity advances our understanding of intact tissue-specific biological processes. In order to interpret these novel spatial data types, interactive visualization tools are necessary.ResultsWe describe spatialLIBD, an R/Bioconductor package to interactively explore spatially-resolved transcriptomics data generated with the 10x Genomics Visium platform. The package contains functions to interactively access, visualize, and inspect the observed spatial gene expression data and data-driven clusters identified with supervised or unsupervised analyses, either on the user’s computer or through a web application.ConclusionsspatialLIBD is available at https://bioconductor.org/packages/spatialLIBD. It is fully compatible with SpatialExperiment and the Bioconductor ecosystem. Its functionality facilitates analyzing and interactively exploring spatially-resolved data from the Visium platform.

Disrupted long-range gene regulations elucidate shared tissue-specific mechanisms of neuropsychiatric disorders.

Neurological and psychiatric disorders have overlapped phenotypic profiles, but the underlying tissue-specific functional processes remain largely unknown. In this study, we explore the shared tissue-specificity among 14 neuropsychiatric disorders through the disrupted long-range gene regulations by GWAS-identified regulatory SNPs. Through Hi-C interactions, averagely 38.0% and 17.2% of the intergenic regulatory SNPs can be linked to target protein-coding genes in brain and non-brain tissues, respectively. Interestingly, while the regulatory target genes in the brain tend to enrich in nervous system development related processes, those in the non-brain tissues are inclined to interfere with synapse and neuroinflammation related processes. Compared to psychiatric disorders, neurological disorders present more prominently the neuroinflammatory processes in both brain and non-brain tissues, indicating an intrinsic difference in mechanisms. Through tissue-specific gene regulatory networks, we then constructed disorder similarity networks in two brain and three non-brain tissues, highlighting both known disorder clusters (e.g. the neurodevelopmental disorders) and unexpected disorder clusters (e.g. Parkinson's disease is consistently grouped with psychiatric disorders). We showcase the potential pharmaceutical applications of the small bowel and its disorder clusters, illustrated by the known drug targets NR1I3 and NFACT1, and their small bowel-specific regulatory modules. In conclusion, disrupted long-range gene regulations in both brain and non-brain tissues contribute to the similarity among distinct clusters of neuropsychiatric disorders, and the tissue-specifically shared functions and regulators for disease clusters may provide insights for future therapeutic investigations.

Transcriptional atlas analysis from multiple tissues reveals the expression specificity patterns in beef cattle

BackgroundA comprehensive analysis of gene expression profiling across tissues can provide necessary information for an in-depth understanding of their biological functions. We performed a large-scale gene expression analysis and generated a high-resolution atlas of the transcriptome in beef cattle.ResultsOur transcriptome atlas was generated from 135 bovine tissues in adult beef cattle, covering 51 tissue types of major organ systems (e.g., muscular system, digestive system, immune system, reproductive system). Approximately 94.76% of sequencing reads were successfully mapped to the reference genome assembly ARS-UCD1.2. We detected a total of 60,488 transcripts, and 32% of them were not reported before. We identified 2654 housekeeping genes (HKGs) and 477 tissue-specific genes (TSGs) across tissues. Using weighted gene co-expression network analysis, we obtained 24 modules with 237 hub genes (HUBGs). Functional enrichment analysis showed that HKGs mainly maintain the basic biological activities of cells, while TSGs were involved in tissue differentiation and specific physiological processes. HKGs in bovine tissues were more conserved in terms of expression pattern as compared to TSGs and HUBGs among multiple species. Finally, we obtained a subset of tissue-specific differentially expressed genes (DEGs) between beef and dairy cattle and several functional pathways, which may be involved in production and health traits.ConclusionsWe generated a large-scale gene expression atlas across the major tissues in beef cattle, providing valuable information for enhancing genome assembly and annotation. HKGs, TSGs, and HUBGs further contribute to better understanding the biology and evolution of multiple tissues in cattle. DEGs between beef and dairy cattle also fill in the knowledge gaps about differential transcriptome regulation of bovine tissues underlying economically important traits.

Alternative Promoters of GRIK2 (GluR6) Gene in Human Carcinoma Cell Lines Are Regulated by Differential Methylation of CpG Dinucleotides.

The ionotropic glutamate receptor 6 (GluR6 or GRIK2) gene is transcribed by two cell-type-specific promoters in neuronal and non-neuronal cells, which results in five different transcript variants. The purpose of this study was to explore cell-type-specific silencing of these promoters by epigenetic mechanisms. The neuronal and non-neuronal promoter sequences were cloned upstream of the luciferase gene in the pGL3 luciferase reporter vector. Promoter susceptibility to methylation was confirmed by 5-azacytidine and trichostatin treatment, and the status of CpG dinucleotides was determined by bisulfite sequencing of the promoter was determined by bisulfite sequences. GluR6A transcript variant was expressed in the brain, and GluR6B was most abundant in tumor cell lines. The neuronal promoter was methylated in non-neuronal cell lines. The treatment with 5-azacytidine and trichostatin upregulated transcription of the GluR6 gene, and methylation of the GluR6 promoter sequence in the luciferase reporter system led to downregulation of the luciferase gene transcription. Bisulfite sequencing revealed methylation of 3 and 41 CpG sites in non-neuronal and neuronal promoters, respectively. The differential activation/silencing of GluR6 promoters suggests that the transcript variants of GluR6 are involved in tissue-specific biological processes and their aberrant regulation in tumor cells may contribute to distinct properties of tumor cells.

Research progress of Schwann cells regulating bone regeneration

To review the research progress on the role of Schwann cells in regulating bone regeneration. The domestic and foreign literature about the behavior of Schwann cells related to bone regeneration, multiple tissue repair ability, nutritional effects of their neurotrophic factor network, and their application in bone tissue engineering was extensively reviewed. As a critical part of the peripheral nervous system, Schwann cells regulate the expression level of various neurotrophic factors and growth factors through the paracrine effect, and participates in the tissue regeneration and differentiation process of non-neural tissues such as blood vessels and bone, reflecting the nutritional effect of neural-vascular-bone integration. Taking full advantage of the multipotent differentiation ability of Schwann cells in nerve, blood vessel, and bone tissue regeneration may provide novel insights for clinical application of tissue engineered bone.

Tissular Genomic Responses to Oral FB1 Exposure in Pigs.

Fumonisin B1 (FB1) is a widespread mycotoxin produced by fungal Fusarium species—mainly in maize, one of the plants most commonly used for food and feed. Pigs and horses are the animal species most susceptible to this mycotoxin. FB1 exposure can cause highly diverse clinical symptoms, including hepatotoxicity, immunotoxicity, and intestinal barrier function disturbance. Inhibition of ceramide synthetase is a well-understood ubiquitous molecular mechanism of FB1 toxicity, but other more tissue-specific effects remain to be elucidated. To investigate the effects of FB1 in different exposed tissues, we cross-analyzed the transcriptomes of fours organs: liver, jejunum, jejunal Peyer’s patches, and spleen. During a four-week study period, pigs were fed a control diet or a FB1-contaminated diet (10 mg/kg feed). In response to oral FB1 exposure, we observed common biological processes in the four organs, including predominant and recurrent processes (extracellular matrix organization, integrin activation, granulocyte chemotaxis, neutrophil migration, and lipid and sterol homeostasis), as well as more tissue-specific processes that appeared to be related to lipid outcomes (cell cycle regulation in jejunum, and gluconeogenesis in liver).

The differential activity of biological processes in tissues and cell subsets can illuminate disease-related processes and cell-type identities.

The distinct functionalities of human tissues and cell types underlie complex phenotype-genotype relationships, yet often remain elusive. Harnessing the multitude of bulk and single-cell human transcriptomes while focusing on processes can help reveal these distinct functionalities. The Tissue-Process Activity (TiPA) method aims to identify processes that are preferentially active or under-expressed in specific contexts, by comparing the expression levels of process genes between contexts. We tested TiPA on 1579 tissue-specific processes and bulk tissue transcriptomes, finding that it performed better than another method. Next, we used TiPA to ask whether the activity of certain processes could underlie the tissue-specific manifestation of 1233 hereditary diseases. We found that 21% of the disease-causing genes indeed participated in such processes, thereby illuminating their genotype-phenotype relationships. Lastly, we applied TiPA to single-cell transcriptomes of 108 human cell types, revealing that process activities often match cell-type identities and can thus aid annotation efforts. Hence, differential activity of processes can highlight the distinct functionality of tissues and cells in a robust and meaningful manner. TiPA code is available in GitHub (https://github.com/moranshar/TiPA). In addition, all data are available as part of the Supplementary Material. Supplementary data are available at Bioinformatics online.

MORPHOLOGICAL FEATURES OF TUBULAR BONES REPARATIVE REGENERATION UNDER THE INFLUENCE OF ANTITUMOR CHEMOTHERAPEUTICS

The aim: Determination of morphological features of reparative regeneration of diaphysis defect of long tubular bones under the influence of antitumor chemotherapeutics in a model experiment. Materials and methods: 96 white nonlinear rats after application of the perforated defect of the femur were administered the appropriate antitumor drug (doxorubicin, 5-fluorouracil, methotrexate) three times with an interval of 21 days. Morphological features of bone tissue formation and remodeling in the regenerate area were studied using histological and morphometric methods. Results: The inhibitory effect of antitumor chemotherapeutics on the formation of regenerate, expressed by slowing down the process of bone tissue differentiation was found. This is confirmed by a decrease in the area of reticulofibrous and lamellar bone tissue, chaotic arrangement and narrowing of bone trabeculae with uneven color, slow formation of bonding lines between the maternal bone and the regenerate. Conclusions: The revealed morphological features of reparative regeneration of the diaphysis defect of long tubular bones under the influence of antitumor chemotherapeutics doxorubicin, 5-fluorouracil and methotrexate in a model experiment indicate a slowing of reparative regeneration processes at all stages of recovery after injury.

Arginase 2 and Polyamines in Human Pancreatic Beta Cells: Possible Role in the Pathogenesis of Type 2 Diabetes.

Arginase 2 (ARG2) is a manganese metalloenzyme involved in several tissue specific processes, from physiology to pathophysiology. It is variably expressed in extra-hepatic tissues and is located in the mitochondria. In human pancreatic beta cells, ARG2 is downregulated in type 2 diabetes. The enzyme regulates the synthesis of polyamines, that are involved in pancreas development and regulation of beta cell function. Here, we discuss several features of ARG2 and polyamines, which can be relevant to the pathophysiology of type 2 diabetes.

Neural is Fundamental: Neural Stemness as the Ground State of Cell Tumorigenicity and Differentiation Potential.

Tumorigenic cells are similar to neural stem cells or embryonic neural cells in regulatory networks, tumorigenicity and pluripotent differentiation potential. By integrating the evidence from developmental biology, tumor biology and evolution, I will make a detailed discussion on the observations and propose that neural stemness underlies two coupled cell properties, tumorigenicity and pluripotent differentiation potential. Neural stemness property of tumorigenic cells can hopefully integrate different observations/concepts underlying tumorigenesis. Neural stem cells and tumorigenic cells share regulatory networks; both exhibit neural stemness, tumorigenicity and pluripotent differentiation potential; both depend on expression or activation of ancestral genes; both rely primarily on aerobic glycolytic metabolism; both can differentiate into various cells/tissues that are derived from three germ layers, leading to tumor formation resembling severely disorganized or more degenerated process of embryonic tissue differentiation; both are enriched in long genes with more splice variants that provide more plastic scaffolds for cell differentiation, etc. Neural regulatory networks, which include higher levels of basic machineries of cell physiological functions and developmental programs, work concertedly to define a basic state with fast cell cycle and proliferation. This is predestined by the evolutionary advantage of neural state, the ground or initial state for multicellularity with adaptation to an ancient environment. Tumorigenesis might represent a process of restoration of neural ground state, thereby restoring a state with fast proliferation and pluripotent differentiation potential in somatic cells. Tumorigenesis and pluripotent differentiation potential might be better understood from understanding neural stemness, and cancer therapy should benefit more from targeting neural stemness.

Serum Level of Parathyroid Hormone, Alkaline Phosphatase, Calcium and Ionized Calcium After Forearm Fractures

Abstract Background During the last two decades, our understanding of fracture healing has evolved rapidly. Bone is one of the few body tissues that can heal without forming a fibrous scar and, as such, the process of fracture healing recapitulates bone development and may be considered a form of tissue regeneration. The complex cell and tissue proliferation and differentiation processes involved in fracture healing are regulated by growth factors, inflammatory cytokines, antioxidants, hormones, amino acids, and other nutrients. Objective: To identify changes in serum level of calcium, ionized calcium, alkaline phosphatase and parathyroid hormone according to mode of trauma (low and high energy) in forearm fractures and their role in fracture healing. Patients and Methods 50 Patients with forearm fracture were prospectively recruited from the Accident and Emergency Department of Trauma Surgery, El Zaitoun specialized hospital within 48 hours of sustaining the fracture. Patients included in the study were asked to avoid calcium supplementation during fracture healing. Results Mean PTH was elevated in both groups at Day 1 with low energy group was insignificantly higher than high energy group, whereas after 8 weeks mean PTH level decreased in both groups but in low energy group mean PTH level was significantly higher than high energy group. Mean ALP level increased in both groups at Day 1 whereas in low energy group it was insignificantly higher than that of high energy group, After 8 weeks mean ALP level insignificantly decreased to normal level in both groups. Mean serum calcium level was below normal level in both groups where it was insignificantly higher in high energy group than that of low energy group which increased after 8 weeks in both groups but remained elevated in high energy than low energy group. Mean serum ionized calcium level was below normal level at Day 1 in both groups whereas it was insignificantly higher in high energy group than low energy group which after 8 weeks increased in both groups but remained elevated in high energy group than low energy group. Conclusion Serial monitoring of these physiological markers reflect the actual status of bone resorption, and bone formation respectively over a short period. Thus, they can be used as an adjunct to clinical and radiological evidence of fracture healing.

Distant-detector versus integrating sphere measurements for estimating tissue optical parameters: A comparative experimental study

Accurate determination of the optical absorption and scattering properties of biological tissues is a vital issue in many clinical and biomedical applications. These properties assist in planning and monitoring therapeutic protocols in addition to understanding many diagnostic measurements. Diffuse optical diagnosis is a non-invasive technique to monitor tissue physiological changes using light in the red to near infrared range. In the typical procedure, light is recorded after passing through thick tissue and the optical properties are spatially reconstructed using suitable mathematical models. Tissue diffuse reflectance and transmittance are experimentally measured using two common techniques; integrating sphere and distant-detector. These two methods are widely used for tissue diffusion measurements in the biomedical field for ex-vivo and non-invasive investigations. In the present study, these two experimental methods have been implemented and compared under verification with Monte-Carlo simulation giving 0.0245 and 0.009 absolute errors at 808-nm laser radiation for integrating sphere and distant-detector methods respectively. Although, integrating sphere shows more accurate results, the distant-detector based method is non-invasive and gives more specific information which helps in tissue differentiation process.

Diapause differentially modulates the transcriptomes of fat body and flight muscle in the Colorado potato beetle

Many temperate insects, such as the Colorado potato beetle, enter diapause in winter, during which they arrest their development, suppress their metabolic rate and have high stress tolerance. Diapause phenotypes can be transcriptionally regulated, however many studies to date report only whole animal gene expression rather than tissue-specific processes during diapause. We used RNA-seq to measure gene expression in fat body and flight muscle of diapausing and non-diapausing beetles. We used differential expression and GO enrichment analyses to evaluate longstanding hypotheses about the mechanisms that drive arrested development, changes in energy metabolism, and increased stress tolerance during diapause. We found evidence of G2/M cell cycle arrest, juvenile hormone catabolism, increased antioxidant metabolism, epigenetic modification, transposable element regulation, and cytoskeletal remodeling in both the fat body and flight muscle of diapausing beetles. Beetles differentially modulated the fat body and flight muscle transcriptomes during diapause with fat body playing a larger role in the hypoxia response and immunity, whereas flight muscle had higher abundance of transcripts related to the chaperone response and proteostasis. Our transcriptome provides evidence for distinct roles and responses of fat body and flight muscle during diapause in the Colorado potato beetle, and we provide testable hypotheses for biological processes that appear to drive diapause phenotypes in insects.

Tissue specificity of DNA repair: the CRISPR compass

CRISPR-Cas9-mediated genome editing holds great promise for the correction of pathogenic variants in humans. However, its therapeutic implementation is hampered due to unwanted editing outcomes. A better understanding of cell type- and tissue-specific DNA repair processes will ultimately enable precise control of editing outcomes for safer and effective therapies.

Transcriptome-Wide Association Study for Inflammatory Bowel Disease Reveals Novel Candidate Susceptibility Genes in Specific Colon Subsites and Tissue Categories

Genome-wide association studies [GWAS] for inflammatory bowel disease [IBD] have identified 240 risk variants. However, the benefit of understanding the genetic architecture of IBD remains to be exploited. Transcriptome-wide association studies [TWAS] associate gene expression with genetic susceptibility to disease, providing functional insight into risk loci. In this study, we integrate relevant datasets for IBD and perform a TWAS to nominate novel genes implicated in IBD genetic susceptibility. We applied elastic net regression to generate gene expression prediction models for the University of Barcelona and University of Virginia RNA sequencing project [BarcUVa-Seq] and correlated expression and disease association research [CEDAR] datasets. Together with Genotype-Tissue Expression project [GTEx] data, and GWAS results from about 60 000 individuals, we employed Summary-PrediXcan and Summary-MultiXcan for single and joint analyses of TWAS results, respectively. BarcUVa-Seq TWAS revealed 39 novel genes whose expression in the colon is associated with IBD genetic susceptibility. They included expression markers for specific colon cell types. TWAS meta-analysis including all tissues/cell types provided 186 novel candidate susceptibility genes. Additionally, we identified 78 novel susceptibility genes whose expression is associated with IBD exclusively in immune (N = 19), epithelial (N = 25), mesenchymal (N = 22) and neural (N = 12) tissue categories. Associated genes were involved in relevant molecular pathways, including pathways related to known IBD therapeutics, such as tumour necrosis factor signalling. These findings provide insight into tissue-specific molecular processes underlying IBD genetic susceptibility. Associated genes could be candidate targets for new therapeutics and should be prioritized in functional studies.

Close to Optimal Cell Sensing Ensures the Robustness of Tissue Differentiation Process: The Avian Photoreceptor Mosaic Case.

The way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility), but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP can predict the cone color spatial distribution in the avian retina and, at the same time, suggest that such a spatial pattern is associated with quasi-optimal cell sensing. By means of the stochastic thermodynamics formalism, we find out that thermodynamic robustness of differentiated tissues depends on cell metabolism and cell sensing properties. In turn, we calculate the limits of the cell sensing radius that ensure the robustness of differentiated tissue spatial order. Finally, we further constrain our model predictions to the avian photoreceptor mosaic.

HERV-Derived Ervpb1 Is Conserved in Simiiformes, Exhibiting Expression in Hematopoietic Cell Lineages Including Macrophages.

(1) Background: The ERVPb1 gene in humans is derived from an envelope (Env) gene of a human endogenous retrovirus group, HERV-P(b). The ERVPb1 gene reportedly has a conserved open reading frame (ORF) in Old World monkeys. Although its forced expression led to cell-fusion in an ex vivo cell culture system, like other Env-derived genes such as syncytin-1 and -2, its mRNA expression is not placenta-specific, but almost ubiquitous, albeit being quite low in human tissues and organs, implying a distinct role for ERVPb1. (2) Methods: To elucidate the cell lineage(s) in which the ERVPb1 protein is translated in human development, we developed a novel, highly sensitive system for detecting HERV-derived proteins/peptides expressed in the tissue differentiation process of human induced pluripotent stem cells (iPSCs). (3) Results: We first determined that ERVPb1 is also conserved in New World monkeys. Then, we showed that the ERVPb1 protein is translated from a uniquely spliced ERVPb1 transcript in hematopoietic cell lineages, including a subset of macrophages, and further showed that its mRNA expression is upregulated by lipopolysaccharide (LPS) stimulation in primary human monocytes. (4) Conclusions: ERVPb1 is unique to Simiiformes and actually translated in hematopoietic cell lineages, including a subset of macrophages.

Emerging Role of AP-1 Transcription Factor JunB in Angiogenesis and Vascular Development.

Blood vessels are essential for the formation and maintenance of almost all functional tissues. They play fundamental roles in the supply of oxygen and nutrition, as well as development and morphogenesis. Vascular endothelial cells are the main factor in blood vessel formation. Recently, research findings showed heterogeneity in vascular endothelial cells in different tissue/organs. Endothelial cells alter their gene expressions depending on their cell fate or angiogenic states of vascular development in normal and pathological processes. Studies on gene regulation in endothelial cells demonstrated that the activator protein 1 (AP-1) transcription factors are implicated in angiogenesis and vascular development. In particular, it has been revealed that JunB (a member of the AP-1 transcription factor family) is transiently induced in endothelial cells at the angiogenic frontier and controls them on tip cells specification during vascular development. Moreover, JunB plays a role in tissue-specific vascular maturation processes during neurovascular interaction in mouse embryonic skin and retina vasculatures. Thus, JunB appears to be a new angiogenic factor that induces endothelial cell migration and sprouting particularly in neurovascular interaction during vascular development. In this review, we discuss the recently identified role of JunB in endothelial cells and blood vessel formation.

MicroRNA Profiling of HL-1 Cardiac Cells-Derived Extracellular Vesicles.

HL-1 is a cell line that shows a phenotype similar to adult cardiomyocytes. All major cardiac cell types release extracellular vesicles (EVs) that emerge as key mediators of intercellular communication. EVs can mediate intercellular cross-talk through the transfer of specific microRNAs (miRNAs). MiRNAs are known to play important regulatory roles during tissue differentiation and regeneration processes. Furthermore, miRNAs have recently been shown to be involved in the proliferation of adult cardiomyocytes. In this context, the purpose of this study was to analyze the transcriptomic profile of miRNAs expressed from HL-1 cardiac muscle cell-derived EVs, using next generation sequencing (NGS). Specifically, our transcriptomic analysis showed that the EVs derived from our HL-1 cells contained miRNAs that induce blood vessel formation and increase cell proliferation. Indeed, our bioinformatics analysis revealed 26 miRNAs expressed in EVs derived from our HL-1 that target genes related to cardiovascular development. In particular, their targets are enriched for the following biological processes related to cardiovascular development: heart morphogenesis, positive regulation of angiogenesis, artery development, ventricular septum development, cardiac atrium development, and myoblast differentiation. Consequently, EVs could become important in the field of regenerative medicine.

N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer\u2019s disease

BackgroundN6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain.ResultsWe show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer’s disease, which is correlated with reduced protein levels.ConclusionsOur results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer’s disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.