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Top 10 enriched nervous system?related biological functions among the genes overlapping between the micro-RNA targets in typically developing regional analysis and autism-implicated genes. Of the 844 messenger RNA targets of the 11 mature micro-RNA (Table 2) in the typical superior temporal sulcus (STS) versus primary auditory cortex (PAC) analysis, there were 40 genes that overlapped with the 573 autism-implicated genes from the SFARI AutDB database (P < .05) (data provided on request). These 40 genes were inputed into an Ingenuity Pathway Analysis to yield the top 10 nervous system?related functions shown in light yellow (P < .05). Of the 40 genes, 18 genes (shown in light purple) were most associated with these top 10 functions.
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Small noncoding RNAs play a critical role in regulating messenger RNA throughout brain development and when altered could have profound effects leading to disorders such as autism spectrum disorders (ASD). We assessed small noncoding RNAs, including microRNA and small nucleolar RNA, in superior temporal sulcus association cortex and primary auditor...
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Citations
... Furthermore, as snoRNAs from this cluster display tissue-specific expression, it is essential to identify which of these snoRNAs are involved in ASD. For example, SNORD114-14 was upregulated in the superior temporal sulcus region of the brain in ASD patients, and SNORD114-27 was upregulated in induced neurons derived from fibroblasts of neurofibromatosis 1 (NF1) patients; interestingly, NF1 has a high co-occurrence in ASD (Sagata et al., 2017;Stamova et al., 2015). Intellectual disability and developmental delay clinical phenotypes have been reported in a subset of individuals with KOS14 and TS14. ...
The 14q32.2 ( DLK1‐DIO3 ) and 15q11‐q13 ( SNURF‐SNRPN ) imprinted gene loci harbor the largest known small nucleolar RNA clusters expressed from the respective maternal and paternal alleles. Recent studies have demonstrated significant roles for the 15q11‐q13 located SNORD115‐SNORD116 C/D box snoRNAs in Prader‐Willi syndrome (PWS), a neurodevelopmental disorder. Even though the effect of SNORD116 deletion is apparent in the PWS phenotype, similar effects of a SNORD113‐SNORD114 cluster deletion from the 14q32.2 locus in Kagami‐Ogata syndrome (KOS14) and upregulation in Temple syndrome (TS14) remain to be explored. Moreover, apart from their probable involvement in neurodevelopmental disorders, snoRNAs from the SNORD113‐SNORD114 cluster have been implicated in multiple biological processes, including pluripotency, development, cancers, and RNA modifications. Here we summarize the current understanding of the system to explore the possibility of a link between developmental disorders and C/D box snoRNA expression from the imprinted 14q32.2 locus.
This article is categorized under: RNA in Disease and Development > RNA in Disease
RNA in Disease and Development > RNA in Development
RNA Processing > Processing of Small RNAs
... In summary, our age-related findings support the premise brain development in individuals with ASD deviates from that of the neurotypical trajectory beginning in childhood and continues to evolve across the lifespan (70,71). Although the STG remains relatively unexplored (72)(73)(74), other brain regions display early excess followed by reductions in volume, connectivity, and cell densities as people with ASD age through adulthood. Initial excess and overconnectivity may lead to hyperexcitation, rendering the brain vulnerable to agerelated and pro-inflammatory mechanisms contributing to later degenerative outcomes. ...
Autism spectrum disorder (ASD) is a highly heterogeneous disorder, yet transcriptomic profiling of bulk brain tissue has identified substantial convergence among dysregulated genes and pathways in ASD. However, this approach lacks cell-specific resolution. We performed comprehensive transcriptomic analyses on bulk tissue and laser-capture microdissected (LCM) neurons from 59 postmortem human brains (27 ASD and 32 controls) in the superior temporal gyrus (STG) of individuals ranging from 2 to 73 years of age. In bulk tissue, synaptic signaling, heat shock protein-related pathways, and RNA splicing were significantly altered in ASD. There was age-dependent dysregulation of genes involved in gamma aminobutyric acid (GABA) (GAD1 and GAD2) and glutamate (SLC38A1) signaling pathways. In LCM neurons, AP-1-mediated neuroinflammation and insulin/IGF-1 signaling pathways were upregulated in ASD, while mitochondrial function, ribosome, and spliceosome components were downregulated. GABA synthesizing enzymes GAD1 and GAD2 were both downregulated in ASD neurons. Mechanistic modeling suggested a direct link between inflammation and ASD in neurons, and prioritized inflammation-associated genes for future study. Alterations in small nucleolar RNAs (snoRNAs) associated with splicing events suggested interplay between snoRNA dysregulation and splicing disruption in neurons of individuals with ASD. Our findings supported the fundamental hypothesis of altered neuronal communication in ASD, demonstrated that inflammation was elevated at least in part in ASD neurons, and may reveal windows of opportunity for biotherapeutics to target the trajectory of gene expression and clinical manifestation of ASD throughout the human lifespan.
... On the other hand, the expression of miR-378 involved in regulation of learning and memory 57 decreased with age in STS regions, which was not detectable in ASD brain. 58 Further miRNA microarray analysis confirmed that this region associated dysregulation in the STS (up-regulation of miR-4753-5p and downregulation of miR-1) and PAC (down-regulation of miR-297 and miR-4742-3p) of ASD patients 59 (Figure 1). In silico analysis of data from the above studies found that specific miRNAs exhibit sex-based differences in expression-these abnormalities of miRNAs appeared more common in females than males, with STS regions accounting for the vast majority. ...
Autism spectrum disorder (ASD) — a congenital mental disorder accompanied by social dysfunction and stereotyped behaviors — has attracted a great deal of attention worldwide. A combination of genetic and environmental factors may determine the pathogenesis of ASD. Recent research of multiple ASD models indicates that microRNAs (miRNAs) play a central role at onset and progression of ASD by repressing the translation of key mRNAs in neural development and functions. As such, miRNAs show great potential to serve as biomarkers for ASD diagnosis or prognosis and therapeutic targets for the treatment of ASD. In this review, we discuss the regulatory mechanisms by which miRNAs influence ASD phenotypes through various in vivo and in vitro models, including necropsy specimens, animal models and cellular models, and, in particular, induced pluripotent stem cells derived from patients with ASD. We then discuss the potential of miRNA-based therapeutic strategies for ASD currently being evaluated in preclinical studies.
... Similarly, specific studies looking at ncRNA have also provided evidence for possible brain profiles for ASD; miRNA profiles [122][123][124] and small ncRNA profile [125], lncRNA profiles [126] and even non-coding antisense transcripts [127] are reported. However, there is a startling lack of concordance amongst study findings [113], possibly attributable to the extreme variability inherent in transcriptomic experimental methods as well as within the ASD samples themselves. ...
With the advent of genome-wide screening methods—beginning with microarray technologies and moving onto next generation sequencing methods—the era of precision and personalized medicine was born. Genomics led the way, and its contributions are well recognized. However, “other-omics” fields have rapidly emerged and are becoming as important toward defining disease causes and exploring therapeutic benefits. In this review, we focus on the impacts of transcriptomics, and its extension—epitranscriptomics—on personalized and precision medicine efforts. There has been an explosion of transcriptomic studies particularly in the last decade, along with a growing number of recent epitranscriptomic studies in several disease areas. Here, we summarize and overview major efforts for cancer, cardiovascular disease, and neurodevelopmental disorders (including autism spectrum disorder and intellectual disability) for transcriptomics/epitranscriptomics in precision and personalized medicine. We show that leading advances are being made in both diagnostics, and in investigative and landscaping disease pathophysiological studies. As transcriptomics/epitranscriptomics screens become more widespread, it is certain that they will yield vital and transformative precision and personalized medicine contributions in ways that will significantly further genomics gains.
... The genes regulated by these miRNAs have all been predicted to be directly or indirectly involved in the pathophysiology of ASD and its associated comorbidities. Age-dependent alterations in miRNA expression levels have also been observed in patients with ASD (Stamova et al. 2015); this could explain the lack of a coherent trend in previous studies. ...
... Altered pre-miRNA and miRNA expression levels have also been also detected in the superior temporal sulcus (miR-4753-5p and miR-1) and in the primary auditory cortex (miR-664-3p, miR-4709-3p, miR-4742-3p and miR-297) of patients withASD (Ander et al. 2015). The target genes of these miRNAs have been reported to be functionally involved in the cell cycle, various neural processes, immune pathways, and canonical signaling pathways such as the PI3K-Akt signaling pathway, all of which have been associated with the development of ASD(Ander et al. 2015). ...
Neurodevelopmental disorders are defined as a set of abnormal brain developmental conditions marked by the early childhood onset of cognitive, behavioral, and functional deficits leading to memory and learning problems, emotional instability, and impulsivity. Autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, fragile X syndrome, and Down’s syndrome are a few known examples of neurodevelopmental disorders. Although they are relatively common in both developed and developing countries, very little is currently known about their underlying molecular mechanisms. Both genetic and environmental factors are known to increase the risk of neurodevelopmental disorders. Current diagnostic and screening tests for neurodevelopmental disorders are not reliable; hence, individuals with neurodevelopmental disorders are often diagnosed in the later stages. This negatively affects their prognosis and quality of life, prompting the need for a better diagnostic biomarker. Recent studies on microRNAs and their altered regulation in diseases have shed some light on the possible role they could play in the development of the central nervous system. This review attempts to elucidate our current understanding of the role that microRNAs play in neurodevelopmental disorders with the hope of utilizing them as potential biomarkers in the future.
... Moreover, several studies evidenced that short non-coding RNAs, such as microRNAs, are differentially expressed in brain tissue [40] as well as in the periphery (i.e., serum/plasma, saliva) [41,42] of ASD patients compared to typically developing controls. ...
... Non-coding RNAs, such as microRNAs, represent a further epigenetic mechanism. They resulted in being differentially expressed in brain tissue [40] and in the periphery (i.e., serum/plasma, saliva) [41] in ASD subjects compared to controls. Notably, most differences in ASD patients involved immune response and protein synthesis regulation [99]. ...
The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called ‘First 1000 Days’) are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.
... Moreover, several studies evidenced that short non-coding RNAs, such as microRNAs, are differentially expressed in brain tissue [40] as well as in the periphery (i.e., serum/plasma, saliva) [41,42] of ASD patients compared to typically developing controls. ...
... Non-coding RNAs, such as microRNAs, represent a further epigenetic mechanism. They resulted in being differentially expressed in brain tissue [40] and in the periphery (i.e., serum/plasma, saliva) [41] in ASD subjects compared to controls. Notably, most differences in ASD patients involved immune response and protein synthesis regulation [99]. ...
The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called 'First 1000 Days') are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach
... These pathways are shown to be involved in the transmission of signals to and from the PAG [91]. Furthermore, estrogen signaling pathway, oocyte meiosis pathway, and prolactin signaling pathway miR-34c − AD [75], PD [76] miR-489 − ASD [77], Sc [72] miR-320 − ASD [78], S [61] miR-27b-3p − S [79], AD [80], MS [60], Sc [72] miR-181a − Sc [72] miR-181b − S [81], Sc [72] miR-30e-5p − MS [60] miR-30a-5p − MS [60], Sc [71] miR-28-3p − Sc [72] miR-30b-5p − MS [82], Sc [71] miR-185 − PD [83], MD [84] miR-150 − S [85], Sc [72] miR-191 − AD [86] miR-124a + S [61] miR-128 + Sc [72] miR-126-3p + S [61] miR-92a + Sc [71] miR-99a-5p + S [61], Sc [72] let-7i-5p + S [61] miR-138 + S c [72] miR-148a-3p + MS [60], S [61] miR-219b-3p + S [61] Sc schizophrenia, AD Alzheimer's disease, PD Parkinson's disease, ASD autism spectrum disorders, MS multiple sclerosis, S stroke, MD major depression (Fig. 4, Table 1) were statistically significantly overrepresented by the identified DE miRNAs. The enrichment of these pathways is not surprising having taken into consideration the investigated influence of miRNA-related sex differences on biological processes. ...
Background
MicroRNAs indirectly orchestrate myriads of essential biological processes. A wide diversity of miRNAs of the neurodevelopmental importance characterizes the brain tissue, which, however, exhibits region-specific miRNA profile differences. One of the most conservative regions of the brain is periaqueductal grey (PAG) playing vital roles in significant functions of this organ, also those observed to be sex-influenced. The domestic pig is an important livestock species but is also believed to be an excellent human model. This is of particular importance for neurological research because of the similarity of pig and human brains as well as difficult access to human samples. However, the pig PAG profile has not been characterized so far. Moreover, molecular bases of sex differences connected with brain functioning, including miRNA expression profiles, have not been fully deciphered yet.
Methods
Thus, in this study, we applied next-generation sequencing to characterize pig PAG expressed microRNAs. Furthermore, we performed differential expression analysis between females and males to identify changes of the miRNA profile and reveal candidates underlying sex-related differences.
Results
As a result, known brain-enriched, and new miRNAs which will expand the available profile, were identified. The downstream analysis revealed 38 miRNAs being differentially expressed (DE) between female and male samples. Subsequent pathway analysis showed that they enrich processes vital for neuron growth and functioning, such as long-term depression and axon guidance. Among the identified sex-influenced miRNAs were also those associated with the PAG physiology and diseases related to this region.
Conclusions
The obtained results broaden the knowledge on the porcine PAG miRNAome, along with its dynamism reflected in different isomiR signatures. Moreover, they indicate possible mechanisms associated with sex-influenced differences mediated via miRNAs in the PAG functioning. They also provide candidate miRNAs for further research concerning, i.e., sex-related bases of physiological and pathological processes occurring in the nervous system.
Graphical abstract
... Several studies have attempted to perform miRNA profiling in ASD patients in a range of tissues such as post mortem brain regions [45][46][47][48], peripheral blood [49], blood serum [50], lymphoblastoid cell lines [51][52][53], olfactory mucosal stem cells and primary skin fibroblasts [54]. There are a total of 156 unique miRNAs reported in these studies to be either upregulated or downregulated in ASD patients compared to healthy controls. ...
... Even among these overlapping miRNAs, only 12 were reported to be deregulated in the same direction. Whereas eight of these 26 miRNAs were reported to change within the ASD cohort and control cohort with age [47], six were expressed at either low levels or undetectable in the dorsal frontal cortex of healthy human brains [55]. Another study using microarray profiling in a small group of Chinese patients with autism showed that a total of 77 miRNAs were differentially regulated compared to healthy controls. ...
Neuropsychiatric disorders, including autism spectrum disorders (ASD) and anxiety disorders are characterized by a complex range of symptoms, including social behaviour and cognitive deficits, depression and repetitive behaviours. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their aetiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as a new gene regulatory layer in the pathophysiology of mental illness. These small RNAs can bind to the 3′-UTR of mRNA thereby negatively regulating gene expression at the post-transcriptional level. Their ability to regulate hundreds of target mRNAs simultaneously predestines them to control the activity of entire cellular pathways, with obvious implications for the regulation of complex processes such as animal behaviour. There is growing evidence to suggest that numerous miRNAs are dysregulated in pathophysiology of neuropsychiatric disorders, and there is strong genetic support for the association of miRNA genes and their targets with several of these conditions. This review attempts to cover the most relevant microRNAs for which an important contribution to the control of social and anxiety-related behaviour has been demonstrated by functional studies in animal models. In addition, it provides an overview of recent expression profiling and genetic association studies in human patient-derived samples in an attempt to highlight the most promising candidates for biomarker discovery and therapeutic intervention.
... Stamova et al. collected 28 samples of STS and PAC, including 12 typical developing brain (TYP) control samples (six STS and six PAC), and 16 ASD samples (eight STS and eight PAC) [127]. Stamova et al. studied the correlation between the miRNAs of TYP samples and their ages and found that 18 and 27 dysregulated miRNAs in TYP_STS and TYP_PAC were associated with the ages of the individuals, respectively. ...
... Meanwhile, in the study of the correlation between miRNAs and the ages of ASD samples, they found that four and two dysregulated miRNAs in ASD_STS and ASD_PAC were associated with age, respectively. Among the four dysregulated miRNAs in ASD_STS, miR-1260b was positively correlated with age, while miR-424-3p, miR-484, and miR-3916 were negatively correlated with age [127]. The two dysregulated miRNAs in ASD_PAC, i.e., miR-93-3p and miR-3607-5p, were negatively correlated with age [127]. ...
... Among the four dysregulated miRNAs in ASD_STS, miR-1260b was positively correlated with age, while miR-424-3p, miR-484, and miR-3916 were negatively correlated with age [127]. The two dysregulated miRNAs in ASD_PAC, i.e., miR-93-3p and miR-3607-5p, were negatively correlated with age [127]. This research indicates that the numbers of miRNAs with dynamic expression during developmental procedures significantly decreased compared to normal controls, suggesting that the changes in miRNAs in the STS in ASD were related to social impairment, which may contribute to the molecular pathogenic mechanism of ASD [127]. ...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathogenesis is unclear and is affected by both genetic and environmental factors. The microRNAs (miRNAs) are a kind of single-stranded non-coding RNA with 20-22 nucleotides, which normally inhibit their target mRNAs at a post-transcriptional level. miRNAs are involved in almost all biological processes and are closely related to ASD and many other diseases. In this review, we summarize relevant miRNAs in ASD, and analyze dysregulated miRNAs in brain tissues and body fluids of ASD patients, which may contribute to the pathogenesis and diagnosis of ASD.
