Epitranscriptomic modifications in embryonic development: insights into natural and ART-induced mechanisms and implications.

Similar to epigenetic DNA and histone modifications, epitranscriptomic modifications (RNA modifications) have emerged as crucial regulators in temporal and spatial gene expression during eukaryotic development. To date, over 170 diverse types of chemical modifications have been identified upon RNA nucleobases. Some of these post-synthesized modifications can be reversibly installed, removed, and decoded by their specific cellular components and play critical roles in different biological processes. Accordingly, dysregulation of RNA modification effectors is tightly orchestrated with developmental processes. Here, we particularly focus on three well-studied RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N1-methyladenosine (m1A), and summarize recent knowledge of underlying mechanisms and critical roles of these RNA modifications in stem cell fate determination, embryonic development, and cancer progression, providing a better understanding of the whole association between epitranscriptomic regulation and mammalian development.

N6-methyladenosine (m6A) RNA modification is a conserved mechanism to regulate gene expression that plays vital roles in the development of plants. However, the m6A RNA modification in forest trees remains limited. Here, we performed a complete analysis of m6A writers, erasers and readers in Poplar 84K, including gene location, gene structures, conserved motifs, phylogenetic relationships, promoter analysis, expression profiles and the homology modeling. We have identified 61 m6A pathway genes in Poplar 84K (Populus alba × Populus glandulosa), including 14 m6A writers, 14 m6A erasers and 33 m6A readers. Phylogenetic analysis indicated that the m6A writers and erasers were clustered into four groups and m6A readers were clustered into two groups. Promoter analysis showed that m6A pathway genes were mainly responsive to low oxygen followed by ABA and ethylene. The expression of the identified m6A pathway genes showed tissue-specific expression patterns in leaves, xylem, phloem and roots. Moreover, 17 genes were significantly up-regulated and 13 genes were significantly down-regulated in poplar overexpressing the transcription factor LBD15. Homology modeling and molecular docking results suggested that PagFIP37b was most likely to be regulated by LBD15, and the qPCRshowed that PagFIP37b were up-regulated in the LBD15-oe plants. The results provide insights that aid in the future elucidation of the functions of these m6A pathway genes and the epigenetic regulation mechanism of these genes in Poplar 84K.

Delineating the Role of Interplay between m6A Machinery Genes and IGF2BP Group of RNA-Binding Proteins in B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Among several known RNA modifications, N6-methyladenosine (m6A) is the most studied RNA epitranscriptomic modification and controls multiple cellular functions during development, differentiation, and disease. Current research advancements have made it possible to examine the regulatory mechanisms associated with RNA methylation and reveal its functional consequences in the pathobiology of many diseases, including heart failure. m6A methylation has been described both on coding (mRNA) and non-coding RNA species including rRNA, tRNA, small nuclear RNA and circular RNAs. The protein components which catalyze the m6A methylation are termed methyltransferase or 'm6A writers'. The family of proteins that recognize this methylation are termed 'm6A readers' and finally the enzymes involved in the removal of a methyl group from RNA are known as demethylases or 'm6A erasers'. At the cellular level, different components of methylation machinery are tightly regulated by many factors to maintain the m6A methylation dynamics. The m6A methylation process impacts different stages of mRNA metabolism and the biogenesis of long non-coding RNA and miRNA. Although, mRNA methylation was initially described in the 1970s, its regulatory roles in various diseases, including cardiovascular diseases are broadly unexplored. Recent investigations suggest the important role of m6A mRNA methylation in both hypertrophic and ischaemic heart diseases. In the present review, we evaluate the significance of m6A methylation in the cardiovascular system, in cardiac homeostasis and disease, all of which may help to improve therapeutic intervention for the treatment of heart failure. RNA methylation in cardiovascular diseases: altered m6A RNA (coding and non-coding RNA) methylation is identified during different cardiovascular diseases. Increased cardiac hypertrophy is observed following METTL3 overexpression. In contrast, reduced FTO level was seen in mice following myocardial infarction. Increased cardiac fibroblasts activation or increased atherosclerotic plaques were also co-related with m6A RNA methylation.

N6-methyladenosine (m6A) RNA modification is the most prevalent form of RNA methylation and plays a crucial role in plant development. However, our understanding of m6A modification in Masson pine (Pinus massoniana Lamb.) remains limited. In this study, a complete analysis of m6A writers, erasers, and readers in Masson pine was performed, and 22 m6A regulatory genes were identified in total, including 7 m6A writers, 7 m6A erases, and 8 readers. Phylogenetic analysis revealed that all m6A regulators involved in Masson pine could be classified into three distinct groups based on their domains and motifs. The tissue expression analysis revealed that the m6A regulatory gene may exert a significant influence on the development of reproductive organs and leaves in Masson pine. Moreover, the results from stress and hormone expression analysis indicated that the m6A regulatory gene in Masson pine might be involved in drought stress response, ABA-signaling-pathway activation, as well as resistance to Monochamus alternatus. This study provided valuable and anticipated insights into the regulatory genes of m6A modification and their potential epigenetic regulatory mechanisms in Masson pine.

Emerging roles of biological m6A proteins in regulating virus infection: A review

N6-methyladenosine (m6A) is one of the most prevalent internal reversible chemical modification of RNAs in eukaryotes, which has attracted widespread attention recently owing to its regulatory roles in a plethora of normal developmental processes and human diseases like cancer. Deposition of the m6A mark on RNAs is mediated by the dynamic interplay between m6A regulatory proteins such as m6A RNA methyltransferases (m6A writers), m6A RNA demethylases (m6A erasers) and m6A RNA binding proteins (m6A readers). m6A regulators are ectopically expressed in various cancer types, often leading to aberrant expression of tumor-suppressor and oncogenic mRNAs either directly or indirectly via regulating the biogenesis of non-coding RNAs like miRNAs. miRNAs are tiny regulators of gene expression, which often impact various hallmarks of cancer and thus influence tumorigenesis. It is becoming increasingly clear that m6A RNA modification impacts biogenesis and function of miRNAs, and recent studies have interestingly, uncovered many miRNAs whose biogenesis and function are regulated by m6A writers, erasers and readers. In this review, we discuss various mechanisms by which m6A RNA methylation regulates miRNA biogenesis, the functional crosstalk between m6A RNA methylation and miRNAs and how it modulates various aspects of tumorigenesis. The potential of m6A RNA methylation regulated miRNAs as biomarkers and novel therapeutic targets to treat various cancers is also addressed.

UPF1 promotes rapid degradation of m6A-containing RNAs

Congenital malformations after assisted reproduction: risks and implications for prenatal diagnosis and fetal medicine

During early mammalian embryo development, different epigenetic marks undergo reprogramming and play crucial roles in the mediation of gene expression. Currently, several databases provide multi-omics information on early embryos. However, how interconnected epigenetic markers function together to coordinate the expression of the genetic code in a spatiotemporal manner remains difficult to analyze, markedly limiting scientific and clinical research. Here, we present dbEmbryo, an integrated and interactive multi-omics database for human and mouse early embryos. dbEmbryo integrates data on gene expression, DNA methylation, histone modifications, chromatin accessibility, and higher-order chromatin structure profiles for human and mouse early embryos. It incorporates customized analysis tools, such as “multi-omics visualization,” “Gene&Peak annotation,” “ZGA gene cluster,” “cis-regulation,” “synergistic regulation,” “promoter signal enrichment,” and “3D genome.” Users can retrieve gene expression and epigenetic profile patterns to analyze synergistic changes across different early embryo developmental stages. We showed the uniqueness of dbEmbryo among extant databases containing data on early embryo development and provided an overview. Using dbEmbryo, we obtained a phase-separated model of transcriptional control during early embryo development. dbEmbryo offers web-based analytical tools and a comprehensive resource for biologists and clinicians to decipher molecular regulatory mechanisms of human and mouse early embryo development.

N6-methyladenosine (m6A) RNA modification is the most prevalent type of RNA methylation and plays a pivotal role in the development of plants. However, knowledge of the m6A modification in litchi remains limited. In this study, a complete analysis of m6A writers, erasers, and readers in litchi was performed and 31 litchi m6A regulatory genes were identified in total, including 7 m6A writers, 12 m6A erases, and 12 readers. Phylogeny analysis showed that all three of the kinds of litchi m6A regulatory proteins could be divided into three groups; domains and motifs exhibited similar patterns in the same group. MiRNA target site prediction showed that 77 miRNA target sites were located in 25 (80.6%) litchi m6A regulatory genes. Cis-elements analysis exhibited that litchi m6A regulatory genes were mainly responsive to light and plant hormones, followed by environmental stress and plant development. Expression analysis revealed litchi m6A regulatory genes might play an important role during the peel coloration and fruit abscission of litchi. This study provided valuable and expectable information of litchi m6A regulatory genes and their potential epigenetic regulation mechanism in litchi.

N6-methyladenosine (m6A) is the most abundant internal modification present in Eukaryotic mRNA. The functions of this chemical modification are mediated by m6A-binding proteins (m6A readers) and regulated by methyltransferases (m6A writers) and demethylases (m6A erasers), which together are proposed to be responsible of a new layer of post-transcriptional control of gene expression. Despite the presence of m6A in a retroviral genome was reported more than 40 years ago, the recent development of sequencing-based technologies allowing the mapping of m6A in a transcriptome-wide manner made it possible to identify the topology and dynamics of m6A during replication of HIV-1 as well as other viruses. As such, three independent groups recently reported the presence of m6A along the HIV-1 genomic RNA (gRNA) and described the impact of cellular m6A writers, erasers and readers on different steps of viral RNA metabolism and replication. Interestingly, while two groups reported a positive role of m6A at different steps of viral gene expression it was also proposed that the presence of m6A within the gRNA reduces viral infectivity by inducing the early degradation of the incoming viral genome. This review summarizes the recent advances in this emerging field and discusses the relevance of m6A during HIV-1 replication.

Regulation of assisted reproductive technologies in the United States

A Positive Feedback Loop between YTHDC1 and EP300 Drives Tumorigenesis in Multiple Myeloma

Citrus grandis “Tomentosa” (“Huajuhong”) is a famous traditional Chinese medicine. The aim of the present study is to provide a comprehensive characterization of the m6A regulatory genes from C. grandis, and examine their expression patterns in fruits of C. grandis “Tomentosa” during various developmental stages. A total of 26 N6-methyladenosine (m6A) regulatory proteins were identified from the genome of C. grandis, which were distributed across nine chromosomes in C. grandis. Phylogenetic relationships revealed that all m6A regulatory genes were divided into groups of m6A writers, erasers, and readers. The m6A writer groups included CgMTA, CgMTB, and CgMTC three MTs (methyltransferases), one CgVIR (virilizer), one CgHAKAI (E3 ubiquitin ligase HAKAI), and one CgFIP37 (FKBP interacting protein 37). Moreover, 10 CgALKBH (α-ketoglutarate-dependent dioxygenase homolog) members (numbered from CgALKBH1 to CgALKBH10) and 10 CgECT (C-terminal region) members (numbered from CgECT1 to CgECT10) in C. grandis were identified as m6A erasers and readers, respectively. The domain structures and motif architectures among the groups of m6A writers, erasers, and readers were diverse. Cis-acting elements in the promoters of the 26 m6A regulatory genes predicted that the abscisic acid-responsive (ABA) element (ABRE) was present on the promoters of 19 genes. In addition, the expression profiles of all m6A regulatory genes were examined in the fruits of two varieties of C. grandis “Tomentosa” during different growth stages to give basic hints for further investigation of the function of the N6-methyladenosine regulatory genes in C. grandis “Tomentosa”.