Current Genomics

As the biology and medical science are developing, we are realizing cell heterogeneity makes pathophysiology mechanism very comprehensive. For instance, tumor cell heterogeneity is an obstacle for the treatment of the diseases. The solid organs are composed of millions of cells in which there are many different cell types. Thanks to the rapidly developing high-throughput sequencing technology, every single cell genomics in one experiment can be observed. The single cell sequencing era is coming. Now we can capture and analyze the difference among cells and the interaction between cells and microenvironments. Although there are many high impact studies published using single cell sequencing, this method is still an emerging technology. Many problems need to be solved, for instance, different methods have different sequencing depths and the question arises how to choose a suitable method for our experiment should be considered before the start. In this issue, we want to systemically introduce the single cell sequencing and review recent advances in this field. I believe this special issue will provide valuable inspirations for the readers. The first letter article Discrepant mRNA and Protein Expression in Immune Cells by Li et al. [1] demonstrated an interesting and important phenomenon in immune research using single cell RNA sequencing (scRNA-seq). The disconnect between the levels of mRNA and surface protein expression has confused many researchers. In this study, the authors suggested that scRNA-seq should be combined with other sequencing methods in single-cell studies (e.g., CITE-seq) in certain circumstances. The first review entitled Single-cell RNA Sequencing in Immunology by Cao et al. [2] systemically introduced the history, development, methodology of scRNA-seq and its application in immunology. The advantages of single-cell sequencing include (1) accuracy and sensitivity over traditional methods, and the ability to accurately analyze gene expression in each cell; (2) detection of the transcriptomics of rare cells or newly found cells without known markers; (3) ability to analyze and interpret the intercellular relationship in the microenvironment; and (4) ability to distinguish and compare among cell populations objectively. This review summarized the mainstream applications of single cell sequencing, for instance, cell anatomy, redefining cellular markers and so on. The next two reviews introduced recent advances of single cell sequencing in stem cell research and cardiovascular diseases. In Single-cell Sequencing in the Field of Stem Cells, Chen et al. [3] introduced new discoveries of single cell sequencing in pluripotent stem cells, tissue-specific stem cells and cancer stem cells. Variation and heterogeneity between cells are the basic characteristics of stem cells. This review might help readers to understand the importance of investigating stem cells as different individuals. The cardiac system is a combination of a complex structure, various cells, and versatile specified functions and sophisticated regulatory mechanisms. The review entitled Single-cell RNA Sequencing: In-depth Decoding of Heart Biology and Cardiovascular Diseases by Dr. Chen [4] reviewed recent advances in single cell studies of cardiovascular system and summarized new insights provided by scRNA-seq in heart developmental sciences, stem-cell researches as well as normal or disease-related mechanisms. In the last article of this issue, Gao et al. [5] compared two mainstream scRNA-seq platforms in the review The Comparison of Two Single-cell Sequencing Platforms: BD Rhapsody and 10x Genomics Chromium. Although these two platforms follow a similar basic strategy, there are still some differences between them in terms of mechanisms, operations and output results from same experiments. In most labs, it is not practical to choose both platforms. Therefore, we have to be familiar with their similarities and differences. I think this review is able to provide valuable information. I believe all the articles and reviews in this issue will attract your attention and give you inspiration for your further research.

The last part of the thematic issue consists of two review and two research articles. Some of the articles, with important insights into genomics approaches to understand plant-microbe interactions, have already been published in the first three parts of the issue [1-3]. The issue starts with the article by Pagano et al., which presented a review on the genomic tools that are being used for the enhancement in the production of soybean [4]. Going through this article would lead researchers to know in detail about the soybean production, in general, as well as the cutting-edge approaches such as gene-editing technology that has the potential to reveal more insight into the right modification of soil microbes, rhizobial genomes, and soybean microbiome. The authors extensively discussed the Nitrogen fixation, genome research, microbial associations, rhizobial inoculants and microbial genomic research in soybean. Baruah and co-authors presented an article to provide understanding about the role of promoters of genes, which are known to be pathogen-sensitive during plant defense mechanisms [5]. This article goes deep into the conceptual analysis of key motifs and promoter elements in the genes obtained from the TransGene promoter database. The titles and abstracts of the published articles for the genes were collected, and text mining was performed by the authors to provide frequent keywords in the form of the word cloud. With the help of Plant CARE, the promoter elements were identified and presented in the form of a chord diagram containing connections between the promoters and respective elements. The article suggests various important and frequently connected factors that influence the pathogen-induced promoters in the plant defense. WRKY and GT-1 are the most significant transcription factors found along with cis-acting elements ABRE, MYC and MYB and also the elements such as Wbox, Gbox, WUN motif, and TC-rich repeats. Ratnaparkhe and co-authors performed a whole-genome sequencing and comparative analysis to provide better insight into the development of rust-resistant soybean cultivars [6]. The study aimed at the identification of genomic variations between the rust-resistant lineEC241780 and susceptible cultivar JS-335. A whole-genome pair-end re-sequencing using Illumina HiSeq2500 platform was carried out on the genomic DNA of soybean genotype EC241780 leaf samples. Following the sequencing, the read was mapped; SNPs, as well as InDels, were identified and annotated. The authors also performed the haplotype analysis using Glycine max accessions and identified a rust resistance locus. The authors briefly discussed the Rpp (Resistance to P. pachyrhizi) genes that play a vital role in plant-microbe interaction. Comparative analysis identified three genes encoding for NBS-LRR family protein, which are Glyma18G51715, Glyma18G51741 and Glyma18G51765 and the most prominent candidate for Rpp1 locus. Kangabam and co-authors did a metagenome analysis on soil samples collected during post-monsoon and winter season with the objective to present a seasonal profile of the Loktak Lake that had undergone different anthropogenic impacts [7]. The authors provided a well-description of the sampling sites with information such as ecosystems and keystone taxa in the form of a table. The MISEQ library was prepared, followed by sequencing, cluster generation and analysis of metagenomic data. Summary of measured environmental variables such as pH, temperature, salinity, etc. has been provided with their mean and standard deviations across the post-monsoon and winter season. Co-occurrence microbial interaction sub-networks have also been constructed to find that the network density and heterogeneity alter across the season. It also indicated that temperature among all the variables was the maximum number of Operational Taxonomic Units connections both in the case of monsoon and winter data. Bringing all the variables together provided a great understanding of the seasonal profile of microbial communities across different land uses patterns in Loktak Lake, which will help in biodiversity markers for improving the aquatic ecosystem.

This part brings three interesting articles which are very unique and enlightening reviews on important areas of plantmicrobe interaction. The parts I and II have been able to present extensive insights into plant-microbe interactions in various fields which is in continuation in this part too [1, 2]. This part puts light on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 (CRISPR-associated protein 9) Era plant-microbe interaction, translational research on Fusarium Head Blight (FHB) in Wheat and plant-virus interaction with reference to viral effector proteins. Beginning with the article by Prabhukarthikeyan and co-authors, it presents the emerging CRISPR/Cas9 approach which has gained immense attention in the last few years [3]. The authors here have started with a brief introduction about the plantmicrobe interactions and the CRISPR/Cas9 technique and continued with descriptive but precise mention of the use of this technique for resistance against fungal, bacterial and viral disease. Apart from these, the use of CRISPR/Cas9 technique in case of beneficial microbes and phytopathogens is also discussed. Collections of information from earlier studies have been collated into a table to highlight the target genes. The table mentioned very important genes such as WRKY, eIF4E, etc. which are wellknown to be the regulators of many important signaling pathways in various crops. The authors have pointed the fact that despite this powerful technique in our hands for a time, it has only been extensively used in validating the previously identified genes/pathways and still need to be employed in the successful development of durable resistance in crops against multiple pathogens. Teli et al. discuss a major threat to most cereal crops such as wheat and barley, commonly known as Fusarium head blight or scab [4]. The pathogenic strains of Fusarium are generally devastating for the host plants due to their adaptability and multifaceted nature [5]. History of FHB has documented evidences of most threatening epidemics during the years 1917, 1919, 1928, 1932, and 1935 in the United States [6]. The authors have provided a comprehensive delineation on FHB along with its symptoms, complexity and survivability. There are figures to illustrate the predominance of FHB associated pathogens worldwide, biochemical foundation of host-pathogen interaction in FHB and cutting-edge techniques such as RNA interference (RNAi) and CRISPR to remodel the host defence. There are two tables presenting the information regarding the RNA and CRISPR interference mediated defense against FHB. Extensive description about various strategies such as the conventional breeding, molecular marker, transgenic and non-transgenic genome engineering approaches has been well-documented in this article to offer insights into host-pathogen interaction in FHB. The third article by Marwal and Gaur describes specifically the plant-virus interactions and viral effector proteins [7]. Plant defense machinery is very difficult to understand as it behaves differently depending upon the type of pathogen attack. It is even more critical in case of virus infection as all viruses infecting plants can augment their transmission leading to damaging the host plants. The authors have provided a schematic illustration of R gene mediated resistance in plants, signaling molecule induction, plant antiviral pathways and viral counter-defenses as well as virus effector proteins in plant resistance development. Detailed understanding of R-Avr interactions and mode of their actions can lead to unravel the mystery of plant-virus interactions and this article aimed for providing available information in a brief and precise way to help broaden our knowledge in this regard.

In continuation with part I, this part describes the use of genetically modified microbes, rhizospheric microbial communities, various molecular techniques and omics approaches to shed the light on understanding plant-microbe interactions [1]. Due to the long ongoing controversies regarding the use of application of genetically engineered microbial inoculants in the field, it has been a hot topic since the last two decades. The authors have been able to provide descriptive information regarding the same with special application towards plant-microbe interactions. A bright study carried out with the help of omics technologies, especially bioinformatics approaches to understand the microbial communities in coal samples. Sudheer and co-authors presented a mini-review on engineered microbes and their applications in sustainable agriculture [2]. Authors emphasized especially on methods to shape the rhizosphere zone, which can ultimately promote the beneficial microbial population in the soil. Microbial communities in the soil can be diverse and a deeper understanding of their nature can help plants to provide enhanced stress tolerance, disease resistance, nutrient acquisition and also many other important factors. There are various efficient genetic engineering/molecular techniques which are available and being used to attain better plant health and yield. The authors provided a simpler version of understanding plant-microbe interaction and how the networks work in the soil. Also mentioned briefly about the microbial inoculants and their function as biofertilizers, biocontrol agents, and in biotic and abiotic stress tolerance. Though the application of genetically engineered microbial inoculants in the field is still not approved fully, the potential of these cannot be denied. Upon more research and better as well as safe practices, these can be used as huge assets to achieve sustainable agriculture. In addition, a review is presented on genomics approaches to provide insights into the role of rhizospheric microbial communities in plant-microbe synergy for enhanced phytoremediation [3]. This review aims at drawing an understanding of genetic approach integrated with bioremediation of contaminated sites. Authors have described extensively on phytoremediation and the role of predominant rhizospheric microbial communities in it. In the later part, the application of genetically modified plants and microbes for phytoremediation has been described. The cutting-edge genomic approaches such as CRISPR (clustered regularly interspaced short palindromic repeats) technology was illustrated in plant-microbe synergy. Authors also presented a table containing various plants, microbes, target pollutants and their enhanced effect on phytoremediation. Another review by Sharma and co-authors provided insights into overall omics technologies for plant-microbe interaction [4]. The review tries to bring together important aspects such as plant growth promotion, nitrogen fixation, stress suppressions and metabolic interactions along with the recent studies on various advanced omics approaches. The basics of various types of plant-microbe interactions have been stated briefly with a vivid description of various molecular techniques. It continues with an extensive discussion of applications of next generation sequencing techniques and meta-omics approaches in unravelling plant-microbe interaction understandings. The authors also discussed the research gaps and future prospects of omics approaches with respect to plant-microbe interaction studies. Jha and team carried out bioinformatics analyses of the metagenomic data obtained from the West Jharia coal seam, Moonidih, Jharkhand [5]. Pyrosequencing was performed on DNA extracted from the coal samples following by bioinformatics analyses which are taxonomic assignment and functional analysis. The upshot of the study helped in revealing important information regarding biodiversity such as the dominance of hyperthermophilic archaea Pyrococcus furiosus along with Thermococcus kodakarensis present in the underground coal mines of Jharia. The results also revealed the presence of dissimilatory sulfite reductase and formylmethanofuran dehydrogenase enzymes involved in sulfite reduction and methanogenesis processes respectively. Much information about real efficiency of coal degrading microbes is still hidden. The study has been able to provide preliminary as well as extensive insight into meta-genomic information such as taxonomic and functional diversity of the microbial communities in coal mines.

In the present scenario, increasing pollution and green house effect on climate are serious concerns that lead to extreme environment conditions. Therefore, the major aim of scientist is to resolve environmental issues in an economic and sustainable way. To deal with extreme conditions, extremophiles are safer option for scientist or industries. In industries, most of possesses are completed in extreme environment like temperature, pH, pressure etc. However, the majority of enzymes used in industrial process are derived from mesophilic microbes, few are from extremophiles. The mesophilic enzymes are unable to perform at extreme conditions in industrial processes [1]. Thus, the need of extrmophilic enzymes is increasing globally to meet out the industrial requirements. In addition, industrial processes are also performed with chemical compounds or enzymes, which are very cost effective and harmful. In this context, extremophilic microbes can be used directly as a cell or enzymes (extremozymes) to carry out chemical reaction in an eco-friendly manner [2]. Extremophiles are used in food, pharmaceutical, textile, beverages and agricultural industries. Extremophilic microbes possess different types of enzymes and metabolites, which can work on harsh condition and make them perfect for the industrial purposes. These microbes are used at different physical conditions i.e. elevated level of extreme temperature, pH, heavy metal contamination, organic solvents etc [3]. We can improve the efficiency of extremophiles by using modern technologies such as genetic engineering and protein engineering. The demand of extremophilic products is very large in global market. The fulfilling of this demand requires recombinant technology for large scale production and also purification [3]. However, there is still need to explore multiple extremophilic microbes that can be used for society. In continuation to first part of this special issue, this part describes different extremophilic microbes and their role in biofuel production, industrial dye degradation and abiotic stress tolerance. Topic is also included on metagenomic analysis of plastic degrading bacteria. In this sense, a review article by Fongaro et al. [4] described the importance of muiti-omics tools including (genomics, transcriptomics, proteiomics and metabolomics) in exploitation of extremophile microorganism and their novel metabolites for bioenergitic application. Authors discussed about different types of extremozymes including, thermophilic, psychrophilic, piezophilic, acidophilic and halophilic in details. In another review, Purohit et al. [5] documented about metagenomic approach for exploration of microbial population involved in plastic biodegradation. Metagenomic approach helps in harnessing predominant uncultured microbial species and also opens up the scope for mining genes or enzymes (hydrolases, laccase, etc.) engaged in polymer or plastic degradation. The comparative metagenomic study allows us to engineer microbial community to speed up the degradation process. Authors have targeted different metagenomic approach based on 16S V2-V6 regions for identifying plastic degrading microbes from different habitat. In a research article, Ghosh et al. [6], studied the diversity of the psychrotolerant actinomycetes sp. nov., in the Bay of Bengal and recovered cold active industrial and pharmaceutical biomolecules. In this study, authors have isolated cold-adapted actinomycetes from 1200 mts below the surface in Bay-of-Bengal. A total number of 37 novel actinomycetes from 17 distinct groups were characterized on the basis of phenotypic and genotypic level. The major dominant group was Streptomyces. The optimum growth of isolated strains was observed at 15°C to 20°C and also able to survive at 4°C. All the recovered isolates were able to produce extracellular enzymes including amylase, cellulase, lipase, pectinase, and L-asparaginase and also showed antagonistic activity. In another study, Mawad et al. [7] have applied microbial consortium including Pseudomoans aeruginosa and Aspergillus flavus for the degradation of Disperse Blue 64 (DB 64) and Acid Yellow 17 (AY 17) dyes. The consortium was able to possess higher ability to degrade dye even at 300mg/L as compared to individual one. This microbial consortium and their derived metabolites were also able to promote Vicia faba and Triticum vulgaris germination and health of seedlings in in-vitro assay. Chatterjee et al. [8] studied the abiotic stress tolerance mechanism of Cyanobacteria through Alr0765 protein study of Anabaena PCC7120. Alr0765 is a novel CBS-CP12 domain protein that has function to provide protection against stress through involving cellular energy mechanism and iron homeostasis. The gene expression of Alr0765 was found to increase in Anabaena PCC7120 treated under heat, arsenic, cadmium, butachlor, salt, mannitol (drought), UV-B, and methyl viologen stresses. Further study with FTIR confirmed the binding of Alr0765 with ATP, ADP, AMP and NADH. The same protein was also able to accumulate iron in E. coli cells upon heterologous expression. The ROS content and total cellular H2O2 content was reduced when Alr0765 was expressed.

For the last few decades, the constant striving to understand the mechanism of plant-microbe interaction has increased manifold, even though a lot of inaccessible information is yet to unfold. Ingress into such covered information can be a notable aid for mankind, particularly by helping plants fight against pathogens and other stresses. Crops are continuously exposed to many stresses, which may be abiotic or/and biotic. At times the interactivity of microbes with plants assists plants to stand against various environmental stresses; on the contrary, sometimes they act as stresses for plants. Plants are always at higher risks as most of the microbes interact with the plants to feed or to survive [1, 2]. There is an extensive range of beneficial microorganisms which play vital role in plant growth, development and survival [3]. These are most often known as agriculturally important microbes which not only help plants to get proper nutrients but also regulate the plant and other microbe interactions. Knowing the nature of microbe and its connection with particular plants be useful to control diseases in plants. There are several mechanisms for plant-microbe interactions which vary from plant to plant and microbe to microbe as well [4]. The interaction can materialize in any part of the plants, may it be underground or above the soil. It can also be both endophytic and epiphytic, depending on the microbes. In addition to these two major participants, it also relies on the environment neighboring the area where the interaction occurs. Zooming into the high definition resolution of the genomic arrangements with the help of emerging and advanced techniques in the post-genomics era has been of primary focus. Comparative genomics studies have successfully revealed the genetic make-up of both plants and microbes in the past using powerful molecular approaches. In the last few decades, the advancement in the sequencing, as well as data analysis techniques have provided the most efficient way of studying the genetic variation, differential expression, gene regulatory networks, and many more [5]. Microarray technologies created a new world for the scientists which has been almost replaced by the Next generation sequencing (NGS) and before the NGS has been used to even its full capabilities, we have single cell genomics in the picture which promises to provide the genomic resolution up to the single cell level. Technologies such as CRISPR-Cas-9 (Clustered regularly interspaced short palindromic repeats- CRISPRassociated protein 9) have been a boon to the world of research, especially in the field of plant pathology. Keeping in mind all these points, the current issue is aiming at shining light into the current scenario as well as past researches that brought so much useful information to improve crop protection. The review article by Agrahari et al. [6] describes the importance of studying plant-microbe interaction and its use to crop improvement. The article discusses the post-genomic era omics approaches such as next-generation sequencing (NGS) in association with marker assisted selection, cloning and recombination techniques, Genome-wide association studies (GWAS) and also CRISPR-Cas-9 technology. A brief overview of various models such as zig-zag model, invasion model, spatial immunity model, etc. has been provided to understand plant defense responses against various pathogens. To fight against various abiotic and biotic stress conditions, deployment plant-associated microbial population has the potential to help up to a great extent. Last but not the least, the article describes the beneficial microbes and their applications in crop improvement. Another article by Anupriya et al. [7] describes the genomics and molecular aspects of white rust disease along with how the white rust resistance can be transferred in the susceptible varieties of oilseed Mustard. This review broadly defines the nucleotide binding leucine rich repeat receptor (NLR) signaling and its application to exhibit oomycetes resistance in plants with special reference to effector molecules, Albugo candida secretome. It also describes various efficient approaches such as NLR repertoire enrichment, r-avr gene interaction, RNAi, and CRSPR-Cas technologies, which are being used to understand the pathogen-resistance mechanism. Shukla et al., [8] in their article, have reviewed biotechnological approaches for bioremediation of xenobiotics. They specifically discuss potential extremophiles, basically microorganisms living in extreme conditions. This review provides information on the previous studies regarding the extremophiles (microbes) and the pollutants which can been degraded. The use of extremozymes such as amylases, proteases, etc. are highly stable and can act as good novel catalysts. There are reports of more than 3,000 such enzymes which have been isolated from various extremophiles and have immense importance industrial uses.

Survival of life in extreme environments has always caught the attention of scientists and researchers as it can lead to understand several mechanisms leading to humanity. A few groups of organisms, including animals, plants and microorganisms can survive against harsh environmental conditions such as extreme temperature (cold and hot), salt, pressure, pH (acidic and alkaline) and drought. The organisms surviving on these niches are individually called thermophiles, psychrophiles, halophiles, piezophiles, acidophiles, alkaliphiles and xerophiles. The collective term for all these organisms is extremophiles. The study of extremophiles has received significant interest in both environmental and industrial perspectives. It has already been reported that microorganisms are present in a huge diversity in extreme niches. A great interest in the exploration of extreme habitats with a diversity of extremophilic microbes and their survival mechanisms has been shown in recent years. Some microbes represented the very ancient life forms when the environmental conditions were totally different than today, hence studying about these microbial physiology helps to answer the evolution of life. In addition, extremophiles had also shown their role in astrobiology [1]. The genetic and metabolic machinery of these microbes has been adapted for harsh conditions. For instance, thermophiles, psychrophiles and piezophiles have thermostable proteins, cell wall and cell membrane that resist extreme temperature; halophiles and xerophiles possess osmolytes and antioxidants in high concentration and; acidophiles/alkaliphiles have specific ion transporters to pump out excess ions and maintain neutral pH. Extremophiles also maintain their cell membrane fluidity, which protects their genetic material. They have unique genes that produce important metabolites which are stable at extreme environments known as extremozymes. Such types of metabolites, including protein and enzymes, have proven their importance in the field of biotechnology. For example, a DNA polymerase enzyme used in Polymerase Chain Reaction (PCR) technique is extracted from thermophilic bacteria (Thermus aquaticus). A large number of extremozymes approximately 3000 have been recovered from different extremophiles and are being used in several biotechnological and industrial purposes. However, there are so many extreme niches as well as microbes and their metabolites which are needed to be explored and utilized for improving the quality of life. The recent advances in genomics technologies have allowed for the investigation of extremophiles diversity and their survival mechanism as has never been seen before. Such advance genome-based studies will transform our understanding of physiology, genetic basis and genetic mechanisms of extremophiles and will reveal the importance of extremophiles and their products in multiple aspects of biotechnology including medicine, food technology, biofuel production, agriculture, waste management and many more [2]. The first part of this special issue explores genomic aspects of extremophiles including their survival mechanisms, gene expression and their applications in agriculture and other biotechnology purposes. The extremophiles have unique genetic material that is needed to be mined, which may be useful for genetic engineering in mesophillic microbes and their metabolites can be used in industries. The physiology and diversity of extremophiles including halophiles, psychrophiles and heavy metal tolerance will be presented in this special issue. Topics will also include the engineering of extremophiles and their application in pigment production, waste management and bioenergetic purposes. In this sense, a research article by Mawad et al. [3] explored phenanthrene degrading bacteria Pseudomonas fluorescens AH-40 from oily sludge sample. This bacterium requires less time for degrading complete phenanthrene as compared to previously reported bacterial cultures. Mawadand colleagues quantified the expression of phenathrene degrading genes i.e. naphthalene dioxygenase (nahAc) and catechol 2,3-dioxygenase (C23O) in AH-40 culture and found their increased expression during the degradation process. Authors suggested the role of nahAc and C23O as a marker gene in phenanthrene degradation and recommend to AH-40 culture for bioremediation process. In a review, specific metabolic and genomic features of thermophiles and psychrophiles are discussed by Kohli et al. [4]. Kohli and colleagues reported the role of hydrophobic molecules in cell membrane structure, amino acid composition, tRNA structure, GC content in genomes and many more in the stability of extremophiles under harsh conditions. They also described some examples of different enzymes extracted from both thermophiles and psychrophiles and their applications for industrial purposes. Another review by Usmani et al. [5] described the importance of bioengineering technologies on microbes and their uses for producing microbial pigments using agricultural wastes as substrate. In this review, advance techniques such as Multivariate modular metabolic engineering (MMME) and Multiplex automated genome engineering (MAGE) are reported for modulation in secondary metabolism of extremophiles. These techniques are used for the production of carotenoid and anthocyanin compounds. In addition, use of different agro-wastes such as Apple pomace, Rice powder, Palm date waste, Sugar-beet molasses, Orange waste and many more in production of microbial pigments are reported.

Except for mRNA that encodes proteins, there is another kind of RNA, known as non-coding RNA (ncRNAs), that does not encode proteins. ncRNAs control various levels of gene expression in physiology and development, such as RNA splicing, RNA translation, cell proliferation and apoptosis. Accumulated evidence have demonstrated that ncRNAs are correlated with the progression of a series of diseases. Besides ncRNAs, RNA modification is another layer of epigenetic regulation of gene expression. Since the first modified RNA ribonucleic acid was found in 1957, more than 150 kinds of known RNA modifications have been reported. RNA modifications play critical roles in a series of biological processes, such as RNA degradation, localization and degradation, and even circadian rhythm. Recent studies revealed that RNA modifications are also associated with metabolic diseases, cancer, neurological disorders and cardiovascular diseases. Due to their important roles, more researchers have devoted to the researches on ncRNAs and RNA modification. However, the biological functions and mechanisms of ncRNAs and RNA modification are still unclear. Since experimental methods are cost-ineffective to rapidly and effectively reveal their biological functions, it is highly desirable to develop computational methods which are good complements to experimental techniques for this aim. In recent years, a series of computational methods have been developed to infer the regulatory functions of RNA modification and ncRNA. Therefore, the thematic issue was proposed with the aim to collect a diverse and complementary set of articles that demonstrate new developments and applications of machine learning methods in computational RNA epigenetics. This thematic issue has attracted 6 papers from highly regarded researchers around the world. After the rigorous peer review, 3 of them were accepted for publication. Guan et al. [1] contributed a review article, where they summarized the recent advances in pre-miRNA recognition from the following aspects, namely the benchmark dataset, feature extraction, prediction algorithms, and the evaluation of existing models. The challenges and future perspectives are also discussed. It is believed that this review will provide novel insights into researches on computational identification of miRNA precursors. In a mini review paper contributed by Li et al. [2], the authors reviewed available machine learning based methods for identifying RNA 5-methylcytosine (m5C) sites. Three essential elements, namely dataset, sequence encoding scheme, and machinelearning algorithms, required to constitute a predictor for identifying m5C sites were firstly discussed. More importantly, the bottleneck of those predictors was also pointed out, which should be considered when developing predictors for identifying m5C and even the other kinds of RNA modifications. Govindaraj et al. [3] proposed a novel computational predictor termed as ERT-m6Apred based on extremely randomized tree to identify N6-methyladenosine (m6A), in which a two-step feature selection technique was used to obtain the optimal feature set. Finally, the guest editor would like to thank all the authors who contributed their original works to the thematic issue and to the reviewers for their valuable comments on those works. The guest editor would also like to express sincere gratitude to the Editor in Chief, Dr. Christian Néri, of Current Genomics and the Assistant Manager Publications, Ms. Iqra Shafi for their excellent supports and providing the opportunity to organize the thematic issue.

With systems genomics burgeoning, there is always a need to prioritise candidates post bioinformatics analyses. This is where machine learning approaches have steadfastly been in use. While the articles in part I have seen a seminal research on the applications of the genes, this second part constituting three articles emphasizing the need for machine learning heuristics. Roy et al. in their article entitled, “Deciphering the novel target genes involved in the epigenetics of hepatocellular carcinoma using graph theory approach” [1] applied graph theory approaches for drawing a network of genes in identifying novel targets for hepatocellular carcinoma epigenetic therapy. The candidates they found were statistically coherent for the therapeutic use. Natarajan et al., in their article entitled, “Helicobacter pylori reactivates Human Immunodeficiency Virus-1 in latently infected monocytes with increased expression of IL-1β and CXCL8” [2] have aptly used HIV infected monocytes for measuring the expression of genes reactivated by H. Pylori. Parveen et al. emphasized a review on “Applications of machine learning in miRNA discovery and target prediction” [3] which brings a subtle understanding of these approaches for miRNA target prediction and early phase discovery. In conclusion, systems genomics has shaped up from nascent stage to a phase where we set actions to prevent diseases, thanks to machine learning approaches. “The goal of getting your genome done is not to tell you what you will die from, but it's how to learn how to take action to prevent disease”. George M. Church.

In the last years, research efforts have been focused on the understanding of the evolutionary mechanisms linked to the control of the transcriptional activity and developmental processes. The study of developmental mechanisms has advanced significance over the last decade, and developmental programs that have undergone evolutionary specialization among species have recently been characterized. Epigenetics, which includes analysis of DNA methylation, histone code (i.e., histone methylation/ demethylation, acetylation/deacetylation, phosphorylation, ubiquitination, etc.), noncoding RNA (ncRNA) pathways and 3D genome organization, has made important progress towards understanding of the complexity of developmental processes. Epigenetic factors involved in the regulation of development are increasingly being identified in organisms ranging from yeast to humans, and it has been shown that epigenetic phenomena such as genomic imprinting, paramutation and transgenerational epigenetic inheritance are often closely linked to these processes. The main objective of this thematic issue is to present current research into the epigenetic mechanisms involved in developmental programming, their evolution and their roles in disease states. In the first article of this issue, Vaschetto and Ortiz [1] provide an opinion on the role of the duplication of sequence in the mechanisms of gene regulation and its importance in genome evolution and developmental programming. By the analysis of information based on master developmental genes (i.e., HOX genes), repetitive ribosomal DNA (rDNA) arrays, sequences encoding noncoding RNAs (ncRNAs,) and distinct classes of Transposable Elements (i.e., MITEs, SINEs, R2, etc.), the authors explain how sequence duplication may function as an evolutionary strategy to regulate the transcriptional expression at genome-level. In the next article, Csaba [2] provides a review on the mechanisms associated with the hormonal imprinting, an epigenetic phenomenon that involves the first encounter between a hormone and the target receptor, which occurs in the perinatal period. Remarkably, Dr. Csaba postulated the theory of hormonal imprinting [3], and his laboratory has made important research efforts to understand the faulty hormonal imprinting in the Developmental Origin of Health and Disease (DOHaD). In the third article, Şanlı and Kabaran [4] examine the consequences of the maternal obesity and maternal overnutrition on fetal programming. In this article, the authors analyze how maternal obesity is associated with epigenetic modifications that influence fetal growth and underlie metabolic diseases during adulthood. Next, Lecoutre et al. review the mechanisms for which maternal obesity may induce adipose tissue remodeling of offspring and explore the role of the epigenetic inheritance in developmental programming of obesity [5]. In the next article, Alsayegh et al. [6] examine the potential of pluripotent stem cells (PSCs) as de novo source of Hematopoietic Stem Cells (HSCs), and the mechanism of regulation of HOX and GATA factors in hematopoiesis. In this review, the authors also evaluate the relationships existing between the HOX and GATA master regulators and microRNA (miRNA) pathways. Lastly, Kadayifci et al. [7] discuss the importance of the epigenetic mechanisms for the nutritional programming of Type 2 Diabetes Mellitus and their roles in the developmental origin of this worldwide chronic disease.

As anticipated in the editorial of the Part I of this special issue, Early Life Stress (ELS) profoundly impairs child’s brain development and behavior giving rise to either temporary or permanent effects on cognitive, behavioral and psychological functions. Furthermore, possible long-term cumulative effects of various types of early adversity may show up in adulthood [1]. ELS-related pathological consequences greatly vary among individuals and depend upon genetic and environmental factors. This second part of the issue includes four additional reviews and provides novel exciting aspects linking genomics and epigenomics to neuropsychiatric disorders associated to Early-Life Stress. A natural extension of this second part of the thematic issue is the double-edged sword of epigenetic processes: their potential reversibility and long-term stability via non-Mendelian inheritance mechanisms. A growing amount of evidence has showed that our DNA remembers past traumatic experiences through the storage of epigenetic marks that can be transmitted into subsequent generations. Epigenetic alterations may cause a variety of latent biological dysfunctions in the stress system of the offspring and result as pre-traumatic vulnerable factors [2, 3]. These novel and exciting mechanisms of trans-generational inheritance suggest the possibility to deliver integrative solutions in the clinical diagnosis and therapeutic approach against various long-term consequences to ELS, and in later family life. Based on these observations, the paper by Lux highlights the role of a parallel synaptic and hormonal activation of epigenetic programming in human and rodent models. Liu et al. elucidate both genomic and non-genomic mechanisms related to stress modulation of the hypothalamic-pituitary-adrenal (HPA) axis leading to methylation of the glucocorticoid receptor gene (NR3C1) and activation of lifelong impairments. Bearer et al. provide an in-depth introduction to genome-wide changes in the child's methylome pattern induced by early adversity in life, potentially linked to the development and function of brain circuits, immune and endocrine system. Stenz et al. describe the still largely unexplored concept of the intergenerational transmission of DNA methylation signatures associated to the increased risk for developmental psychopathology. The aforementioned reviews are mostly focused on genomic and epigenomic variations in neuropsychiatric disorders associated to ELS phenomena. Moving these advanced findings into the routine medical practice will offer a revolutionary care and rehabilitation approach for patients, either adults or children generally poorly managed, who suffer from psychopathologies following ELS exposure. The overall aim of this Special Issue is to prove how the developmental age may represent a window of opportunity to implement novel early interventions in the diagnosis and treatment of individuals subjected to ELS. Likewise, the resulting collection of the present reviews examines wider strategic significance. A greater understanding of neuroplasticity and the brain interactions with the social environment will promote a fertile ground of investigations to the pathogenesis of neurodegenerative disorders and other psychiatric illnesses (e.g. schizophrenia), characterized by disruptive processes of cerebral growth and synaptic plasticity [4, 5].

Early Life Stress (ELS) profoundly impairs child’s brain development and behaviour giving rise to either temporary or permanent effects on cognitive, behavioural and psychological functions. Furthermore, possible long-term cumulative effects of various types of early adversity may show up in adulthood [1]. ELS-related pathological consequences greatly vary among individuals and depend on genetic and environmental factors. With regard to the onset of neurodevelopmental and psychiatric disorders associated to ELS exposure, great emphasis must be laid on the influence of various pre-, peri- and post-traumatic components in the environmental social context in which childhood abuse occurs. Namely, other influence factors related to the nature of the early trauma, such as its duration, chronicity, and severity, strongly predispose towards either pathological outcomes or resilient reactions. Together, genetic and environmental factors influence the individual stress responses although the most remarkable effects of such an interplay are those concerning a critical period of vulnerability spanning from fetal to postnatal development and adolescence. During this developmental window, the genome within neurons appears to be more plastic and sensitive to both positive and negative environmental stimuli. These gene-environment interactions contribute to optimal brain development, establishing a proper neural and behavioural developmental trajectory [2]. As previously anticipated, it is now clear that there is a causal link between ELS and the onset of neuropsychiatric and behavioural consequences, both with short- and long-term effects [3]. With the advent of Omic technologies, we are getting a considerable amount of information on the gene-environment interplay mechanisms, and learning biological underpinnings of those long-lasting changes that influence the pathological effects of ELS during the development of brain and behavioural traits [4]. In recent years, we have witnessed the rapid evolution of knowledge about several potential mediators responsible for the high phenotypic heterogeneity observed among individuals exposed to ELS. Ultimately, epigenetic changes in response to stress signalling are also known to influence the development and susceptibility to early trauma-related pathologies. Epigenetic variations depict potentially reversible and transitory biochemical changes that cause altered gene expression without modifying the DNA sequence and dynamically switch transcription rates in response to a multitude of environmental stimuli and developmental states. These epigenetic changes mirror the great flexibility of diverse biological processes of the organism including the modulation of proper and adaptive neurobiological responses to various stressor agents throughout the life. However, experiencing prematurely a stress challenge causes widespread alterations in brain plasticity and neuroendocrine system that correlate with marked and persistent changes in functional activity of a large number of stress responsive genes [5]. It follows that the epigenetic deregulation may be implicated in many long-term pathological consequences of physical and mental health. The above key concepts are well represented by the seven reviews selected for the present Special Issue, which aims to provide an extensive overview of the interplay between ELS and the genome. This Special Issue is divided into two parts: the first comprises two papers and features a very constructive analysis of ELS-driven processes that program the cerebral decline to neurodevelopment and neuropsychiatric disorders. To this end, Drake et al. examine the intriguing and relatively little-known mechanisms linking preterm birth with neurodevelopmental effects. From the viewpoint of clinical neuroscience, there is substantial interest in studying the delayed effects of ELS in neurodegeneration. Therefore, the scope of the paper by Lemche is to provide a highly informative overview of genomic association studies supporting the relevance of ELS as a powerful mediator of Late-Onset Alzheimer’s Disease (LOAD). Taken as a whole, the pioneering works of this first part of the Issue invite the readers to discover some interesting genomics and epigenomics insights into the programming of the neuronal cell fate during the developmental age. These new findings build the foundation for precision medicine to improve the treatment of neuropathological sequelae induced by ELS injury, develop preclinical screening and, possibly, offer more reliable and integrative therapeutic models.

The past twenty-five years significantly expanded our knowledge of Copy Number Variants (CNVs), genomic imbalances belonging to structural genetic variations, and their role in both human health and disease, particularly in the neurological field. In 1991, Lupski was the first to associate a CNV (a DNA duplication) to a human autosomal dominant neurodegenerative disease, the Charcot-Marie-Tooth Disease Type 1A [1]. In the last years, different technologies succeeded one another, increasing the power of resolution and the regions of application. However, technological and conceptual barriers have hampered the investigation of neurodegenerative diseases from a polygenic point of view, not only for complex neurodegenerative diseases but also for monogenic ones. For example, even if Neurofibromatosis type 1 represents a monogenic autosomal dominant disorder with complete penetrance, it is characterized by a variable expressivity that is hard to address in a genotype-phenotype correlation [2, 3]. In this mini-thematic issue, we aim to describe the progress in the study of these important types of structural variations in medicine, exploring the use of CNVs analysis in neurological disorders, as recently reviewed for Alzheimer’s Disease, Parkinson’s Disease and Amyotrophic Lateral Sclerosis studies [4-6]. Taken together, the three manuscripts published in the present mini-thematic issue provide the reader an overview of the recent findings regarding inherited neuropathies (Salpietro et al.) and adult-onset neuropsychiatric disorders, i.e. Schizophrenia and Alzheimer’s disease (Lew et al.), and emphasize the need of custom technologies, such as a customized exon-centric aCGH, to detect overlapping gene signatures among neurological conditions (La Cognata et al.).

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