Editorial: Bioinformatics of Genome Regulation, Volume II

A patient’s response to immune checkpoint inhibitors (ICIs) is a complex quantitative trait, and determined by multiple intrinsic and extrinsic factors. Three currently FDA-approved predictive biomarkers (progra1mmed cell death ligand-1 (PD-L1); microsatellite instability (MSI); tumor mutational burden (TMB)) are routinely used for patient selection for ICI response in clinical practice. Although clinical utility of these biomarkers has been demonstrated in ample clinical trials, many variables involved in using these biomarkers have poised serious challenges in daily practice. Furthermore, the predicted responders by these three biomarkers only have a small percentage of overlap, suggesting that each biomarker captures different contributing factors to ICI response. Optimized use of currently FDA-approved biomarkers and development of a new generation of predictive biomarkers are urgently needed. In this review, we will first discuss three widely used FDA-approved predictive biomarkers and their optimal use. Secondly, we will review four novel gene signature biomarkers: T-cell inflamed gene expression profile (GEP), T-cell dysfunction and exclusion gene signature (TIDE), melanocytic plasticity signature (MPS) and B-cell focused gene signature. The GEP and TIDE have shown better predictive performance than PD-L1, and PD-L1 or TMB, respectively. The MPS is superior to PD-L1, TMB, and TIDE. The B-cell focused gene signature represents a previously unexplored predictive biomarker to ICI response. Thirdly, we will highlight two combined predictive biomarkers: TMB+GEP and MPS+TIDE. These integrated biomarkers showed improved predictive outcomes compared to a single predictor. Finally, we will present a potential nucleic acid biomarker signature, allowing DNA and RNA biomarkers to be analyzed in one assay. This comprehensive signature could represent a future direction of developing robust predictive biomarkers, particularly for the cold tumors, for ICI response.

This special issue continues the series of BioMed Central special post-conference journal issues (BMC Genetics, BMC Plant biology, BMC Genomics, BMC Evolutionary biology, BMC Systems Biology). All these issues collate the papers presented at BGRS\SB-2016, 10th International Conference “Bioinformatics of Genome Regulation and Structure\Systems Biology” which took place at August 29 - September 2, 2016 in Novosibirsk, Russia. The BGRS conference series started in 1998 in Novosibirsk Akademgorodok (http://conf.bionet.nsc.ru/bgrssb2016/archive/) Since then BGRS/SB was been organized biannually by the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences (ICG SB RAS). Across all these years, the Conference was chaired by Prof. Nikolay A. Kolchanov (ICG SB RAS, Russia) and Prof. Ralf Hofestädt (Bielefeld University, Germany). In 2016, the multi-conference held parallel events and symposia on systems biology and biomedicine (SBioMed-2016) (http://conf.bionet.nsc.ru/ishg2016/en/), cognitive sciences (http://physiol.ru/csgb2016/), and mathematical modeling in biology (MM-HPC-BBB-2016) (http://conf.bionet.nsc.ru/mm-hpc-bbb-2016/en/). Since 2014, the BGRS Program Committee has collaborated with BioMed Central on full-text thematic issues reflecting the main science achievements of the conference series in past years. Recently BioMed Central had published several special issues based on best materials presented at the conference in BMC Genetics [1] (http://bmcgenet.biomedcentral.com/articles/supplements/volume-16-supplement-1), BMC Genomics (http://bmcgenomics.biomedcentral.com/articles/supplements/volume-15-supplement-12), BMC Evolutionary Biology (http://bmcevolbiol.biomedcentral.com/articles/supplements/volume-15-supplement-1), and BMC Systems biology (http://bmcsystbiol.biomedcentral.com/articles/supplements/volume-9-supplement-2). Current issue of BMC Genetics represents latest breakthroughs in genetics discussed at the conference and includes applications of high-throughput sequencing and computational biology for genetics studies in humans and in laboratory animal models. At the Institute of Cytology and Genetics SB RAS – the host of the BGRS\SB-2016 multiconference - these types of studies represent one of the most important research themes. Many of these works are done in frame of national and international collaborations, and involve young researchers working on their PhD Thesis projects. The paper by E.V.Ignatieva and colleagues [2] opens this special issue by endeavor into the functional annotation of genes regulating feeding behavior, which is a complex problem related to obesity and pre-disposition to the associated diseases. The authors proposed a computational approach to annotation by integrating various mined sources, including previously published original research and review articles, GWAS meta-analyses, and OMIM (Online Mendelian Inheritance in Man) data. A compendium comprising more than 500 human genes controlling food behavior is expected to be useful for pathology risk estimation and for design of new pharmacology approaches to treat human obesity. The work by Matveeva et al. considers regulatory single nucleotide polymorphisms (rSNPs) in the tumour suppressor APC gene. It was shown that both putative promoters of APC (1A and 1B) drive transcription in an in vitro reporter experiment, many SNPs are functionally relevant and allele G of rs79896135 may be associated with the predisposition to colorectal cancer [3]. The article by Kudryavtseva et al. highlights molecular mechanism of hexokinases function in tumorigenesis of human colorectal cancer and melanoma. The authors studied the effect of silencing hexokinase genes (HKI, HK2, and HK3) in colorectal cancer and melanoma cells using short hairpin RNA (shRNA) lentiviral vectors suggesting the HK1 and HK2 genes as the key therapeutic targets for reducing aerobic glycolysis [4]. Two papers by Korbolina et al. [5] and Ryazanova et al. [6] represent the studies on ISIAH and OXYS rat models developed in ICG SB RAS to study the molecular genetics mechanisms of complex human diseases such as stress-sensitive arterial hypertension and Alzheimer disease. The paper by Elena Korbolina and colleagues [5] describes the genetic architecture of complex traits, particularly age-related neurodegenerative disorders. The backcrossing of Wistar Albino Glaxo (WAG) and OXYS (an inbred prematurely aging rat strain characterized by high sensitivity to oxidative stress) rat strains to generate the congenics strains resulted in two congenic strains with high susceptibility to cataract and retinopathy but with no signs of Alzheimer’s disease-like brain pathology that are specific for OXYS rats. A comparative analysis of previously defined QTLs and congenic chromosomal segments led to identification of candidate genes with a suspected effect on the brain neurodegeneration. The ISIAH rat strain (Inherited stress-induced arterial hypertension) was developed by selection for high systolic arterial blood pressure (SABP) induced by restraint stress. Earlier studies showed that the ISIAH rats may be considered as a model of the human stress sensitive hypertensive disease with predominant involvement of the neuroendocrine hypothalamic-pituitary-adrenal (HPA) and sympathoadrenal systems in the pathogenesis of the hypertensive state [7].The studies of the genetic background underlying the stress-sensitive hypertension in the ISIAH rats were already published in special issues of BMC Genetics after BGRS\SB-2014 and SBB-2015 events [8–10]. Current paper outlines the results of the gene-expression profiling in renal medulla of the ISIAH rats and reveal the genes which affect renal function and the long-term control of arterial blood pressure are discussed. The paper by A. Kononov et al. [11] highlights evolutionary aspects of the moths of genus Dendrolimus (Lepidoptera: Lasiocampidae), which are among the major pests of coniferous forests worldwide. The study clarifies the taxonomy of the moths of this genus in Eurasia using mitochondrial markers. Finally, the work by P. Drozdova et al. [12] discusses a reversible phenotypic switch in yeast model at translation stage. This reversible switching had been attributed to a prion termed [ISP+] and, therefore, is fundamentally relevant to protein aggregate pathologies. All BGRS\SB-2016 Proceedings including “Bioinformatics and Systems Biology of Plants” section are available at the multi-conference web-site: http://www.bionet.nsc.ru/files/2016/conference/BGRS2016.pdf. Additionally, special issues on bioinformatics were published at the Journal of Bioinformatics and Computational Biology (http://www.worldscientific.com/toc/jbcb/13/01) [13] and “Vavilov Journal of Selection and Breeding” (http://vavilov.elpub.ru/jour/issue/view/15/showToc) (in Russian). As usual, BGRS/SB-2016 was accompanied by a number of satellite events, including already traditional Young Scientists School “Systems Biology and Bioinformatics” (SBB-2016) (http://conf.bionet.nsc.ru/sbb2016/en/) and Open Russian-German workshop on bioinformatics network “Systems computational biology”.

This Research Topic presents the studies in the field of computational genomics. These papers were discussed at BGRS\SB-2018 (Bioinformatics of Genome Regulation and Structure Systems Biology) multi-conference, along with the hybrid wet-lab/computational genetics studies focused on genome-wide gene expression regulation. The BGRS is the major event in the computational biology field, which has been held in Novosibirsk, Russia biannually since 1998. The main conference is typically followed by a series of special post-conference journal issues covering contemporary computational genetics and genomics applications (Orlov et al., 2016, 2019a; Tatarinova et al., 2019). First Special Issues covering BGRS\SB conference were presented in the Journal of Bioinformatics and Computational Biology in 2012 (Kolchanov and Orlov, 2013; Orlov et al., 2015, 2019b) and other platforms (Chen et al., 2017; Baranova et al., 2019; Orlov, 2019; Medical Genetics and Bioinformatics special issue). Starting in 2018, extended discussion of the conference materials in genetics and genomics is being presented in Frontiers in Genetics. In this Research Topic, we arranged the papers by areas of applications—clinical bioinformatics and human genome studies are followed by the plant genetics and then by systems biology applications. Bah et al. comprehensively reviewed genomics tools and databases allowing us to dissect the pathophysiology of bacterial and parasitic infection, spanning the species from Mycobacterium tuberculosis to Plasmodium falciparum. These databases provide the data and tools for in-depth investigations of disease outbreaks and pathophysiological mechanisms, genomic variation and co-evolution of hosts and pathogens, diagnostic markers and vaccine targets, with special attention to the contributions of genomics and bioinformatics to the management of both common and neglected tropical diseases, including tuberculosis, dengue fever, malaria, and filariasis. The TCGA (The Cancer Genome Atlas) database was mined from an entirely new technical viewpoint of developing reference genes with stable mRNA levels for quantitative PCR studies of cancer cells (Krasnov et al.). A scoring system for the assessment of gene expression stability allowed authors to highlight previously untried reference gene candidates, specific to each cancer type, along with several more “universal,” pan-cancer reference gene candidates, namely SF3A1, CIAO1, and SFRS4. The application on colon adenocarcinoma was presented in Fedorova et al. (2019), another work in the frames of BGRS SB conference series. The study by Ivanov et al. highlighted methodological problems for an up-and-coming biomarker mining technique, a sequencing of cell-free DNA (cfDNA) in human plasma. As fragmentation patterns of cfDNA are far from being random due to nucleosome patterns reflecting tissue-specific epigenetic signatures, these patterns may be used for guiding the design of amplicon-based NGS panels. Therefore, the sensitivity of mutation detection in liquid biopsy samples may be much improved, allowing for a lessening of the amount of body fluids collected from patients. Khatun et al. work in the medical bioinformatics field; they have developed a computational tool PreAIP (Predictor of Anti-Inflammatory Peptides), aimed at augmenting the search for novel biologics. Integrative analysis of stomach carcinoma samples by pairing DNA methylation patterns with gene regulatory network topology was presented in Wu et al.. The authors showed conservation of epigenetic patterns across various stages of this important type of human malignancies. Gene expression regulation at genome level is important in evolution and adaptation studies (Ponomarenko et al., 2017; Igoshin et al.). Igoshin et al. looked into the adaptation of humans to cold climate. They have concentrated on the TRPM8 gene, which encodes for a cold-sensing ion channel. In a population data set, they found a very promising single nucleotide polymorphism rs7577262 with a signature of selective sweep. Chadaeva et al. employed bioinformatics to discern behavioral pattern in mice and identify variants contributing to the dominance and the subordination traits continuing bioinformatics behavior studies in laboratory animals (Bragin et al., 2017). Using the prediction on-line tool SNP_TATA_Comparator (Ponomarenko et al., 2017) a set of candidate SNP markers contributing to the dominance and the subordination were uncovered. The studies using same SNP analysis tool were continued in Oshchepkov et al. (2019) and Ponomarenko et al. (2020). Zverkov et al. considered a problem of genome reduction in primitive parasites. Among the two groups of microscopic parasitic invertebrates, the Dicyemida, and Orthonectida, overall morphological organization is much simplified, with tissues and organs almost absent. In these species, homeodomain transcription factors, G-protein-coupled receptors, and many other protein families have undergone a massive reduction. Interestingly, it seems that the dramatic simplification of body plans in dicyemids and orthonectids has evolved independently. Das et al. discuss the application of ancestry informative markers (AIMs), previously developed for the inference of genomic ancestry in humans (Das and Upadhyai, 2018), for the delineation of gorilla lineages. Three of the four AIMs-determining approaches were successful for gorilla species (Das et al.). The next group of papers in the Research Topic highlight the findings in genome regulation related to plants genetics. Kovalev et al. developed a computer pipeline and a machine learning classifier of deleterious coding mutations in agricultural plants, with the performance exceeding that of the popular PolyPhen-2 tool. The novel tool will improve the annotation of genes located in QTL and GWAS hit regions. This work was initially discussed at BGRS\SB-2018 plant biology session as well (Orlov et al., 2019c). Zhang et al. studied abiotic stress in a model of Populus euphratica and its sister species P. pruinosa, differing by their adaptability to the content of salt in the soil. The authors performed transcriptome analyses of three seed germination phases from both of the species of desert poplar, and presented their findings in a form of a database suitable for use by poplar breeders. Wang et al. also studied Populus euphratica, in this case to infer genetics mechanisms of crossover Interference. Four-point linkage analysis allowed them to show the distribution of the crossover interference through the entire genome of this tree, uniquely suited for survival in saline deserts. The following work by Khassanova et al. continues the line of studies of salinity resistance by exploring expression profiles in the chickpea (Cicer arietinum L.). They have tested six accessions of Chickpea ecotypes, all selected from field trials, for tolerance to abiotic stresses, found the involvement of CaRabC gene and developed markers for genotyping chickpea germplasm. Gene expression patterns in bread wheat exposed to drought were studied in Zotova et al.. The authors' team had identified general transcription repressor TaDr1, a part of TaDr1, TaDr1A and TaDr1B gene set, with drought-dependent variable expression. It seems that the general transcription repressor TaDr1 controls expression of TaVrn1 and TaFT1 and, consequently, flowering time. These finding have direct implications for plant productivity in the dry environment. Flowering time in plants is important agricultural feature determined by genetics and environment. Gursky et al. dissected the core genetic regulatory network canalizing the flowering signals to the decision to flower. While discovered and extensively studied in the model plant Arabidopsis thaliana, the flowering model may hold in other species (Kozlov et al., 2019). When the authors built a model gene network in chickpea (Cicer arietinum), activation from the FLOWERING LOCUS T gene or its homologs to the flowering decision led to a high expression of the meristem identity genes, including AP1. Different levels of activation from AP1 may explain the differences observed in the expression of the two homologs of the repressor gene TFL1 in species compared. Zhao et al. worked on tea plant (Camellia sinensis). In this plant, the development of new sprouts directly affects the yield and quality of the tea leaves, by affecting the content of catechins, theanine, and caffeine. Using High-Performance Liquid Chromatography-Mass Spectrometry, authors showed that conserved miRNA are playing a role in primary metabolism of a tea plant during sprouting. Li et al. presented their study of the chloroplast genomes of Vicia sepium, an important wild resource plant suitable for cultivation in extreme cold and dry conditions. The authors have compared a new complete chloroplast genome of V. sepium with the chloroplast genomes from related genera belonging to tribe Fabeae, then reconstructed the evolutionary history of the chloroplast genomes in these species. Orlov M. et al. have studied promoters of Mycoplasma gallisepticum, an intracellular parasite affecting the respiratory tract of poultry, and found that the vlhA promoters differ by carrying a variable GAA repeats region upstream of transcription start site. These data have implications for the studies of the phase variation in M. gallisepticum. The computer technique of such promoter studies were continued in Orlov and Sorokin (2020). Liu et al. presented their study of gender differences in solitary parasitoid species Brachymeria lasus, which has been evaluated as a potential candidate for release to control the gypsy moth, Lymantria dispar, a pest of worldwide importance. Work by Qin et al. considers the polyploidy problem in vertebrates. They have analyzed genome organization in the autotetraploid of the red crucian carp (Carassius auratus red var.). The loss of chromosomal loci, base variations in non-transcribed spacer, and array recombination of repeat units have been detected. Overall, we are proud of the Research Topic at Frontiers in Genetics we collated. We hope that you will find this paper collection a stimulating reading, and will consider coming to the next BGRS\SB conferences in Novosibirsk, Russia as well as read next “Bioinformatics of Genome Regulation” Research Topic in Frontiers (https://www.frontiersin.org/research-topics/14266/bioinformatics-of-genome-regulation). Author Contributions YO and AB organized the Research Topic as guest editors, supervised the reviewing of the manuscript, and wrote this Editorial paper. All authors contributed to the article and approved the submitted version. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.