Hua Li
Guoshuai Cai
Wen-Lian Chen
Xiaodong Zhao
Yuriy L. Orlov- 1Jiangsu Province Engineering Research Center of Development and Translation of Key Technologies for Chronic Disease Prevention and Control, Suzhou Vocational Health College, Suzhou, China
- 2Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
- 3Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, United States
- 4Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- 5The Digital Health Center, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
- 6Systems Biology Department, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
Editorial on the Research Topic
High-throughput sequencing-based investigation of chronic disease markers and mechanisms, volume II
Introduction
Second-generation (short-read, massively parallel) sequencing and third-generation (long-read, single-molecule) sequencing technologies have matured rapidly, irreversibly altering how we interrogate human health and disease. A series of Frontiers in genetics Research Topics highlight this area (Orlov and Baranova, 2020; Anashkina et al., 2023). Building on the inaugural 2022 Research Topic (Orlov et al., 2022), this second volume of “High-throughput Sequencing-based Investigation of Chronic Disease Markers and Mechanisms” (https://www.frontiersin.org/research-topics/53085/high-throughput-sequencing-based-investigation-of-chronic-disease-markers-and-mechanisms-volume-ii/articles) again harnesses deep sequencing technologies, sophisticated analytics, and cross-scale validation to illuminate biomarkers and mechanisms that underlie a spectrum of chronic conditions - from inflammatory bowel disease to neuromuscular degeneration and pandemic infection. Together, the nine articles accepted in this Research Topic exemplify three converging trends: (i) omics integration across genome, epigenome, transcriptome and proteome; (ii) fast sequencing applications that translate into clinically actionable diagnostics; and (iii) mechanistic dissection of how candidate markers shape or signal pathophysiology.
Gastrointestinal and metabolic diseases: decoding tissue-specific signatures
Crohn’s disease remains clinically heterogeneous and therapeutically stubborn. Yang et al. performed bulk RNA-seq of intact bowel walls and revealed two strikingly upregulated transcripts, PDE1A [OMIM 171890] and SEMA3D [OMIM 609907], associated with smooth muscle cell apoptosis and autonomic dysregulation, respectively, providing a plausible axis for the distinctive neuromuscular complications of this disease.
Turning to metabolic syndromes, Yao et al. mined public expression datasets, intersected them with ER-stress gene sets, and narrowed 49 differentially expressed genes down to three diagnostic markers - CLGN [OMIM 601858], ILF2 [OMIM 603181], IMPA1 [OMIM 602064] - that were subsequently validated in mouse models and patient sera. The study underscores how in silico LASSO feature selection, when wedded to wet-lab confirmation, can yield serum-accessible biomarkers for type 2 diabetes mellitus.
Oncology: multi-omics and precise mutation discovery
Two cancer-focused articles showcase complementary high-throughput strategies. Wang et al. isolated a circulating bio-active peptide (YG-22) generated when adjuvant chemotherapy was combined with the traditional Chinese Jianpi formula; multi-layer omics (transcriptome, metabolome, chromatin accessibility, H3K4me3 ChIP-seq, NF-κB ChIP-seq) revealed that YG-22 reprograms epigenetic states and lysosomal pathways to suppress colorectal cancer cell viability. This study demonstrates the added value of peptide therapeutics derived from phytochemical regimens.
At the single-gene end of the spectrum, Zhang et al. applied targeted next-generation sequencing to four myeloproliferative-neoplasm cases that were “triple negative” by canonical testing, unmasking novel driver lesions and arguing for routine targeted sequencing in ambiguous myeloid diagnoses.
Neuromuscular and neurodevelopmental research: from modifiers to toxicants
By pairing bulk and single-nucleus RNA-seq in healthy vastus lateralis versus tibialis anterior, Nieves-Rodriguez et al. identified >3,400 genes - including those related to calcium release and collagen-containing extracellular matrix transcripts - that may dictate differential vulnerability of muscles in Duchenne muscular dystrophy, supplying an invaluable reference for stratified gene-therapy design.
Li et al. then leveraged whole-exome sequencing of 113 patients with intellectual disability to uncover a novel de novo SYNGAP1 [OMIM 603384] splice-site variant (c.664-2A>G). Minigene assays confirmed exon 7 skipping, emphasizing that modest intronic changes that are detectable by high-depth sequencing can produce profound neurodevelopmental phenotypes.
Complementing human genetics, Lyu et al. used comparative transcriptomics in zebrafish embryos to show that extremely small iron-oxide nanoparticles (ESIONPs) perturb neuro-muscular development and trigger ferroptosis. Weighted gene co-expression network analysis (WGCNA) pinpointed stage-specific hub genes (highly connected nodes in the network), such as neurodevelopmental regulators and oxidative-stress mediators, whose dysregulation, together with elevated apoptosis markers, signals potential health risks of nanoparticle biomedical imaging.
Infection and immunity: from viral alternative polyadenylation to host GWAS loci
The interface between host gene regulation and pathogen assault is another recurring theme. Tan et al. profiled grass-carp cells during early grass carp reovirus infection and uncovered extensive shifts in alternative polyadenylation (APA) despite stable DNA methylation patterns, particularly affecting cytoskeletal and microtubule genes - an underappreciated layer of post-transcriptional control in fish viral pathogenesis.
On the human front, Loktionov et al. genotyped 10 GWAS-significant loci in nearly 800 Russians and confirmed that the SLC6A20-LZTFL1 rs17713054 risk allele magnifies severe COVID-19 particularly in obese, low-activity, or low-dietary-fruit subgroups, with concordant effects on thrombodynamics. Network analyses further highlighted interactive SNP constellations linking coagulation and immune genes. Such population-targeted validation of multi-locus risk underlines the translational scope of sequencing even after the acute pandemic phase.
Methodological cross-talk and shared biological threads
The field of gene expression regulation including chronic disease markers has been covered in a Frontiers in Genetics Research Topic (Anashkina et al., 2023) based on omics data integration. Sequencing technologies give background for gene expression regulation studies at genome scale (Anashkina et al., 2021; Orlov et al., 2023).
Across the current Research Topic, several common methodological themes emerge. First, multi-omics integration - whether combining peptidomics with chromatin readouts, or pairing methylome and APA maps - magnifies biological signals and reveals underlying mechanisms. Second, targeted or panel-based sequencing continues to sharpen genetic diagnosis where standard assays falter. Third, bioinformatics methods (WGCNA, LASSO, SNP-SNP interaction models) distill high-dimensional data into clinically tractable results.
Biologically, six recurrent pathways unite otherwise disparate studies: ER stress, calcium homeostasis, apoptotic regulation, extracellular-matrix remodeling, innate immune activation, and ferroptosis. This convergence reinforces the idea that chronic diseases, despite tissue specificity, share certain conserved response architectures that are captured by high-throughput sequencing.
Outlook
Together, the nine articles in this volume broaden the map of chronic-disease markers, bring sequencing into daily clinical applications, and deepen our grasp of how genetic and epigenetic patterns drive long-term illness. Looking forward to this Research Topic development, we may anticipate:
• Single-cell and spatial omics will dissect cell type-restricted marker function within complex tissues such as muscle, gut, and tumor microenvironments.
• Long-read platforms will resolve structural and splice isoform diversity.
• Prospective, multi-center cohorts integrating more data (e.g., diet, exercise) with host genetics, as illustrated in the COVID-19 study, will refine gene-environment risk algorithms.
• In addition, from the current perspective, AI applications will get a more important role in complex disease studies (Koshechkin et al., 2022; Zhang et al., 2024).
Author contributions
HL: Conceptualization, Funding acquisition, Writing – original draft, Writing – review and editing. GC: Writing – review and editing. W-LC: Writing – review and editing. XZ: Writing – review and editing. YO: Conceptualization, Funding acquisition, Writing – original draft, Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This research was supported by RSF (grant 24-24-00563) for YO. This research was supported by Jiangsu Province Engineering Research Center of Development and Translation of Key Technologies for Chronic Disease Prevention and Control (CDSGK1202503). This research was supported by the Fundamental Research Funds for the Central Universities (KLSB2024KF-02).
Acknowledgments
We thank all authors and reviewers for their pivotal contributions to this Research Topic.
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.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
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References
Anashkina, A. A., Leberfarb, E. Y., and Orlov, Y. L. (2021). Recent trends in cancer genomics and bioinformatics tools development. Int. J. Mol. Sci. 22, 12146. doi:10.3390/ijms222212146
Anashkina, A. A., Orlova, N. G., Ignatov, A. N., Chen, M., and Orlov, Y. L. (2023). Editorial: bioinformatics of genome regulation and systems biology, Volume III. Front. Genet. 14, 1215987. doi:10.3389/fgene.2023.1215987
Koshechkin, K. A., Lebedev, G. S., Fartushnyi, E. N., and Orlov, Y. L. (2022). Holistic approach for artificial intelligence implementation in pharmaceutical products lifecycle: a meta-analysis. Appl. Sci. 12 (16), 8373. doi:10.3390/app12168373
Orlov, Y. L., Anashkina, A. A., Kumeiko, V. V., Chen, M., and Kolchanov, N. A. (2023). Research topics of the bioinformatics of gene regulation. Int. J. Mol. Sci. 24 (10), 8774. doi:10.3390/ijms24108774
Orlov, Y. L., and Baranova, A. V. (2020). Editorial: bioinformatics of genome regulation and systems biology. Front. Genet. 11, 625. doi:10.3389/fgene.2020.00625
Orlov, Y. L., Chen, W. L., Sekacheva, M. I., Cai, G., and Li, H. (2022). Editorial: high-throughput sequencing-based investigation of chronic disease markers and mechanisms. Front. Genet. 13, 922206. doi:10.3389/fgene.2022.922206
Keywords: high-throughput sequencing, biomarker development, chronic disease, omics study, disease mechanism
Citation: Li H, Cai G, Chen W-L, Zhao X and Orlov YL (2025) Editorial: High-throughput sequencing-based investigation of chronic disease markers and mechanisms, volume II. Front. Genet. 16:1627976. doi: 10.3389/fgene.2025.1627976
Received: 13 May 2025; Accepted: 19 May 2025;
Published: 29 May 2025.
Edited and reviewed by:
Jared C. Roach, Institute for Systems Biology (ISB), United StatesCopyright © 2025 Li, Cai, Chen, Zhao and Orlov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yuriy L. Orlov, b3Jsb3ZAZC1oZWFsdGguaW5zdGl0dXRl