arXiv subjects

Gennadi Glinsky

Publications and source records attributed to Gennadi Glinsky.

11 recordsLinked to original sources

arXiv2024

Highly conserved sequence-specific double-stranded DNA binding networks contributing to divergent genomic evolution of human and chimpanzee brain development

Emergence during mammalian evolution of concordant and divergent traits of genomic regulatory networks encompassing ubiquitous, qualitatively nearly identical yet quantitatively distinct arrays of sequences of transcription factor binding sites (TFBS) for 716 proteins is reported. A vast majority of TFs (770 of 716; 98%) comprising protein constituents of these networks appear to share common Gene Ontology (GO) features of sequence-specific double-stranded DNA binding (GO: 1990837). Genome-wide and individual chromosome-level analyses of 17,935 ATAC-seq-defined brain development regulatory regions (BDRRs) revealed nearly universal representations of TFBS for TF-constituents of these networks, TFBS densities of which appear consistently higher within thousands BDRRs of Modern Humans compare to Chimpanzee. Transposable elements (TE), including LTR/HERV, SINE/Alu, SVA, and LINE families, appear to harbor and spread genome-wide consensus regulatory nodes of identified herein highly conserved sequence-specific double-stranded DNA binding networks, selections of TFBS panels of which manifest individual chromosome-specific profiles and species-specific divergence patterns. Collectively, observations reported in this contribution highlight a previously unrecognized essential function of human genomic DNA sequences encoded by TE in providing genome-wide regulatory seed templates of highly conserved sequence-specific double-stranded DNA binding networks likely contributing to continuing divergent genomic evolution of human and chimpanzee brain development.

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arXiv2023

Genomic regulatory architecture of human embryo retroviral LTR elements affecting evolution, development, and pathophysiology of Modern Humans

Two distinct families of pan-primate endogenous retroviruses, namely HERVL and HERVH, infected primates germline, colonized host genomes, and evolved into the global retroviral genomic regulatory dominion (GRD) operating during human embryogenesis (HE). HE retroviral GRD constitutes 8839 highly conserved fixed LTR elements linked to 5444 down-stream target genes forged by evolution into a functionally-consonant constellation of 26 genome-wide multimodular genomic regulatory networks (GRNs), each of which is defined by significant enrichment of numerous single gene ontology (GO)-specific traits. Locations of GRNs appear scattered across chromosomes to occupy from 5.5%-15.09% of human genome. Each GRN harbors from 529-1486 retroviral LTRs derived from LTR7, MLT2A1, and MLT2A2 sequences that are quantitatively balanced according to their genome-wide abundance. GRNs integrate activities from 199-805 down-stream target genes, including transcription factors, chromatin-state remodelers, signal-sensing and signal-transduction mediators, enzymatic and receptor binding effectors, intracellular complexes and extracellular matrix elements, and cell-cell adhesion molecules. GRNs compositions consist of several hundred to thousands smaller GO enrichment-defined genomic regulatory modules (GRMs) combining from a dozen to hundreds LTRs and down-stream target genes, which appear to operate on individuals life-span timescale along specific phenotypic avenues to exert profound effects on patterns of transcription, protein-protein interactions, developmental phenotypes, physiological traits, and pathological conditions of Modern Humans. Overall, this study identifies 69,573 statistically significant retroviral LTR-linked GRMs (Binominal FDR q-value threshold of 0.001), including 27,601 GRMs validated by the single GO-specific directed acyclic graph (DAG) analyses across six GO annotations.

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arXiv2020

Genomics-guided drawing of malignant regulatory signatures revealed a pivotal role of human stem cell-associated retroviral sequences (SCARS) and functionally-active hESC enhancers

From patients and physicians perspectives, the clinical definition of a tumor malignant phenotype could be restricted to the early diagnosis of sub-types of malignancies with the increased risk of existing therapy failure and high likelihood of death from cancer. It is the viewpoint from which the understanding of malignant regulatory signatures is considered in this contribution. Analyses from this perspective of experimental and clinical observations revealed the pivotal role of human stem cell-associated retroviral sequences (SCARS) in the origin and pathophysiology of clinically-lethal malignancies. SCARS represent evolutionary- and biologically-related family of genomic regulatory sequences, the principal physiological function of which is to create and maintain the stemness phenotype during human preimplantation embryogenesis. SCARS expression must be silenced during cellular differentiation and SCARS activity remains silent in most terminally-differentiated human cells performing specialized functions in the human body. De-repression and sustained activation of SCARS result in differentiation-defective phenotypes, tissue- and organ-specific clinical manifestations of which are diagnosed as pathological conditions defined by a consensus of pathomorphological, molecular, and genetic examinations as the malignant growth. Contemporary evidence are presented that high-fidelity molecular signals of continuing activities of SCARS in association with genomic regulatory networks of thousands functionally-active enhancers triggering engagements of down-stream genetic loci may serve as both reliable diagnostic tools and druggable molecular targets readily amenable for diagnosis and efficient therapeutic management of clinically-lethal malignancies.

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arXiv2020

Genomics-guided molecular maps of coronavirus targets in human cells: a path toward the repurposing of existing drugs to mitigate the pandemic

Human genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomics-guided maps of up-stream regulatory elements, their expression and functions in human body, including pathophysiologically-relevant cell types. Genes acting as repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1) were then employed to identify existing drugs that could be repurposed to mitigate the coronavirus infection. Present analyses identify Vitamin D and Quercetin as promising pandemic mitigation agents. Gene expression profiles of Vitamin D and Quercetin activities and their established safety records as over-the-counter medicinal substances suggest that they may represent viable candidates for further assessment and considerations of their potential as coronavirus pandemic mitigation agents. Notably, gene set enrichment analyses and expression profiling experiments identify multiple drugs, most notably testosterone, dexamethasone, and doxorubicin, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of Testosterone versus Estradiol impacts on SCARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during coronavirus pandemic.

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arXiv2018

Analysis of evolutionary origins of genomic loci harboring 59,732 candidate human-specific regulatory sequences identifies genetic divergence patterns during evolution of Great Apes

Our view of the universe of genomic regions harboring various types of candidate human-specific regulatory sequences (HSRS) has been markedly expanded in recent years. To infer the evolutionary origins of loci harboring HSRS, analyses of conservations patterns of 59,732 loci in Modern Humans, Chimpanzee, Bonobo, Gorilla, Orangutan, Gibbon, and Rhesus genomes have been performed. Two major evolutionary pathways have been identified comprising thousands of sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in humans after human/chimpanzee split. Thousands of HSRS appear inherited from ECAs yet bypassed genomes of our closest evolutionary relatives, presumably due to the incomplete lineage sorting and/or species-specific loss or regulatory DNA. The bypassing pattern is prominent for HSRS associated with development and functions of human brain. Common genomic loci that may contributed to speciation during evolution of Great Apes comprise 248 insertions sites of African Great Ape-specific retrovirus PtERV1 (45.9%; p = 1.03E-44) intersecting regions harboring 442 HSRS, which are enriched for HSRS associated with human-specific (HS) changes of gene expression in cerebral organoids. Among non-human primates (NHP), most significant fractions of candidate HSRS associated with HS expression changes in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in Gorilla genome. Modern Humans acquired unique combinations of regulatory sequences highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique mosaic of regulatory sequences inherited from ECAs was supplemented with 12,486 created de novo HSRS. These observations support the model of complex continuous speciation process during evolution of Great Apes that is not likely to occur as an instantaneous event.

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arXiv2017

Role of distal enhancers in shaping 3D-folding patterns and defining human-specific features of interphase chromatin architecture in embryonic stem cells

Molecular and genetic definitions of human-specific changes to genomic regulatory networks (GRNs) contributing to development of unique to human phenotypes remain a highly significant challenge. Genome-wide proximity placement analysis of diverse families of human-specific genomic regulatory loci (HSGRL) identified topologically-associating domains (TADs) that are significantly enriched for HSGRL and designated rapidly-evolving in humans TADs (Genome Biol Evol. 2016 8; 2774-88). Here, the analysis of HSGRL, hESC-enriched enhancers, super-enhancers (SEs), and specific sub-TAD structures termed super-enhancer domains (SEDs) has been performed. Markedly distinct features of the principal regulatory structures of interphase chromatin evolved in the hESC genome compared to mouse: the SED quantity is 3-fold higher and the median SED size is significantly larger. Concomitantly, the overall TAD quantity is increased by 42% while the median TAD size is significantly decreased (p = 9.11E-37) in the hESC genome. Present analyses illustrate a putative global role for HSGRL in shaping the human-specific features of the interphase chromatin organization and functions, which are facilitated by accelerated creation of new enhancers associated with targeted placement of HSGRL at defined genomic coordinates. A trend toward the convergence of TAD and SED architectures of interphase chromatin in the hESC genome may reflect changes of 3D-folding patterns of linear chromatin fibers designed to enhance both regulatory complexity and functional precision of GRNs by creating predominantly a single gene per regulatory domain structures.

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arXiv2016

Malignant field signature analysis in biopsy samples at diagnosis identifies lethal disease in patients with localized Gleason 6 and 7 prostate cancer

Overtreatment of early-stage low-risk prostate cancer (PC) patients represents a significant problem in disease management and has socio-economic implications. Development of genetic and molecular markers of clinically significant disease in patients diagnosed with low grade localized PC would have a major impact in disease management. A gene expression signature (GES) is reported for lethal PC in biopsy specimens obtained at the time of diagnosis from patients with Gleason 6 and Gleason 7 tumors in a Swedish watchful waiting cohort with up to 30 years follow-up. A 98-genes GES identified 89 and 100 percent of all death events 4 years after diagnosis in G7 and G6 patients, respectively; at 6 years follow-up, 83 and 100 percent of all deaths events were captured. Remarkably, the 98-genes GES appears to perform successfully in patients stratification with as little as 2% of cancer cells in a specimen, strongly indicating that it captures a malignant field effect in prostates harboring cancer cells of different degrees of aggressiveness. In G6 and G7 tumors from PC patients of age 65 or younger, GES identified 86 percent of all death events during the entire follow-up period. In G6 and G7 tumors from PC patients of age 70 or younger, GES identified 90 percent of all death events 6 years after diagnosis. Classification performance of the reported in this study 98-genes GES of lethal PC appeared suitable to meet design and feasibility requirements of a prospective 4 to 6 years clinical trial, which is essential for regulatory approval of diagnostic and prognostic tests in clinical setting. Prospectively validated GES of lethal PC in biopsy specimens of G6 and G7 tumors will help physicians to identify, at the time of diagnosis, patients who should be considered for exclusion from active surveillance programs and who would most likely benefit from immediate curative interventions.

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arXiv2015

Phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via two mechanistically distinct pathways of creation of divergent regulatory DNA sequences

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the hypothesis that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Here, conservation patterns analysis of 18,364 candidate HSRS was carried out based on definition of the sequence conservation threshold as the minimum ratio of bases that must remap of 1.00. A total of 5,535 candidate HSRS were identified that are: i) highly conserved in Great Apes; ii) evolved by the exaptation of highly conserved ancestral DNA; iii) defined by either the acceleration of mutation rates on the human lineage or the functional divergence from nonhuman primates. The exaptation of highly conserved ancestral DNA pathway seems mechanistically distinct from the evolution of regulatory DNA segments driven by the species-specific expansion of transposable elements. Present analysis supports the idea that phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via two mechanistically distinct pathways of creation of divergent sequences of regulatory DNA: i) exaptation of the highly conserved ancestral regulatory DNA segments; ii) human-specific insertions of transposable elements.

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arXiv2015

SCARs: endogenous human stem cell-associated retroviruses and therapy-resistant malignant tumors

Discoveries of endogenous human stem cell-associated retroviruses (SCARs) revealed consistent activation of specific endogenous retroviral elements in human preimplantation embryos and documented the essential role of the sustained retroviral activities in the maintenance of pluripotency, functional identity and integrity of naive-state embryonic stem cells, and anti-viral resistance of the early-stage human embryos. Activation of specific SCARs, namely LTR7.HERVH and LTR5Hs.HERVK, has been demonstrated in patients diagnosed with multiple types of cancer, autoimmune diseases, neurodegenerative disorders and it is likely associated with the emergence of clinically lethal therapy resistant death-from-cancer phenotypes in a sub-set of cancer patients diagnosed with different types of malignant tumors.

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arXiv2015

Rapidly evolving in humans topologically associating domains

Genome-wide proximity placement analysis of 10,598 HSGRL within the context of the principal regulatory structures of the interphase chromatin, namely topologically-associating domains (TADs) and specific sub-TAD structures termed super-enhancer domains (SEDs) revealed that 0.8%-10.3% of TADs contain more than half of HSGRL. Of the 3,127 TADs in the hESC genome, 24 (0.8%); 53 (1.7%); 259 (8.3%); and 322 (10.3%) harbor 1,110 (52.4%); 1,936 (50.9%); 1,151 (59.6%); and 1,601 (58.3%) HSGRL sequences from four distinct families, respectively. TADs that are enriched for HSGRL and termed rapidly-evolving in humans TADs (revTADs) manifest distinct correlation patterns between HSGRL placements and recombination rates. There are significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (p < 0.0001 in all instances). In hESC genome, 331 of 504 (66%) of SE-harboring TADs contain HSGRL and 68% of SEs co-localize with HSGRL, suggesting that HSGRL rewired SE-driven GRNs within revTADs by inserting novel and/or erasing existing regulatory sequences. Consequently, markedly distinct features of chromatin structures evolved in hESC compared to mouse: the SE quantity is 3-fold higher and the median SE size is significantly larger; concomitantly, the TAD number is increased by 42% while the median TAD size is decreased (p=9.11E-37). Present analyses revealed a global role for HSGRL in increasing both quantity and size of SEs and increasing the number and size reduction of TADs, which may facilitate a convergence of TAD and SED architectures of interphase chromatin and define a trend of increasing regulatory complexity during evolution of GRNs.

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arXiv2014

Identification and characterization of unique to human regulatory sequences in embryonic stem cells reveal associations with transposable elements, distal enhancers, non-coding RNA, and DNA methylation-driven mechanisms of genome editing

Despite significant progress in structural and functional characterization of human genome, understanding of mechanisms underlying the genetic basis of human phenotypic uniqueness remains limited. We report that non-randomly distributed transposable element-derived sequences, most notably HERV-H/LTR7 and L1HS, are associated with creation of 99.8% unique to human transcription factor binding sites in genome of embryonic stem cells (ESC). 4,094 unique to human regulatory loci display selective and site-specific binding of critical regulators (NANOG, POU5F1, CTCF, Lamin B1) and are preferentially placed within the matrix of transcriptionally active DNA segments hyper-methylated in ESC. Unique to human NANOG-binding sites are enriched near the rapidly evolving in primates protein-coding genes regulating brain size, pluripotency lncRNAs, hESC enhancers, and 5-hydroxymethylcytosine-harboring regions immediately adjacent to binding sites. We propose a proximity placement model explaining how 33-47% excess of NANOG and POU5F1 proteins immobilized on a DNA scaffold may play a functional role at distal regulatory elements.

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