Biology subjects

Gennadi Glinsky

Publications and source records attributed to Gennadi Glinsky.

5 recordsLinked to original sources

bioRxiv2016

Microarray analysis identifies malignant field signatures in biopsy samples at diagnosis predicting the likelihood of lethal disease in patients with localized Gleason 6 and 7 prostate cancer.

Overtreatment of early-stage low-risk prostate cancer patients represents a significant problem in disease management and has significant socio-economic implications. Development of genetic and molecular markers of clinically significant disease in patients diagnosed with low grade localized prostate cancer would have a major impact in disease management. A gene expression signature (GES) is reported for lethal prostate cancer 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% of all death events 4 years after diagnosis in Gleason 7 and Gleason 6 patients, respectively; at 6 years follow-up, 83% and 100% of all deaths events were captured in Gleason 7 and Gleason 6 patients, respectively. 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 human prostates harboring cancer cells of different degrees of aggressiveness. In Gleason 6 and Gleason 7 tumors from prostate cancer patients of age 65 or younger, GES identified 86% of all death events during the entire follow-up period. In Gleason 6 and Gleason 7 tumors from prostate cancer patients of age 70 or younger, GES identified 90% of all death events 6 years after diagnosis. Classification performance of the reported in this study 98-genes GES of lethal prostate cancer 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 Gleason 6 and Gleason 7 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.

Genomics↗

bioRxiv2015

Conservation patterns’ analysis of 18,364 candidate human-specific regulatory sequences revealed two distinct pathways of the human regulatory DNA divergence

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the idea that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Here, conservation patterns analysis of 18,364 regulatory DNA segments comprising candidate HSRS was carried out using the most recent releases of the reference genomes databases of humans and nonhuman primates (NHP) and defining the sequence conservation threshold as the minimum ratio of bases that must remap of 1.00. Present analyses identified 5,535 candidate HSRS defined by either the acceleration of mutation rates on the human lineage or the functional divergence from chimpanzee that are highly conserved in NHP and appear to evolve by the exaptation of ancestral DNA pathway. This pathway seems mechanistically distinct from the evolution of regulatory DNA driven by the species-specific expansion of transposable elements. It is proposed that phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via at least 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.

Genomics↗

bioRxiv2015

Effects of reference databases’ refinements on the validity of molecular definitions of 15,371 candidate human-specific regulatory sequences

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the idea that unique to human phenotypes result from human-specific changes to genomic regulatory networks (GRNs). The sequence quality of reference genome databases is essential for the accurate definition of regulatory DNA segments as candidate HSRS. It is unclear how database improvements would affect the validity of the HSRS definition. Sequence conservation analysis of 15,371 candidate HSRS was carried out using the most recent releases of reference genomes databases of humans and nonhuman primates (NHP) defining the conservation threshold as the minimum ratio of bases that must remap of 1.00. This analysis identifies 3,793 regulatory DNA segments that lack evidence of human-specific mutations and represent regulatory sequences highly conserved in humans, Bonobo, and Chimpanzee. Present analysis revealed a major database refinements effect on the validity of HSRS definition and suggests that human-specific phenotypes may evolve as a results of integration into human-specific GRNs of both conserved in NHP and human-specific genomic regulatory elements.

Genomics↗

bioRxiv2015

Endogenous human stem cell-associated retroviruses

Recent 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. SCARs activity have been implicated in seeding thousands human-specific regulatory sequences in the hESC genome. Activation of specific SCARs, namely LTR7/HERVH and LTR5_Hs/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.

Genomics↗

bioRxiv2015

Remodeling of the interphase chromatin domain structures in embryonic stem cells by targeted placement of human-specific regulatory loci

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 termed rapidly-evolving in humans TADs (revTADs; Genome Biol Evol. 2016 8; 2774-88). Here, human-specific genomic features of pluripotency regulatory networks in hESC have been analyzed. The primary focus was on identification of human-specific elements of the interphase chromatin architecture of TADs responsible for transcriptional regulatory control of the NANOG, POU5F1, and POU3F2 genes. Comparative analyses of the four adjacent TADs spanning ~3.3 Mb NANOG locus-associated genomic region were carried-out to highlight primate-specific genomic features. Lastly, the putative mechanisms of the genome-wide regulatory effects of human-specific NANOG-binding sites (HSNBS) on expression of genes implicated in the fetal and adult brain development have been examined. Acquisition of primate-specific regulatory loci appears to rewire TADs exerting transcriptional control on pluripotency regulators, revealing a genomic placement pattern consistent with the enhanced regulatory impact of NANOG in primates. Proximity placement analysis of HSNBS identified a large expression signature in the human fetal neocortex temporal lobe comprising 4,957 genes, which appear to retain acquired in the embryo expression changes for many years of human brain development and maintain highly concordant expression profiles in the neocortex and prefrontal cortex regions of adult human brain. Collectively, reported herein observations indicate that genomic elements of pluripotency regulatory circuitry associated with HSNBS, specifically proteins of the classical NurD chromatin remodeling complex, contribute to transcriptional regulation of a large set of genes implicated in development and function of human brain.\n\nList of abbreviations5hmC, 5-Hydromethylcytosine\n\nCTCF, CCCTC-binding factor\n\nDHS, DNase hypersensitivity sites\n\nFHSRR, fixed human-specific regulatory regions\n\nGRNs, genomic regulatory networks\n\nHAR, human accelerated regions\n\nhCONDEL, human-specific conserved deletions\n\nhESC, human embryonic stem cells\n\nHSGRL, human-specific genomic regulatory loci\n\nHSNBS, human-specific NANOG-binding sites\n\nHSTFBS, human-specific transcription factor-binding sites\n\nLAD, lamina-associated domain\n\nLINE, long interspersed nuclear element\n\nlncRNA, long non-coding RNA\n\nLTR, long terminal repeat\n\nMADE, methylation-associated DNA editing\n\nmC, methylcytosine\n\nmESC, mouse embryonic stem cells\n\nNANOG, Nanog homeobox\n\nnt, nucleotide\n\nPOU5F1, POU class 5 homeobox 1\n\nPSDS, partial strand displacement state\n\nTAD, topologically associating domains\n\nTE, transposable elements\n\nTF, transcription factor\n\nTSC, triple-stranded complex\n\nTSS, transcription start sites\n\nSE, super-enhancers\n\nSED, super-enhancer domains\n\nsncRNA, small non coding RNA

Genomics↗