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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 451 records · Page 25
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. Recent data indicate the presence of cancer stem cells (CSC) in many solid tumors, including HNSCC. Here, we assessed the stem cell (SC) characteristics, including cell surface markers, radioresistance, chromosomal instability, and in vivo tumorigenic capacity of CSC isolated from HNSCC patient specimens. We show that spheroid enrichment of CSC from early and short-term HNSCC cell cultures was associated with increased expression of CD44, CD133, SOX2 and BMI1 compared with normal oral epithelial cells. On immunophenotyping, five of 12 SC/CSC markers were homogenously expressed in all tumor cultures, while one of 12 was negative, four of 12 showed variable expression, and two of the 12 were expressed heterogeneously. We showed that irradiated CSCs survived and retained their self-renewal capacity across different ionizing radiation (IR) regimens. Fluorescence in situ hybridization (FISH) analyses of parental and clonally-derived tumor cells revealed different chromosome copy numbers from cell to cell, suggesting the presence of chromosomal instability in HNSCC CSC. Further, our in vitro and in vivo mouse engraftment studies suggest that CD44+/CD66− is a promising, consistent biomarker combination for HNSCC CSC. Overall, our findings add further evidence to the proposed role of HNSCC CSCs in therapeutic resistance. - Highlights: • Spheroid enrichment selects cancer stem cells (CSC) from head & neck tumors (HNSCC). • Compared to normal epithelial cells, isolated CSC express increased SC/CSC markers. • Isolated CSC display enhanced radioresistance, clonogenicity and tumorigenicity. • HNSCC CSC express chromosomal instability. • CD44+/CD66− is a promising, consistent biomarker for HNSCC CSC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Folate deficiency drives mitotic missegregation of the human FRAXA locus

The instability of chromosome fragile sites is implicated as a causative factor in several human diseases, including cancer [for common fragile sites (CFSs)] and neurological disorders [for rare fragile sites (RFSs)]. Previous studies have indicated that problems arising during DNA replication are the underlying source of this instability. Although the role of replication stress in promoting instability at CFSs is well documented, much less is known about how the fragility of RFSs arises. Many RFSs, as exemplified by expansion of a CGG trinucleotide repeat sequence in the fragile X syndrome-associated FRAXA locus, exhibit fragility in response to folate deficiency or other forms of “folate stress.” We hypothesized that such folate stress, through disturbing the replication program within the pathologically expanded repeats within FRAXA, would lead to mitotic abnormalities that exacerbate locus instability. Here, we show that folate stress leads to a dramatic increase in missegregation of FRAXA coupled with the formation of single-stranded DNA bridges in anaphase and micronuclei that contain the FRAXA locus. Moreover, chromosome X aneuploidy is seen when these cells are exposed to folate deficiency for an extended period. We propose that problematic FRAXA replication during interphase leads to a failure to disjoin the sister chromatids during anaphase. This generates further instability not only at FRAXA itself but also of chromosome X. These data have wider implications for the effects of folate deficiency on chromosome instability in human cells.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2003

Induction of genomic instability in TK6 human lymphoblasts exposed to 137Cs gamma radiation: comparison to the induction by exposure to accelerated 56Fe particles

The induction of genomic instability in TK6 human lymphoblasts by exposure to (137)Cs gamma radiation was investigated by measuring the frequency and characteristics of unstable clones isolated approximately 36 generations after exposure. Clones surviving irradiation and control clones were analyzed for 17 characteristics including chromosomal aberrations, growth defects, alterations in response to a second irradiation, and mutant frequencies at the thymidine kinase and Na(+)/K(+) ATPase loci. Putative unstable clones were defined as those that exhibited a significant alteration in one or more characteristics compared to the controls. The frequency and characteristics of the unstable clones were compared in clones exposed to (137)Cs gamma rays or (56)Fe particles. The majority of the unstable clones isolated after exposure to either gamma rays or (56)Fe particles exhibited chromosomal instability. Alterations in growth characteristics, radiation response and mutant frequencies occurred much less often than cytogenetic alterations in these unstable clones. The frequency and complexity of the unstable clones were greater after exposure to (56)Fe particles than to gamma rays. Unstable clones that survived 36 generations after exposure to gamma rays exhibited increases in the incidence of dicentric chromosomes but not of chromatid breaks, whereas unstable clones that survived 36 generations after exposure to (56)Fe particles exhibited increases in both chromatid and chromosome aberrations.

Non-NASA Center↗
NASA NTRS1996

Radiogenic transformation of human mammary epithelial cells in vitro

Cancer induction by space radiations is a major concern for manned space exploration. Accurate assessment of radiation risk at low doses requires basic understanding of mechanism(s) of radiation carcinogenesis. For determining the oncogenic effects of ionizing radiation in human epithelial cells, we transformed a mammary epithelial cell line (185B5), which was immortalized by benzo(a)pyrene, with energetic heavy ions and obtained several transformed clones. These transformed cells showed growth properties on Matrigel similar to human mammary tumor cells. To better understand the mechanisms of radiogenic transformation of human cells, we systematically examined the alterations in chromosomes and cancer genes. Among 16 autosomes examined for translocations, by using fluorescence in situ hybridization (FISH) technique, chromosomes 3, 12, 13, 15, 16, and 18 appeared to be normal in transformed cells. Chromosomes 1, 4, 6, 8, and 17 in transformed cells, however, showed patterns different from those in nontransformed cells. Southern blot analyses indicated no detectable alterations in myc, ras, Rb, or p53 genes. Further studies of chromosome 17 by using in situ hybridization with unique sequence p53 gene probe and a centromere probe showed no loss of p53 gene in transformed cells. Experimental results from cell fusion studies indicated that the transforming gene(s) is recessive. The role of genomic instability and tumor suppressor gene(s) in radiogenic transformation of human breast cells remains to be identified.

NASA Center JSC↗
NASA NTRS1984

Karyological observations

Root tips prepared for metaphase chromosome analysis from seedlings germinated under microgravity on the Space Shuttle (oats and mung bean) or which were exposed to space flight as very young seedlings (sunflower) have been examined. Experimental constraints did not permit pre-fixation in space with a cytostatic agent but arrest was achieved in the first division cycle on Earth after recovery. The number of cells in division was significantly depressed in all three species. Several chromosomal abnormalities were encountered in flight material. Bridge formation was seen in sunflower, as was aneuploidy. Breakage and fracture of chromosomes was prevalent in oats. No aberrant features could be detected in the chromosomes of mung bean. These results, although preliminary, should serve to alert investigators of the need to assess carefully as many aspects of cell division in higher plants exposed to space flight conditions as possible.

STS-2 Shuttle Project↗
NASA NTRS1997

Biodosimetry results from space flight Mir-18

Astronauts are classified as radiation workers due to the presence of ionizing radiation in space. For the assessment of health risks, physical dosimetry has been indispensable. However, the change of the location of dosimeters on the crew members, the variation in dose rate with location inside the spacecraft and the unknown biological effects of microgravity can introduce significant uncertainties in estimating exposure. To circumvent such uncertainty, a study on the cytogenetic effects of space radiation in human lymphocytes was proposed and conducted for Mir-18, a 115-day mission. This study used fluorescence in situ hybridization (FISH) with whole-chromosome painting probes to score chromosomal exchanges and the Giemsa staining method to determine the frequency of dicentrics. The growth kinetics of cells and sister chromatid exchanges (SCEs) were examined to ensure that chromosomal aberrations were scored in the first mitosis and were induced primarily by space radiation. Our results showed that the frequency of chromosomal aberrations increased significantly in postflight samples compared to samples drawn prior to flight, and that the frequency of SCEs was similar for both pre- and postflight samples. Based on a dose-response curve for preflight samples exposed to gamma rays, the absorbed dose received by crew members during the mission was estimated to be about 14.75 cSv. Because the absorbed dose measured by physical dosimeters is 5.2 cGy for the entire mission, the RBE is about 2.8.

NASA Discipline Radiation Health↗
DOE OSTI2010

Influence of GSTs, CYP2E1 and mEH polymorphisms on 1, 3-butadiene-induced micronucleus frequency in Chinese workers

1,3-butadiene (BD) has been classified as a human carcinogen, however, the relationship between chromosomal damage and its metabolic polymorphisms is not clear. The present study used the CBMN assay to detect chromosomal damage in the peripheral lymphocytes of 166 exposed workers and 41 non-exposed healthy individuals. PCR and PCR-RFLP were applied to detect GSTT1, GSTM1, CYP2E1 c1c2 and mEH Tyr113His, His139Arg polymorphisms. The results demonstrated that the micronucleus (MN) frequency of the exposed workers was significantly higher than controls (P < 0.01). Among the exposed workers, the individuals with high BD exposures are more susceptible to chromosomal damage than those with low exposures (FR = 1.30, 95% CI 1.14-1.53; P < 0.05). Gender-difference was also found in our study: males got lower micronucleus frequency than females. Workers who carried the genotypes of GSTM1 (+), CYP2E1 (c1c2/c2c2) and mEH intermediate (I) group had significantly higher MN frequency than those carrying the genotypes of GSTM1 (-) (FR = 1.29, 95% CI 1.05-1.59; P < 0.05), CYP2E1 (c1c1) (FR = 1.55, 95% CI 1.24-1.93; P < 0.01) or mEH high (H) group (FR = 1.57, 95% CI 1.08-2.34; P < 0.05), respectively. Our data indicated that the current BD exposure level could cause significantly higher MN frequency in workers than controls. Polymorphisms of GSTM1, CYP2E1 and mEH are susceptible to altered chromosome damage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Analysis of muntjac deer genome and chromatin architecture reveals rapid karyotype evolution

Abstract Closely related muntjac deer show striking karyotype differences. Here we describe chromosome-scale genome assemblies for Chinese and Indian muntjacs, Muntiacus reevesi (2 n = 46) and Muntiacus muntjak vaginalis (2 n = 6/7), and analyze their evolution and architecture. The genomes show extensive collinearity with each other and with other deer and cattle. We identified numerous fusion events unique to and shared by muntjacs relative to the cervid ancestor, confirming many cytogenetic observations with genome sequence. One of these M. muntjak fusions reversed an earlier fission in the cervid lineage. Comparative Hi-C analysis showed that the chromosome fusions on the M. muntjak lineage altered long-range, three-dimensional chromosome organization relative to M. reevesi in interphase nuclei including A/B compartment structure. This reshaping of multi-megabase contacts occurred without notable change in local chromatin compaction, even near fusion sites. A few genes involved in chromosome maintenance show evidence for rapid evolution, possibly associated with the dramatic changes in karyotype.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Population-based 3D genome structure analysis reveals driving forces in spatial genome organization

Significance We provide a method for population-based structure modeling of whole diploid genomes using Hi-C data. The method considers the stochastic nature of chromosome structures, which allows a detailed analysis of the dynamic landscape of genome organizations. We predict and experimentally validate the presence of chromosome-specific higher-order centromere clusters, which can play a key role in the spatial organization of the human genome, specifically influencing the overall chromosome positioning, as well as the preference of specific chromosome conformations. Our approach generate predictive structural models of diploid genomes from Hi-C data, which can provide insights into the guiding principles of 3D genome organizations.

3D genome organization↗
DOE OSTI2016

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

The ring-shaped cohesin complex topologically entraps chromosomes and regulates chromosome segregation, transcription, and DNA repair. The cohesin core consists of the structural maintenance of chromosomes 1 and 3 (Smc1–Smc3) heterodimeric ATPase, the kleisin subunit sister chromatid cohesion 1 (Scc1) that links the two ATPase heads, and the Scc1-bound adaptor protein Scc3. The sister chromatid cohesion 2 and 4 (Scc2–Scc4) complex loads cohesin onto chromosomes. Mutations of cohesin and its regulators, including Scc2, cause human developmental diseases termed cohesinopathy. Here, we report the crystal structure of Chaetomium thermophilum (Ct) Scc2 and examine its interaction with cohesin. Similar to Scc3 and another Scc1-interacting cohesin regulator, precocious dissociation of sisters 5 (Pds5), Scc2 consists mostly of helical repeats that fold into a hook-shaped structure. Scc2 binds to Scc1 through an N-terminal region of Scc1 that overlaps with its Pds5-binding region. Many cohesinopathy mutations target conserved residues in Scc2 and diminish Ct Scc2 binding to Ct Scc1. Pds5 binding to Scc1 weakens the Scc2–Scc1 interaction. Our study defines a functionally important interaction between the kleisin subunit of cohesin and the hook of Scc2. Through competing with Scc2 for Scc1 binding, Pds5 might contribute to the release of Scc2 from loaded cohesin, freeing Scc2 for additional rounds of loading.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Diatom centromeres suggest a mechanism for nuclear DNA acquisition

Significance Centromeres are genomic sites facilitating chromosome segregation during cell division. We report our discovery of diatom centromeres and the description of centromere identity in the stramenopile protists. We also show that simple requirements for diatom centromeres permit ecologically relevant foreign DNA molecules to function as diatom centromeres by “hijacking” chromosome maintenance features. Because little is known at the molecular level about chromosome maintenance in diatoms, this paper provides experimental data with broad implications for cellular biology studies and biotechnology applications. The ability to maintain circular artificial chromosomes using foreign DNA sequences is unique among organisms with studied centromeres and opens up fascinating evolutionary questions about the mechanisms of nuclear gene acquisition from the multiple endosymbiotic events characterizing the stramenopile lineage.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Statistical relationships across epigenomes using large-scale hierarchical clustering

Recent advances in genomics and sequencing platforms have revolutionized our ability to create immense data sets, particularly for studying epigenetic regulation of gene expression. However, the avalanche of epigenomic data is difficult to parse for biological interpretation given nonlinear complex patterns and relationships. This attractive challenge in epigenomic data lends itself to machine learning for discerning infectivity and susceptibility. In this study, we explore over 3000 epigenomes of uninfected individuals and provide a framework to characterize the relationships among epigenetic modifiers, their modifiers, genetic loci, and specific immune cell types across all chromosomes using hierarchical clustering. Hierarchical clustering of epigenomic data revealed consistent epigenetic patterns across chromosomes, demonstrating that variation due to epigenetic modifiers is greater than variation between cell types. Gene Ontology and KEGG pathway analyses indicated significant enrichment of genes involved in chromatin remodeling, mRNA splicing, immune responses, and the regulation of microRNAs and snoRNAs. Epigenetic modifiers frequently formed biologically relevant clusters, including the cohesin complex, RNA Polymerase II transcription factors, and PRC2 complex members. These clustering behaviors remained consistent across all chromosomes, supported by entropy analysis and high Adjusted Rand Index scores, indicating robust cross-chromosomal similarity. Co-occurrence analysis further revealed specific sets of modifiers that consistently appeared together within clusters, reflecting shared biological functions and interactions. Validation using another dataset confirmed the reproducibility of these clustering patterns and modifier co-occurrence relationships, underscoring the reliability and generalizability of the methodology.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2021

Genomic region associated with run timing has similar haplotypes and phenotypic effects across three lineages of Chinook salmon

Abstract Conserving life‐history variation is a stated goal of many management programs, but the most effective means by which to accomplish this are often far from clear. Early‐ and late‐migrating forms of Chinook salmon ( Oncorhynchus tshawytscha ) face unequal pressure from natural and anthropogenic forces that may alter the impacts of genetic variation underlying heritable migration timing. Genomic regions of chromosome 28 are known to be strongly associated with migration variation in adult Chinook salmon, but it remains unclear whether there is consistent association among diverse lineages and populations in large basins such as the Columbia River. With high‐throughput genotyping (GT‐seq) and phenotyping methods, we examined the association of genetic variation in 28 markers (spanning GREB1L to ROCK1 of chromosome 28) with individual adult migration timing characteristics gleaned from passive integrated transponder recordings of over 5000 Chinook salmon from the three major phylogeographic lineages that inhabit the Columbia River Basin. Despite the strong genetic differences among them in putatively neutral genomic regions, each of the three lineages exhibited very similar genetic variants in the chromosome 28 region that were significantly associated with adult migration timing phenotypes. This is particularly notable for the interior stream‐type lineage, which exhibits an earlier and more constrained freshwater entry than the other lineages. In both interior stream‐type and interior ocean‐type lineages of Chinook salmon, heterozygotes of the most strongly associated linkage groups had largely intermediate migration timing relative to homozygotes, and results indicate codominance or possibly marginal partial dominance of the allele associated with early migration. Our results lend support to utilization of chromosome 28 variation in tracking and predicting run timing in these lineages of Chinook salmon in the Columbia River.

Willis, Stuart C.↗
DOE OSTI2024

Assembly, comparative analysis, and utilization of a single haplotype reference genome for soybean

Cultivar Williams 82 has served as the reference genome for the soybean research community since 2008, but is known to have areas of genomic heterogeneity among different sub-lines. This work provides an updated assembly (version Wm82.a6) derived from a specific sub-line known as Wm82-ISU-01 (seeds available under USDA accession PI 704477). The genome was assembled using Pacific BioSciences HiFi reads and integrated into chromosomes using HiC. The 20 soybean chromosomes assembled into a genome of 1.01Gb, consisting of 36 contigs. The genome annotation identified 48 387 gene models, named in accordance with previous assembly versions Wm82.a2 and Wm82.a4. Comparisons of Wm82.a6 with other near-gapless assemblies of Williams 82 reveal large regions of genomic heterogeneity, including regions of differential introgression from the cultivar Kingwa within approximately 30 Mb and 25 Mb segments on chromosomes 03 and 07, respectively. Additionally, our analysis revealed a previously unknown large (> 20 Mb) heterogeneous region in the pericentromeric region of chromosome 12, where Wm82.a6 matches the ‘Williams’ haplotype while the other two near-gapless assemblies do not match the haplotype of either parent of Williams 82. In addition to the Wm82.a6 assembly, we also assembled the genome of ‘Fiskeby III,’ a rich resource for abiotic stress resistance genes. A genome comparison of Wm82.a6 with Fiskeby III revealed the nucleotide and structural polymorphisms between the two genomes within a QTL region for iron deficiency chlorosis resistance. The Wm82.a6 and Fiskeby III genomes described here will enhance comparative and functional genomics capacities and applications in the soybean community.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Versatile allelic replacement and self-excising integrative vectors for plasmid genome mutation and complementation

ABSTRACT The ability to better understand the function of proteins expressed by bacteria has typically relied upon the development of genetic mutant strains. This approach has been especially challenging for plasmid-encoded genes, as most of the previously described allelic replacement vectors are inefficient for plasmid genome mutation as they either rely on plasmid-derived counterselection toxins or depend on other strategies suchsacB,tetA, andrpsLwhich have been proven to be less efficient for mutant selection. Integrative vectors lack chromophore indicators, thus requiring laborious screening or excision of the vector’s backbone relies on the introduction of a flippase (FLP)-expressing plasmid. The allelic replacement vector, designated here as pDG1, expresses an X-Gal hydrolyzing enzyme (BgaB) that can be used for blue/white screening allowing identification of colonies that integrated and successfully removed the mutagenesis plasmid without a bias for those still carrying it. pDG1 was further improved by including the rhamnose-inducible Tse2 toxin as a potent counterselection system. The efficacy of pDG1 was validated by deleting portions of the plasmid-encoded VirB4/D4 type IV secretion system and aerobactin-synthesizing operons inSalmonella enterica. The integrative vectors, which contain an ΦC31attPsite and genes encoding ΦC31 integrase (int), can seamlessly integrate to target ΦC31attBonSalmonellaplasmids or chromosome. These vectors were improved by insertingbgaBand FLP-encoding genes so that, following integration, most of the vector’s backbone encompassingint,bgaB, and FLP genes can be excised by FLP, without the need for another FLP-expressing vector, creating white colonies carrying a stably integrated target gene. As such, we were able to integrate a 9.3-kb DNA fragment toSalmonellachromosome and flipped out most of the integrated vector in one step, leaving the target fragment in the chromosome. IMPORTANCE In spite of the dissemination of multidrug-resistant plasmids among Gram-negative pathogens, including those carrying virulence genes, vector tools for studying plasmid-born genes are lacking. The allelic replacement vectors can be used to generate plasmid or chromosomal mutations including markless point mutations. This is the first report describing a self-excising integrative vector that can be used as a stable single-copy complementing tool to study medically important pathogens includingin vivostudies without the need for antibiotic selection. Overall, our newly developed vectors can be applied for the assessment of the function of plasmid-encoded genes by specifically creating mutations, moving large operons between plasmids and to/from the chromosome, and complementing phenotypes associated with gene mutation. Furthermore, the vectors express chromophores for the detection of target gene modification or colony isolation, avoiding time-consuming screening procedures.

Microbiology↗
DOE OSTI2012

Genomic determinants of organohalide-respiration in Geobacter lovleyi, an unusual member of the Geobacteraceae

Background: Geobacter lovleyi is a unique member of the Geobacteraceae because strains of this species share the ability to couple tetrachloroethene (PCE) reductive dechlorination to cis-1,2-dichloroethene (cis-DCE) with energy conservation and growth (i.e., organohalide respiration). Strain SZ also reduces U(VI) to U(IV) and contributes to uranium immobilization, making G. lovleyi relevant for bioremediation at sites impacted with chlorinated ethenes and radionuclides. G. lovleyi is the only fully sequenced representative of this distinct Geobacter clade, and comparative genome analyses identified genetic elements associated with organohalide respiration and elucidated genome features that distinguish strain SZ from other members of the Geobacteraceae. Results: Sequencing the G. lovleyi strain SZ genome revealed a 3.9 Mbp chromosome with 54.7% GC content (i.e., the percent of the total guanines (Gs) and cytosines (Cs) among the four bases within the genome), and average amino acid identities of 53–56% compared to other sequenced Geobacter spp. Sequencing also revealed the presence of a 77 kbp plasmid, pSZ77 (53.0% GC), with nearly half of its encoded genes corresponding to chromosomal homologs in other Geobacteraceae genomes. Among these chromosome-derived features, pSZ77 encodes 15 out of the 24 genes required for de novo cobalamin biosynthesis, a required cofactor for organohalide respiration. A plasmid with 99% sequence identity to pSZ77 was subsequently detected in the PCE-dechlorinating G. lovleyi strain KB-1 present in the PCE-to-ethene-dechlorinating consortium KB-1. Additional PCE-to-cis-DCE dechlorinating G. lovleyi strains obtained from the PCE-contaminated Fort Lewis, WA, site did not carry a plasmid indicating that pSZ77 is not a requirement (marker) for PCE respiration within this species. Chromosomal genomic islands found within the G. lovleyi strain SZ genome encode two reductive dehalogenase (RDase) homologs and a putative conjugative pilus system. Despite the loss of many c-type cytochrome and oxidative-stress-responsive genes, strain SZ retained the majority of Geobacter core metabolic capabilities, including U(VI) respiration. Conclusions: Gene acquisitions have expanded strain SZ’s respiratory capabilities to include PCE and TCE as electron acceptors. Respiratory processes core to the Geobacter genus, such as metal reduction, were retained despite a substantially reduced number of c-type cytochrome genes. pSZ77 is stably maintained within its host strains SZ and KB-1, likely because the replicon carries essential genes including genes involved in cobalamin biosynthesis and possibly corrinoid transport. Lateral acquisition of the plasmid replicon and the RDase genomic island represent unique genome features of the PCE-respiring G. lovleyi strains SZ and KB-1, and at least the latter signifies adaptation to PCE contamination.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2011

Cytogenetic analysis of an exposed-referent study: perchloroethylene-exposed dry cleaners compared to unexposed laundry workers

Background: Significant numbers of people are exposed to tetrachloroethylene (perchloroethylene, PCE) every year, including workers in the dry cleaning industry. Adverse health effects have been associated with PCE exposure. However, investigations of possible cumulative cytogenetic damage resulting from PCE exposure are lacking. Methods: Eighteen dry cleaning workers and 18 laundry workers (unexposed controls) provided a peripheral blood sample for cytogenetic analysis by whole chromosome painting. Pre-shift exhaled air on these same participants was collected and analyzed for PCE levels. The laundry workers were matched to the dry cleaners on race, age, and smoking status. The relationships between levels of cytological damage and exposures (including PCE levels in the shop and in workers’ blood, packyears, cumulative alcohol consumption, and age) were compared with correlation coefficients and t-tests. Multiple linear regressions considered blood PCE, packyears, alcohol, and age. Results: There were no significant differences between the PCE-exposed dry cleaners and the laundry workers for chromosome translocation frequencies, but PCE levels were significantly correlated with percentage of cells with acentric fragments (R 2 = 0.488, p < 0.026). Conclusions: There does not appear to be a strong effect in these dry cleaning workers of PCE exposure on persistent chromosome damage as measured by translocations. However, the correlation between frequencies of acentric fragments and PCE exposure level suggests that recent exposures to PCE may induce transient genetic damage. More heavily exposed participants and a larger sample size will be needed to determine whether PCE exposure induces significant levels of persistent chromosome damage.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2026

From 2D to 4D: a containerized workflow and browser to explore dynamic chromatin architecture

Background Characterizing the physical organization of the genome is essential for understanding long-range gene regulation, chromatin compartmentalization, and epigenetic accessibility. Hi-C experiments generate two-dimensional (2D) genome-wide contact maps of chromatin interactions by capturing the spatial proximity between genomic loci, which reveal interaction frequencies but lack the spatial resolution needed to interpret the three-dimensional (3D) genome structure(s). Emerging evidence suggests that epigenetic regulation is closely linked to 3D genome architecture, and that structural changes over time (4D) drive key biological processes in development, disease, and environmental response. Thus, integrating 3D structure with functional data is critical for a more complete understanding of genome regulation. Previous work, most notably the 4DHiC chromosome modeling framework, has shown that physical multi-dimensional modeling approaches rooted in polymer physics and molecular dynamics can resolve these structures at biologically meaningful resolutions by integrating temporal Hi-C data with physical constraints to uncover dynamic chromosome reorganization. Thus, molecular dynamics simulations, constrained by Hi-C contact matrices, can resolve fine-scale structural changes and reveal functionally significant transitions in chromatin conformation. Results Herein, we present the 4D Genome Browser Workflow (4DGBWorkflow) and the 4D Genome Browser (4DGB). The algorithm is based on the 4DHiC method, and the containerized tool is an end-to-end workflow that can transform, filter, and view 4D epigenomics and chromatin datasets, allowing non-specialists to apply three-dimensional modeling principles to diverse datasets and experimental conditions. The software executes on a laptop running macOS, Linux or Windows. From input Hi-C files (.hic), the 4DGBWorkflow produces 3D reconstructions of chromosomes, integrates the reconstruction with track data (e.g., epigenetic marks, transcriptome profiles), and provides comparative visualization of the results in a single workflow. Conclusions The 4DGBWorkflow and 4D Genome Browser are open-source tools for comparative analysis and visualization of 4D chromosome datasets, including chromatin architecture and epigenomic signals. Automatic integration of Hi-C data with molecular dynamics democratizes the construction of time resolved 3D genome structures, simplifying complex simulations and data integration schemes.

3D Genome Browser↗