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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 217 records · Page 12
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

An atlas of dynamic chromatin landscapes in mouse fetal development

The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP–seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC–seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Perspectives on ENCODE

The Encyclopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression. The project has been extended to model organisms, particularly the mouse. Finally, in the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Author Correction: Perspectives on ENCODE

In the original article, the authors Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) were mistakenly omitted from the ENCODE Project Consortium author list. The original Article has been corrected online.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2022

Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes

In the version of this article initially published, two members of the ENCODE Project Consortium were missing from the author list. Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) are now included in the author list. These errors have been corrected in the online version of the article.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Increased enhancer–promoter interactions during developmental enhancer activation in mammals

Remote enhancers are thought to interact with their target promoters via physical proximity, yet the importance of this proximity for enhancer function remains unclear. Here, in this study, we investigate the three-dimensional (3D) conformation of enhancers during mammalian development by generating high-resolution tissue-resolved contact maps for nearly a thousand enhancers with characterized in vivo activities in ten murine embryonic tissues. Sixty-one percent of developmental enhancers bypass their neighboring genes, which are often marked by promoter CpG methylation. The majority of enhancers display tissue-specific 3D conformations, and both enhancer-promoter and enhancer-enhancer interactions are moderately but consistently increased upon enhancer activation in vivo. Less than 14% of enhancer-promoter interactions form stably across tissues; however, these invariant interactions form in the absence of the enhancer and are likely mediated by adjacent CTCF binding. Our results highlight the general importance of enhancer-promoter physical proximity for developmental gene activation in mammals.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Supervised enhancer prediction with epigenetic pattern recognition and targeted validation

Enhancers are important non-coding elements, but they have traditionally been hard to characterize experimentally. The development of massively parallel assays allows the characterization of large numbers of enhancers for the first time. Here, we developed a framework using Drosophila STARR-seq to create shape-matching filters based on meta-profiles of epigenetic features. We integrated these features with supervised machine-learning algorithms to predict enhancers. We further demonstrated that our model could be transferred to predict enhancers in mammals. We comprehensively validated the predictions using a combination of in vivo and in vitro approaches, involving transgenic assays in mice and transduction-based reporter assays in human cell lines (153 enhancers in total). The results confirmed that our model can accurately predict enhancers in different species without re-parameterization. Finally, we examined the transcription factor binding patterns at predicted enhancers versus promoters. Here, we demonstrated that these patterns enable the construction of a secondary model that effectively distinguishes enhancers and promoters.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Topologically associating domain boundaries are required for normal genome function

Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes1,2,3, but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11–80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Transcriptional network orchestrating regional patterning of cortical progenitors

We uncovered a transcription factor (TF) network that regulates cortical regional patterning in radial glial stem cells. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1, and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer–gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning in the mouse.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Meta-virus resource (MetaVR): expanding the frontiers of viral diversity with 24 million uncultivated virus genomes

Viruses are ubiquitous in all environments and impact host metabolism, evolution, and ecology, although our knowledge of their biodiversity is still extremely limited. Viral diversity from genomic and metagenomic datasets has led to an explosion of uncultivated virus genomes (UViGs) and the development of specialized databases to catalog this viral diversity, though many lack comprehensive integration. Here, we introduce meta-virus resource (MetaVR), the successor of the IMG/VR database, designed to overcome previous limitations such as large-scale querying and programmatic access. Drawing on the increase of publicly available genomes and metagenomes, MetaVR significantly expands viral diversity, now comprising 24,435,662 UViGs, a 57.6% increase from its predecessor, organized into over 12 million viral operational taxonomic units. Key enhancements include the integration of curated eukaryotic host information, the integration of protein clusters and predicted structures for comparative studies, and an API for programmatic data access. Furthermore, MetaVR features an updated taxonomic framework based on ICTV release 39, assignment to Baltimore classes, and enhanced host assignment through novel computational tools like iPHoP. These advancements position MetaVR as a unique resource for exploring viral diversity, evolution, and host interactions across diverse environments. MetaVR can be freely accessed at https://www.meta-virome.org/.

Fiamenghi, Mateus B↗
DOE OSTI2026

metagRoot: a comprehensive database of protein families associated with plant root microbiomes

The plant root microbiome is vital in plant health, nutrient uptake, and environmental resilience. To explore and harness this diversity, we present metagRoot, a specialized and enriched database focused on the protein families of the plant root microbiome. MetagRoot integrates metagenomic, metatranscriptomic, and reference genome-derived protein data to characterize 71 091 enriched protein families, each containing at least 100 sequences. These families are annotated with multiple sequence alignments, CRISPR elements, hidden Markov models, taxonomic and functional classifications, ecosystem and geolocation metadata, and predicted 3D structures using AlphaFold2. MetagRoot is a powerful tool for decoding the molecular landscape of root-associated microbial communities and advancing microbiome-informed agricultural practices by enriching protein family information with ecological and structural context. The database is available at https://pavlopoulos-lab.org/metagroot/ or https://www.metagroot.org.

Chasapi, Maria N↗
DOE OSTI2021

Topologically Associating Domain Boundaries are Commonly Required for Normal Genome Function

Topologically associating domain (TAD) boundaries are thought to partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotype, but the overall extent to which this occurs remains unknown. Here we show that TAD boundary deletions commonly disrupt normal genome function in vivo . We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11-80kb in size) from the genome in mice. All deletions examined resulted in at least one detectable molecular or organismal phenotype, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. For 5 of 8 (62%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and suggest that noncoding deletions affecting TAD boundaries should be carefully considered for potential pathogenicity in clinical genetics screening.

Rajderkar, Sudha↗
DOE OSTI2026

Properties of Heavy Cosmic Nuclei Phosphorus, Chlorine, Argon, Potassium, and Calcium: Results from the Alpha Magnetic Spectrometer

We report the unique properties of cosmic phosphorus (P), chlorine (Cl), argon (Ar), potassium (K), and calcium (Ca) fluxes in the GV to TV rigidity range collected by the Alpha Magnetic Spectrometer (AMS) on the International Space Station. With a total of one million events collected over 13.5 years, we observed that the rigidity dependencies of the five fluxes are well described by the sums of a primary cosmic ray component and a secondary cosmic ray component. The abundance ratios of all five elements to Si at the source are accurately determined independent of cosmic ray propagation. The source abundance of Ar and Ca (even-𝑍 elements) is larger than P, Cl, and K (odd-𝑍 elements). The secondary components of the P and the Cl fluxes are each ∼1/3 of the F flux, and the secondary components of the Ar, K, and Ca fluxes are each ∼1/2 of the F flux. The twenty elements measured by AMS, from He to Ca and Fe, can be categorized into four classes, two primary and two secondary, based on their rigidity dependence.

cosmic ray acceleration↗
DOE OSTI2025

Solar Modulation of Cosmic Nuclei over a Solar Cycle: Results from the Alpha Magnetic Spectrometer

We report the properties of precision time structures of cosmic nuclei He, Li, Be, B, C, N, and O fluxes over an 11-year solar cycle from May 2011 to November 2022 in the rigidity range from 1.92 to 60.3 GV. The nuclei fluxes show similar but not identical time variations with amplitudes decreasing with increasing rigidity. In particular, below 3.64 GV the Li, Be, and B fluxes, and below 2.15 GV the C, N, and O fluxes, are significantly less affected by solar modulation than the He flux. We observe that these differences in solar modulation are linearly correlated with the differences in the spectral indices of the cosmic nuclei fluxes. This shows, in a model-independent way, that solar modulation of galactic cosmic nuclei depends on their spectral shape. In addition, solar modulation differences due to nuclei velocity dependence on the mass-to-charge ratio (𝐴/𝑍) are not observed.

cosmic ray composition & spectra↗
DOE OSTI2025

Antiprotons and Elementary Particles over a Solar Cycle: Results from the Alpha Magnetic Spectrometer

We present results over an 11-year Solar cycle of cosmic antiprotons based on 1.1 × 10 6 events in the rigidity range from 1.00 to 41.9 GV. The $\bar{𝑝}$ fluxes exhibit distinct properties. The magnitude of the $\bar{𝑝}$ flux temporal variation is significantly smaller than those of 𝑝, 𝑒 − , and 𝑒 + . A hysteresis between the $\bar{𝑝}$ fluxes and the 𝑝 fluxes is observed, whereas the $\bar{𝑝}$ and 𝑒 − fluxes show a linear correlation. With a model-independent analysis, we found a universal relation between the shape of the rigidity spectrum and the magnitude of flux temporal variation over an 11-year Solar cycle for both positively and negatively charged particles. The simultaneous results on $\bar{𝑝}$ and 𝑝, 𝑒 − , and 𝑒 + provide unique information for understanding particle transport in the Solar System as a function of mass, charge, and spectral shape.

cosmic ray composition & spectra↗
DOE OSTI2025

Properties of Cosmic Lithium Isotopes Measured by the Alpha Magnetic Spectrometer

We present the first measurement of cosmic-ray fluxes of 6 Li and 7 Li isotopes in the rigidity range from 1.9 to 25 GV. The measurements are based on 9.7 × 10 5 6 Li and 1.04 × 10 6 7 Li nuclei collected by the Alpha Magnetic Spectrometer on the International Space Station from May 2011 to October 2023. We observe that over the entire rigidity range the 6 Li and 7 Li fluxes exhibit nearly identical time variations and, above ∼4 GV, the time variations of 6 Li , 7 Li , He, Be, B, C, N, and O fluxes are identical. Above ∼7 GV, we find an identical rigidity dependence of the 6 Li and 7 Li fluxes. This shows that they are both produced by collisions of heavier cosmic-ray nuclei with the interstellar medium and, in particular, excludes the existence of a sizable primary component in the 7 Li flux.

cosmic ray acceleration↗
DOE OSTI2024

A Functional Survey of the Regulatory Landscape of Estrogen Receptor–Positive Breast Cancer Evolution

Abstract Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.

Oncology↗
DOE OSTI2024

Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells

Patients with estrogen receptor–positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs.

60 APPLIED LIFE SCIENCES↗