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DOE OSTI2025

Non-LWR Regulatory Framework Modernization- Fiscal Year 2024

This report provides an end-of-year summary that reflects the progress and status of Idaho National Laboratory’s (INL’s) activities concerning the development of an advanced-reactor regulatory framework and its implementation in the United States (U.S.). The report also provides recommendations for work to be performed in Fiscal Year (FY)-25 and beyond. This work was completed in FY-24 and was supported by the U.S. Department of Energy (DOE) Regulatory Development sub-program. These activities are managed by INL on behalf of DOE.

22 - GENERAL STUDIES OF NUCLEAR REACTORS↗

DOE OSTI2021

Genome-Wide Transcription Factor DNA Binding Sites and Gene Regulatory Networks in Clostridium thermocellum

Clostridium thermocellum is a thermophilic bacterium recognized for its natural ability to effectively deconstruct cellulosic biomass. While there is a large body of studies on the genetic engineering of this bacterium and its physiology to-date, there is limited knowledge in the transcriptional regulation in this organism and thermophilic bacteria in general. The study herein is the first report of a large-scale application of DNA-affinity purification sequencing (DAP-seq) to transcription factors (TFs) from a bacterium. We applied DAP-seq to > 90 TFs in C. thermocellum and detected genome-wide binding sites for 11 of them. We then compiled and aligned DNA binding sequences from these TFs to deduce the primary DNA-binding sequence motifs for each TF. These binding motifs are further validated with electrophoretic mobility shift assay (EMSA) and are used to identify individual TFs’ regulatory targets in C. thermocellum . Our results led to the discovery of novel, uncharacterized TFs as well as homologues of previously studied TFs including RexA-, LexA-, and LacI-type TFs. We then used these data to reconstruct gene regulatory networks for the 11 TFs individually, which resulted in a global network encompassing the TFs with some interconnections. As gene regulation governs and constrains how bacteria behave, our findings shed light on the roles of TFs delineated by their regulons, and potentially provides a means to enable rational, advanced genetic engineering of C. thermocellum and other organisms alike toward a desired phenotype.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Genome-wide Transcription Factor DNA Binding Sites and Gene Regulatory Networks in Clostridium thermocellum

Clostridium thermocellum is a thermophilic bacterium recognized for its natural ability to effectively deconstruct cellulosic biomass. While there is a large body of studies on the genetic engineering of this bacterium and its physiology to-date, there is limited knowledge in the transcriptional regulation in this organism and thermophilic bacteria in general. The study herein is the first report of a high-throughput application of DNA-affinity purification sequencing (DAP-seq) to transcription factors (TFs) from a thermophile. We applied DAP-seq to >90 TFs in C. thermocellum and detected genome-wide binding sites for 11 of them. We then compiled and aligned DNA binding sequences from these TFs to deduce the primary DNA-binding sequence motifs for each TF. These binding motifs are further validated with electrophoretic mobility shift assay (EMSA) and are used to identify individual TFs’ regulatory targets in C. thermocellum. Our results led to the discovery of novel, uncharacterized TFs as well as homologues of previously studied TFs including RexA-, LexA- and LacI-type TFs. We then used these data to reconstruct gene regulatory networks for the 11 TFs individually, which resulted in a global network encompassing the TFs with some interconnections. As gene regulation governs and constrains how bacteria behave, our findings shed light on the roles of TFs delineated by their regulons, and potentially provides a means to enable rational, advanced genetic engineering of C. thermocellum and other organisms alike towards a desired phenotype.

09 BIOMASS FUELS↗

DOE OSTI2021

Summary Status of FY21 Regulatory Framework Development Activities and Associated Progress.

This report provides an end-of-year summary that reflects the progress and status of Idaho National Laboratory’s activities concerning advanced reactor regulatory framework development and implementation in the U.S. This work was done in FY 2021 and supported regulatory development for the U.S. Department of Energy (DOE) Advanced Reactor Technologies Program. These activities are managed by Idaho National Laboratory on behalf of the U.S. DOE.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗

DOE OSTI2024

AquaPV: Regulatory and Environmental Considerations for Floating Photovoltaic Projects Located on Federally Controlled Reservoirs in the United States

To meet the nation's decarbonization goals, the U.S. Department of Energy's Solar Futures study forecasts that installed solar photovoltaic (PV) capacity must increase nearly tenfold, from 80 gigawatts (GW) in 2020 to approximately 760 GW cumulative installed capacity by 2035. Ground-mounted PV is expected to dominate future solar deployment and will require more than 3.5 million acres of land to meet annual demand projections (of nearly 45 GW) by 2030. However, various competing demands for land (e.g., agricultural production, conservation) and high land acquisition costs in specific locations could be challenges to meeting future PV demand solely with ground-mounted PV deployment. Floating photovoltaics (FPV) may be an alternative in locations where ground-mounted PV is not feasible and aid in reaching the nation's PV deployment and decarbonization goals. FPV is a newer siting approach in which a PV array is affixed to a floating apparatus and sited on a water body like a reservoir behind a dam. FPV systems may be stand-alone or co-located at new or existing hydroelectric facilities or pumped storage hydropower (PSH) facility reservoirs. Co-located FPV systems may or may not be operationally paired and work in tandem with the hydroelectric or PSH facility. This report provides novel analysis to understand the opportunities and challenges associated with developing stand-alone and co-located FPV projects on reservoirs in the United States. Specifically, the report explores potential environmental and energy benefits and environmental impacts associated with the siting, construction, and operation of FPV projects. The report also identifies and analyzes U.S. federal- and state-issued permits and authorizations required by federal laws to understand the licensing pathways and regulatory requirements for FPV projects sited on reservoirs licensed by the Federal Energy Regulatory Commission and on powered and non-powered reservoirs owned by the Bureau of Reclamation or U.S. Army Corps of Engineers.

ENERGY PLANNING, POLICY, AND ECONOMY,SOLAR ENERGY↗

DOE OSTI2024

AquaPV: Regulatory and Environmental Considerations for Floating Photovoltaic Projects Located on Federally Controlled Reservoirs in the United States

ENERGY PLANNING, POLICY, AND ECONOMY,SOLAR ENERGY↗

DOE OSTI2024

Non-LWR Regulatory Framework Modernization

This report provides an end-of-year summary that reflects the progress and status of Idaho National Laboratory’s (INL) activities concerning the development of advanced reactor (AR) regulatory framework and its implementation in the United States (U.S.). The report also provides recommendations for work to be performed in Fiscal Year 2025 (FY-25) and beyond. This work was completed in Fiscal Year 2024 (FY-24) and was supported by the U.S. Department of Energy (DOE) Regulatory Development sub-program. These activities are managed by INL on behalf of DOE.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗

DOE OSTI2024

Regulatory Framework Modernization Program

This presentation discusses the work performed/being performed under the DOE Regulatory Development-Regulatory Framework Modernization Area in FY24

99 GENERAL AND MISCELLANEOUS↗

DOE OSTI2026

Change Agent: Energy Storage as a Driver of Regulatory Evolution

Purpose of Review Dividing the electric grid into the functions of generation, transmission, anddistribution enabled the drawing of jurisdictional lines and the application of the U.S.Constitution’s federalist system to energy regulation. Energy storage technologies,which can be placed throughout the grid to increase flexibility, can provide serviceacross all three of those functions. But the jurisdictional boundaries that have beendrawn around those functions have created barriers that restrict energy storagetechnologies from achieving their full potential. This review analyzes regulatory changes made to reduce barriers to storage deployment and their broader impacts on energy regulation in the U.S. Recent Findings Major energy regulations promulgated at the state and federal levels have generally focused on liberalizing the U.S. electric system through deregulation and increased competition. Paradoxically, however, these efforts have erected strict regulatory barriers that prevent energy storage technologies from providing service across multiple functions. A new wave of regulations in recent years has endeavored to reduce and remove those barriers. Summary Energy regulations adopted in recent years to reduce barriers to energy storage functionality in recent years have had deep and far-reaching impacts on U.S. electric regulation. These impacts go beyond storage and affect all energy technologies. This paper traces the development of energy regulation in U.S., the functional barriers that they created that impede energy storage functionality, recent efforts to remove those barriers, and the broader effects of those efforts. It concludes with a brief discussion of remaining barriers that prevent energy storage from reaching their full potential on the U.S. electric grid.

24 POWER TRANSMISSION AND DISTRIBUTION↗

DOE OSTI2026

Evolution of storage monitoring – update in response to commercial and regulatory drivers

Carbon Capture and Storage (CCS) is in transition from first-of-a kind projects and research-orientated pilots to commercially-motivated applications. Monitoring results from many newly developed and planned large scale commercial projects are limited; however, it is worthwhile to assess their evolution and consider new strategies as part of an effort to assess and document best practices. Commercial monitoring is targeted to activities that comply with regulatory drivers and de-risk investments. Commercial monitoring also supports accounting that storage has occurred and is tied to project financing. It deals with long time frames and large volumes injected into multiple wells and multiple projects in favorable areas. We see developing trends toward reproducible workflows that systematically reduce risks and clarify expectations for oversight and long-term surveillance. Monitoring techniques showing increasing trends include injection zone pressure as a history-matching and compliance tool. To reduce cost and environmental impact of time-lapse seismic data collection, deploying new approaches and tools, such as use of fibre and installed sources are increasingly applied. Concern over the risk of induced seismicity by regulatory bodies and the general public has increased, which has also resulted in increased monitoring. Some techniques used in the early research phases have been sidelined or used only in restricted applications. For example, geochemical analyses in the injection zone as well as the environment are now being deployed less than it was in research-oriented programs, except in the US where it is required by the permitting process. Expectations of frequent area-wide near surface monitoring have also decreased.

25 ENERGY STORAGE↗

DOE OSTI2021

Regulatory Considerations in the Development of Radiation-Drug Combinations

Radiation therapy remains a fundamental treatment for patients with cancer. Despite an increasing number of targeted molecular therapies that are US Food and Drug Administration (FDA)-approved for the treatment of patients with metastatic disease, there has been very little progress made in terms of drugs used concurrently with radiation. This article reviews the existing regulatory framework in which cancer drugs may be developed for use in combination with radiation therapy from the perspective of the FDA. To briefly summarize: (1) nonclinical studies are a critical first step to ensure that drugs are safe for use in humans; however, additional nonclinical studies of a drug with radiation may not be required before a clinical trial in combination with radiation as long as the safety profile of the drug has been characterized in humans. The FDA determines the quality of evidence required before studying a drug in combination with radiation on a case-by-case basis. (2) Although often impractical to consider late toxicities during dose-escalation, late adverse events should be captured and taken into consideration when determining the final dose and schedule to take forward during drug development. (3) There are a number of expedited programs for cancer drug development, including accelerated approval, a conditional approval that allows for use of earlier clinical endpoints when the data suggests a clinically meaningful improvement over available therapy. (4) The Agency encourages sponsors to discuss their development plan with the appropriate FDA review division in formal regulatory meetings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2021

Antitumor CD8 T cell responses in glioma patients are effectively suppressed by T follicular regulatory cells

Regulatory T (Treg) cells are thought to contribute to tumor pathogenesis by suppressing tumor immunosurveillance and antitumor immunity. T follicular regulatory (Tfr) cells are a recently characterized Treg subset that expresses both the Treg transcription factor (TF) Foxp3 and the T follicular helper (Tfh) TF Bcl-6. The role of Tfr cells in glioma patients remains unclear. In this study, we found that the level of Tfr cells, identified as Foxp3{sup +}Bcl-6{sup +} CD4 T cells, was significantly elevated in tumor-infiltrating CD4 T cells from resected glioma tumors. Both Tfr cells and Treg cells significantly suppressed the proliferation and the cytotoxic capacity of CD8 T cells toward glioma tumor cells, and the suppression was positively associated with the proportion of Tfr cells and Treg cells, respectively. Tfr and Treg cells from glioma tumor samples demonstrated higher suppression potency than those from healthy blood samples and glioma blood samples. Interestingly, canonical CXCR5{sup -} Treg cells could suppress both CXCR5{sup +} and CXCR5{sup -} CD8 T cells, albeit with stronger potency toward CXCR5{sup -} CD8 T cells. However, Tfr cells presented much higher suppression potency toward CXCR5{sup +} CD8 T cells, whereas CXCR5{sup +} CD8 T cells are a potent CD8 T cell subset previously described to have antiviral and antitumor roles. Overall, these data indicate that Tfr cells are enriched in glioma tumors and have suppressive capacity toward CD8 T cell-mediated effector functions.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Machine-learning from Pseudomonas putida KT2440 transcriptomes reveals its transcriptional regulatory network

Bacterial gene expression is orchestrated by numerous transcription factors (TFs). Elucidating how gene expression is regulated is fundamental to understanding bacterial physiology and engineering it for practical use. In this study, a machine-learning approach was applied to uncover the genome-scale transcriptional regulatory network (TRN) in Pseudomonas putida KT2440, an important organism for bioproduction. We performed independent component analysis of a compendium of 321 high-quality gene expression profiles, which were previously published or newly generated in this study. We identified 84 groups of independently modulated genes (iModulons) that explain 75.7% of the total variance in the compendium. With these iModulons, we (i) expand our understanding of the regulatory functions of 39 iModulon associated TFs (e.g., HexR, Zur) by systematic comparison with 1993 previously reported TF-gene interactions; (ii) outline transcriptional changes after the transition from the exponential growth to stationary phases; (iii) capture group of genes required for utilizing diverse carbon sources and increased stationary response with slower growth rates; (iv) unveil multiple evolutionary strategies of transcriptome reallocation to achieve fast growth rates; and (v) define an osmotic stimulon, which includes the Type VI secretion system, as coordination of multiple iModulon activity changes. Taken together, this study provides the first quantitative genome-scale TRN for P. putida KT2440 and a basis for a comprehensive understanding of its complex transcriptome changes in a variety of physiological states.

09 BIOMASS FUELS↗

DOE OSTI2022

The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation

Yeast Cadmium Factor 1 (Ycf1) sequesters heavy metals and glutathione into the vacuole to counter cell stress. Ycf1 belongs to the ATP binding cassette C-subfamily (ABCC) of transporters, many of which are regulated by phosphorylation on intrinsically-disordered domains. The regulatory mechanism of phosphorylation is still poorly understood. Here, we report two cryo-EM structures of Ycf1 at 3.4 Å and 4.0 Å resolution in inward-facing open conformations that capture previously unobserved ordered states of the intrinsically disordered regulatory domain (R-domain). R-domain phosphorylation is clearly evident and induces a topology promoting electrostatic and hydrophobic interactions with Nucleotide Binding Domain 1 (NBD1) and the Lasso motif. These interactions stay constant between the structures and are related by rigid body movements of the NBD1/R-domain complex. Biochemical data further show R-domain phosphorylation reorganizes the Ycf1 architecture and is required for maximal ATPase activity. Together, we provide insights into how R-domains control ABCC transporter activity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2024

A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders

Abstract Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN)cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genesMAFB, PHOX2A, CHN1, andEBF3– as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

Science & Technology - Other Topics↗

DOE OSTI2026

Single-cell chromatin accessibility and cis -regulatory element analyses in plants using the scPlantReg platform

Understanding gene regulation is fundamental to plant improvement, but the lack of plant-specific single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) frameworks and cross-species databases has limited insights into cell-type-specific cellular regulation. Here we present ‘scPlantReg’, an integrated framework and database for plant scATAC-seq data. scPlantReg supports end-to-end analyses from raw data processing to biological interpretation and features ‘scATACtor’, a supervised machine-learning approach that outperforms existing tools for cell-type annotation. We applied scPlantReg to pearl millet to characterize cell-type-specific chromatin accessibility and identify validated activating and repressing accessible chromatin regions (ACRs), revealing WRKY transcription factors as potential regulators of xylem development. Furthermore, we reanalysed scATAC-seq datasets from 8 plant species, spanning 11 tissues and multiple developmental stages, enabling cross-species comparisons. Furthermore, these analyses uncovered conserved regulatory programmes, including AP2/EREBP-associated ACRs linked to cell wall development and cell-type-conserved TFs across grasses. Collectively, scPlantReg provides a general framework and resource for comparative regulatory analysis in plants.

Epigenomics↗

DOE OSTI2023

Integrating functional scoring and regulatory data to predict the effect of non-coding SNPs in a complex neurological disease

Abstract Most SNPs associated with complex diseases seem to lie in non-coding regions of the genome; however, their contribution to gene expression and disease phenotype remains poorly understood. Here, we established a workflow to provide assistance in prioritising the functional relevance of non-coding SNPs of candidate genes as susceptibility loci in polygenic neurological disorders. To illustrate the applicability of our workflow, we considered the multifactorial disorder migraine as a model to follow our step-by-step approach. We annotated the overlap of selected SNPs with regulatory elements and assessed their potential impact on gene expression based on publicly available prediction algorithms and functional genomics information. Some migraine risk loci have been hypothesised to reside in non-coding regions and to be implicated in the neurotransmission pathway. In this study, we used a set of 22 non-coding SNPs from neurotransmission and synaptic machinery-related genes previously suggested to be involved in migraine susceptibility based on our candidate gene association studies. After prioritising these SNPs, we focused on non-reported ones that demonstrated high regulatory potential: (1) VAMP2_rs1150 (3′ UTR) was predicted as a target of hsa-mir-5010-3p miRNA, possibly disrupting its own gene expression; (2) STX1A_rs6951030 (proximal enhancer) may affect the binding affinity of zinc-finger transcription factors (namely ZNF423) and disturb TBL2 gene expression; and (3) SNAP25_rs2327264 (distal enhancer) expected to be in a binding site of ONECUT2 transcription factor. This study demonstrated the applicability of our practical workflow to facilitate the prioritisation of potentially relevant non-coding SNPs and predict their functional impact in multifactorial neurological diseases.

Felício, Daniela↗

DOE OSTI2026

Single-cell and spatial omics in plants: from cellular atlases to regulatory mechanisms

Single-cell RNA sequencing (scRNA-seq) has transformed transcriptomic studies by enabling gene expression profiling at the resolution of individual cells within and across a broad range of tissue types, revealing cellular heterogeneity that is obscured in bulk tissue transcriptomes. Over the past decade, improvements in microfluidics and library preparation have drastically increased throughput, allowing tens of thousands of cells to be assayed in a single experiment. Although initially developed in animal systems, scRNA-seq has rapidly emerged as a powerful and widely adopted approach in plant biology. Beyond transcriptomics, the integration of single-cell data with chromatin accessibility, proteomics, metabolomics, and spatial omics is enabling a system-level understanding of plant gene regulation and cellular organization. Network-based analytical frameworks further support the reconstruction of gene regulatory networks and the interpretation of complex single-cell data. In this review, we summarize the current technological landscape of plant single-cell studies, discuss key experimental and analytical challenges, and review emerging strategies for validating single-cell discoveries. We also discuss future directions in applying single-cell technologies to woody perennials plants and bioenergy-relevant crops, emphasizing their potential to accelerate the discovery of cell type-specific regulatory mechanisms underlying growth, stress resilience, and biomass production.

Li, Miaomiao [ORNL] (ORCID:0000000321326168)↗