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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 523 records · Page 29
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

miR-675 promotes odontogenic differentiation of human dental pulp cells by epigenetic regulation of DLX3

Highlights: • miR-675 promotes the odontogenic differentiation of human dental pulp cells (hDPCs). • miR-675 regulates the odontogenic differentiation of hDPCs by epigenetic regulating DLX3. • Our findings shed light on the regulatory mechanism of dentin hypoplasia in TDO patients. In a previous study, we showed that microRNA-675 (miR-675) was significantly down-regulated in patients with tricho-dento-osseous (TDO) syndrome. One of the main features of TDO syndrome is dentin hypoplasia. Thus, we hypothesize that miR-675 plays a role in dentin development. In this study, we determined the role of miR-675 in the odontogenic differentiation of human dental pulp cells (hDPCs). Stable overexpression and knockdown of miR-675 in hDPCs were performed using recombinant lentiviruses containing U6 promoter-driven miR-675 and short hairpin-miR675 expression cassettes, respectively. Alkaline phosphatase (ALP) assay, Alizarin red staining assay, quantitative polymerase chain reaction (qPCR), Western blot analysis, and immunofluorescent staining revealed the promotive effects of miR-675 on the odontogenic differentiation of hDPCs. Further, we found that miR-675 facilitates the odontogenic differentiation process of hDPCs by epigenetic regulation of distal-less homeobox (DLX3). Thus, for the first time, we determined that miR-675 regulates the odontogenic differentiation of hDPCs by inhibiting the DNA methyltransferase 3 beta (DNMT3B)-mediated methylation of DLX3. Our findings uncover an unanticipated regulatory role for miR-675 in the odontogenic differentiation of hDPCs by epigenetic changes in DLX3 and provide novel insight into dentin hypoplasia feature in TDO patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms

Highlights: • Tumor suppressor p21protein is reactivated via withaferin A (WA) and sulforaphane (SFN). • Combinatorial nutritive compounds have the ability to impede cell cycle progression. • Mutant p53 is down-regulated via the studied compounds where wild type p53 is not. • Epigenetic mechanisms are regulated by WA and SFN. • The H3K4Me3 marker is increased at the p21 promoter after WA and SFN treatment. Little is known about the effects of combinatorial dietary compounds on the regulation of epigenetic mechanisms involved in breast cancer prevention. The human diet consists of a multitude of components, and there is a need to elucidate how certain compounds interact in collaboration. Withaferin A (WA), found in the Indian winter cherry and documented as a DNA methyltransferase (DNMT) inhibitor, and sulforaphane (SFN), a well-known histone deacetylase (HDAC) inhibitor found in cruciferous vegetables, are two epigenetic modifying compounds that have only recently been studied in conjunction. The use of DNMT and HDAC inhibitors to reverse the malignant expression of certain genes in breast cancer has shown considerable promise. Previously, we found that SFN + WA synergistically promote breast cancer cell death. Herein, we determined that these compounds inhibit cell cycle progression from S to G2 phase in MDA-MB-231 and MCF-7 breast cancer. Furthermore, we demonstrate that this unique combination of epigenetic modifying compounds down-regulates the levels of Cyclin D1 and CDK4, and pRB; conversely, the levels of E2F mRNA and tumor suppressor p21 are increased independently of p53. We find these events coincide with an increase in unrestricted histone methylation. We propose SFN + WA-induced breast cancer cell death is attributed, in part, to epigenetic modifications that result in the modulated expression of key genes responsible for the regulation of cancer cell senescence.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Differentiation in stem/progenitor cells along fetal or adult hepatic stages requires transcriptional regulators independently of oscillations in microRNA expression

Highlights: • The role of microRNAs in differentiation of stem cells is not well understood. • This study found microRNA levels oscillated during differentiation of hepatocytes. • Many functions but not differentiation were regulated by microRNAs in hepatocytes. • Regulators of gene networks independently maintained hepatic differentiation. • These insights will advance how stem cells may contribute in disease mechanisms and therapies. Understanding mechanisms in lineage differentiation is critical for organ development, pathophysiology and oncogenesis. To determine whether microRNAs (miRNA) may serve as drivers or adjuncts in hepatic differentiation, we studied human embryonic stem cell-derived hepatocytes and primary hepatocytes representing fetal or adult stages. Model systems were used for hepatic lineage advancement or regression under culture conditions with molecular assays. Profiles of miRNA in primary fetal and adult hepatocytes shared similarities and distinctions from pluripotent stem cells or stem cell-derived early fetal-like hepatocytes. During phenotypic regression in fetal or adult hepatocytes, miRNA profiles oscillated to regain stemness-associated features that had not been extinguished in stem cell-derived fetal-like hepatocytes. These oscillations in stemness-associated features were not altered in fetal-like hepatocytes by inhibitory mimics for dominantly-expressed miRNA, such as hsa-miR-99b, -100, -214 and -221/222. The stem cell-derived fetal-like hepatocytes were permissive for miRNA characterizing mature hepatocytes, including mimics for hsa-miR-122, -126, -192, -194 and -26b, although transfections of the latter did not advance hepatic differentiation. Examination of genome-wide mRNA expression profiles in stem cell-derived or primary fetal hepatocytes indicated targets of highly abundant miRNA regulated general processes, e.g., cell survival, growth and proliferation, functional maintenance, etc., without directing cell differentiation. Among upstream regulators of gene networks in stem cell-derived hepatocytes included HNF4A, SNAI1, and others, which affect transcriptional circuits directing lineage development or maintenance. Therefore, miRNA expression oscillated in response to microenvironmental conditions, whereas lineage-specific transcriptional regulators, such as HNF4A, were necessary for directing hepatic differentiation. This knowledge will be helpful for understanding the contribution of stem cells in pathophysiological states and oncogenesis, as well as for applications of stem cell-derived hepatocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Human adenylate kinase 6 regulates WNK1 (with no lysine kinase-1) phosphorylation states and affects ion homeostasis in NT2 cells

Highlights: • Depletion of AK6 inhibits cell proliferation and promotes apoptosis in NT2 cells. • AK6 interacts with N terminal of WNK1 and regulates its phosphorylation states. • AK6 mediates Akt/WNK1 signaling pathway and regulates ion homeostasis in NT2 cells. • Chloride channel CLC-3 is responsible for ion transport in NT2 cells. Adenylate kinase 6 (AK6), a nucleus localized phosphotransferase in mammalians, shows ubiquitously expression and broad substrate activity in different tissues and cell types. Although the function of AK6 has been extensively studied in different cancer cell lines, its role in mammalian germline is still unknown. Here we showed that knockdown of AK6 inhibits cell proliferation and promotes cell apoptosis in human testicular carcinoma (NT2 cells). Co-immunoprecipitation experiment and in vitro pull down assay identified WNK1 (with no lysine kinase-1) as one of the AK6 interacting proteins in NT2 cells. Moreover, we found that AK6 regulates the phosphorylation states of WNK1 (Thr60) and affects phosphorylation level of Akt (Ser473) upon hypotonic condition, probably affecting chloride channel and regulating ion transport and homeostasis in NT2 cells and consequently contributing to the decreased cell proliferation rate. In conclusion, AK6 regulates WNK1 phosphorylation states and affects ion homeostasis in NT2 cells. These findings provide new insights into the function of AK6 and WNK1 in human testicular carcinoma. This work also provides foundation for further mechanism study of AK6 in spermatogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Cooperative Electronic and Structural Regulation in a Bioinspired Allosteric Photoredox Catalyst

Here in this article, we report the first allosteric photoredox catalyst regulated via constructively coupled structural and electronic control. While often synergistically exploited in nature, these two types of control mechanisms have only been applied independently in the vast majority of allosteric enzyme mimics and receptors in the literature. By embedding a model of photosystem II in a supramolecular coordination complex that responds to chloride as an allosteric effector, we show that distance and electronic control of light harvesting can be married to maximize allosteric regulation of catalytic activity. This biomimetic system is composed of a Bodipy photoantenna, which is capable of transferring excited-state energy to a photoredox pair, wherein the excitation energy is used to generate a catalytically active charge-separated state. The structural aspect of allosteric regulation is achieved by toggling the coordination chemistry of an antenna-functionalized hemilabile ligand via partial displacement from a Rh I structual node using chloride. In doing so, the distance between the antenna and the central photoredox catalyst is increased, lowering the inherent efficiency of through-space energy transfer. At the same time, coordination of chloride lowers both the charge of the Rh I node and the reduction potential of the Rh II/I couple, to the extent that electronic quenching of the antenna excited state is possible via photoinduced electron transfer from the metal center. Compared to a previously developed system that operates solely via electronic regulation, the present system demonstrates that coupling electronic and structural approaches to allosteric regulation gives rise to improved switching ratios between catalytically active and inactive states. Contributions from both structural and electronic control mechanisms are probed via nuclear magnetic resonance, X-ray diffraction, electrochemical, spectroelectrochemical, and transient absorption studies. Overall, this work establishes that intertwined electronic and structural regulatory mechanisms can be borrowed from nature to build stimuli-responsive inorganic materials with potential applications in sensing, catalysis, and photonic devices.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2014

Strigolactone-Regulated Proteins Revealed by iTRAQ-Based Quantitative Proteomics in Arabidopsis

Strigolactones (SLs) are a new class of plant hormones. In addition to acting as a key inhibitor of shoot branching, SLs stimulate seed germination of root parasitic plants and promote hyphal branching and root colonization of symbiotic arbuscular mycorrhizal fungi. They also regulate many other aspects of plant growth and development. At the transcription level, SL-regulated genes have been reported. However, nothing is known about the proteome regulated by this new class of plant hormones. Here, a quantitative proteomics approach using an isobaric chemical labeling reagent, iTRAQ, to identify the proteome regulated by SLs in Arabidopsis seedlings is presented. It was found SLs regulate the expression of about three dozens of proteins that have not been previously assigned to SL pathways. These findings provide a new tool to investigate the molecular mechanism of action of SLs.

proteomics↗
DOE OSTI2015

CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury

CpG preconditioning reprograms the genomic response to stroke to protect the brain against ischemic injury. The mechanisms that underlie genomic reprogramming are incompletely understood. MicroRNAs (miRNA) are novel regulators of gene expression; however, their potential role in modulating gene responses produced by CpG preconditioning is unknown. We evaluated brain miRNA expression in response to CpG preconditioning prior to and following stroke using microarray. Importantly, we have gene expression data from previous gene microarrays under the same conditions and timepoints, which allowed integration of miRNA and gene expression data to specifically identify regulated miRNA gene targets. Statistical analysis revealed that the miRNA targets were enriched in our regulated gene population, implicating that miRNAs likely orchestrate this gene expression. CpG and saline treatment shared expression of many miRNAs and their gene targets correlate with damaging upregulation of inflammation and protective suppression of metabolism and excitotoxicity. Excitingly, miRNAs that were differentially regulated between CpG and saline treated animals associated with the upregulation of several neuroprotective genes, indicating that these miRNAs are involved in genomic reprogramming to increase protection. This data suggests that miRNAs regulate endogenous responses to stroke and that manipulation of these miRNAs may have the potential to acutely activate novel protective responses to stroke.

systems biology, microRNA, bioinformatics, stroke,↗
DOE OSTI2021

Structural visualization of transcription activated by a multidrug-sensing MerR family regulator

Bacterial RNA polymerase (RNAP) holoenzyme initiates transcription by recognizing the conserved –35 and –10 promoter elements that are optimally separated by a 17-bp spacer. The MerR family of transcriptional regulators activate suboptimal 19–20 bp spacer promoters in response to myriad cellular signals, ranging from heavy metals to drug-like compounds. The regulation of transcription by MerR family regulators is not fully understood. Here we report one crystal structure of a multidrug-sensing MerR family regulator EcmrR and nine cryo-electron microscopy structures that capture the EcmrR-dependent transcription process from promoter opening to initial transcription to RNA elongation. These structures reveal that EcmrR is a dual ligand-binding factor that reshapes the suboptimal 19-bp spacer DNA to enable optimal promoter recognition, sustains promoter remodeling to stabilize initial transcribing complexes, and finally dissociates from the promoter to reverse DNA remodeling and facilitate the transition to elongation. Our findings yield a comprehensive model for transcription regulation by MerR family factors and provide insights into the transition from transcription initiation to elongation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Mechanical Regulation of Photosynthesis in Cyanobacteria

Photosynthetic organisms regulate their responses to many diverse stimuli in an effort to balance light harvesting with utilizable light energy for carbon fixation and growth (source–sink regulation). This balance is critical to prevent the formation of reactive oxygen species that can lead to cell death. However, investigating the molecular mechanisms that underlie the regulation of photosynthesis in cyanobacteria using ensemble-based measurements remains a challenge due to population heterogeneity. Here, to address this problem, we used long-term quantitative time-lapse fluorescence microscopy, transmission electron microscopy, mathematical modelling and genetic manipulation to visualize and analyse the growth and subcellular dynamics of individual wild-type and mutant cyanobacterial cells over multiple generations. We reveal that mechanical confinement of actively growing Synechococcus sp. PCC 7002 cells leads to the physical disassociation of phycobilisomes and energetic decoupling from the photosynthetic reaction centres. We suggest that the mechanical regulation of photosynthesis is a critical failsafe that prevents cell expansion when light and nutrients are plentiful, but when space is limiting. These results imply that cyanobacteria must convert a fraction of the available light energy into mechanical energy to overcome frictional forces in the environment, providing insight into the regulation of photosynthesis and how microorganisms navigate their physical environment.

BASIC BIOLOGICAL SCIENCES,BIOMASS FUELS↗
DOE OSTI2019

Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase

The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating the function of host cells using hundreds of effector proteins delivered via its Dot/Icm secretion system1. Among these, members of the SidE family (SidEs) regulate multiple cellular processes by a unique phosphoribosyl ubiquitination mechanism that bypasses the requirement of ATP and the E1, E2 enzymes of the canonical ubiquitination machinery2-4. The activity of SidEs is regulated by SidJ, another Dot/Icm effector5, but the mechanism of such regulation is not completely understood6,7. Here we demonstrate that SidJ functions to inhibit the activity of SidEs by inducing covalent attachment of a glutamate moiety to Glu860 of SdeA, which is one of the catalytic residues for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation2. Furthermore, we found that the inhibition of SidEs activity by SidJ is restricted in host cells and such spatial regulation is achieved by the requirement of calmodulin (CaM), a eukaryote-specific protein, for its activity. Our results reveal a novel mechanism of regulation in bacterial virulence that features a posttranslational modification and its dependence upon a co-factor specific for host cells.

Gan, Ninghai↗
DOE OSTI2017

Evolution of allosteric regulation in chorismate mutases from early plants

Plants, fungi, and bacteria synthesize the aromatic amino acids: l-phenylalanine, l-tyrosine, and l-tryptophan. Chorismate mutase catalyzes the branch point reaction of phenylalanine and tyrosine biosynthesis to generate prephenate. In Arabidopsis thaliana, there are two plastid-localized chorismate mutases that are allosterically regulated (AtCM1 and AtCM3) and one cytosolic isoform (AtCM2) that is unregulated. Previous analysis of plant chorismate mutases suggested that the enzymes from early plants (i.e. bryophytes/moss, lycophytes, and basal angiosperms) formed a clade distinct from the isoforms found in flowering plants; however, no biochemical information on these enzymes is available. To understand the evolution of allosteric regulation in plant chorismate mutases, we analyzed a basal lineage of plant enzymes homologous to AtCM1 based on sequence similarity. The chorismate mutases from the moss/bryophyte Physcomitrella patens (PpCM1 and PpCM2), the lycophyte Selaginella moellendorffii (SmCM), and the basal angiosperm Amborella trichopoda (AmtCM1 and AmtCM2) were characterized biochemically. Tryptophan was a positive effector for each of the five enzymes examined. Histidine was a weak positive effector for PpCM1 and AmtCM1. Neither tyrosine nor phenylalanine altered the activity of SmCM; however, tyrosine was a negative regulator of the other four enzymes. Phenylalanine down-regulates both moss enzymes and AmtCM2. The 2.0 Å X-ray crystal structure of PpCM1 in complex with the tryptophan identified the allosteric effector site and reveals structural differences between the R- (more active) and T-state (less active) forms of plant chorismate mutases. Molecular insight into the basal plant chorismate mutases guides our understanding of the evolution of allosteric regulation in these enzymes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

COST1 regulates autophagy to control plant drought tolerance

Plants balance their competing requirements for growth and stress tolerance via a sophisticated regulatory circuitry that controls responses to the external environments. We have identified a plant-specific gene, COST1 (constitutively stressed 1), that is required for normal plant growth but negatively regulates drought resistance by influencing the autophagy pathway. An Arabidopsis thaliana cost1 mutant has decreased growth and increased drought tolerance, together with constitutive autophagy and increased expression of drought-response genes, while overexpression of COST1 confers drought hypersensitivity and reduced autophagy. The COST1 protein is degraded upon plant dehydration, and this degradation is reduced upon treatment with inhibitors of the 26S proteasome or autophagy pathways. The drought resistance of a cost1 mutant is dependent on an active autophagy pathway, but independent of other known drought signaling pathways, indicating that COST1 acts through regulation of autophagy. In addition, COST1 colocalizes to autophagosomes with the autophagosome marker ATG8e and the autophagy adaptor NBR1, and affects the level of ATG8e protein through physical interaction with ATG8e, indicating a pivotal role in direct regulation of autophagy. We propose a model in which COST1 represses autophagy under optimal conditions, thus allowing plant growth. Under drought, COST1 is degraded, enabling activation of autophagy and suppression of growth to enhance drought tolerance. Our research places COST1 as an important regulator controlling the balance between growth and stress responses via the direct regulation of autophagy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Regulators of early maize leaf development inferred from transcriptomes of laser capture microdissection (LCM)-isolated embryonic leaf cells

The superior photosynthetic efficiency of C 4 leaves over C 3 leaves is owing to their unique Kranz anatomy, in which the vein is surrounded by one layer of bundle sheath (BS) cells and one layer of mesophyll (M) cells. Kranz anatomy development starts from three contiguous ground meristem (GM) cells, but its regulators and underlying molecular mechanism are largely unknown. To identify the regulators, we obtained the transcriptomes of 11 maize embryonic leaf cell types from five stages of pre-Kranz cells starting from median GM cells and six stages of pre-M cells starting from undifferentiated cells. Principal component and clustering analyses of transcriptomic data revealed rapid pre-Kranz cell differentiation in the first two stages but slow differentiation in the last three stages, suggesting early Kranz cell fate determination. In contrast, pre-M cells exhibit a more prolonged transcriptional differentiation process. Differential gene expression and coexpression analyses identified gene coexpression modules, one of which included 3 auxin transporter and 18 transcription factor (TF) genes, including known regulators of Kranz anatomy and/or vascular development. In situ hybridization of 11 TF genes validated their expression in early Kranz development. We determined the binding motifs of 15 TFs, predicted TF target gene relationships among the 18 TF and 3 auxin transporter genes, and validated 67 predictions by electrophoresis mobility shift assay. From these data, we constructed a gene regulatory network for Kranz development. Our study sheds light on the regulation of early maize leaf development and provides candidate leaf development regulators for future study.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility

The canonical Scribble polarity complex is implicated in regulation of epithelial junctions and apical polarity. Here, we show that SGEF, a RhoG-specific GEF, forms a ternary complex with Scribble and Dlg1, two members of the Scribble complex. SGEF targets to apical junctions in a Scribble-dependent fashion and functions in the regulation of actomyosin-based contractility and barrier function at tight junctions as well as E-cadherin–mediated formation of adherens junctions. Surprisingly, SGEF does not control the establishment of polarity. However, in 3D cysts, SGEF regulates the formation of a single open lumen. Interestingly, SGEF’s nucleotide exchange activity regulates the formation and maintenance of adherens junctions, and in cysts the number of lumens formed, whereas SGEF’s scaffolding activity is critical for regulation of actomyosin contractility and lumen opening. We propose that SGEF plays a key role in coordinating junctional assembly and actomyosin contractility by bringing together Scribble and Dlg1 and targeting RhoG activation to cell–cell junctions.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2012

Permeant calcium ion feed-through regulation of single inositol 1,4,5-trisphosphate receptor channel gating

The ubiquitous inositol 1,4,5-trisphosphate (InsP 3 ) receptor (InsP 3 R) Ca 2+ release channel plays a central role in the generation and modulation of intracellular Ca 2+ signals, and is intricately regulated by multiple mechanisms including cytoplasmic ligand (InsP 3 , free Ca 2+ , free ATP 4- ) binding, posttranslational modifications, and interactions with cytoplasmic and endoplasmic reticulum (ER) luminal proteins. However, regulation of InsP 3 R channel activity by free Ca 2+ in the ER lumen ([Ca 2+ ] ER ) remains poorly understood because of limitations of Ca 2+ flux measurements and imaging techniques. Here, we used nuclear patch-clamp experiments in excised luminal-side-out configuration with perfusion solution exchange to study the effects of [Ca 2+ ] ER on homotetrameric rat type 3 InsP 3 R channel activity. In optimal [Ca 2+ ] i and subsaturating [InsP 3 ], jumps of [Ca 2+ ] ER from 70 nM to 300 µM reduced channel activity significantly. This inhibition was abrogated by saturating InsP 3 but restored when [Ca 2+ ] ER was raised to 1.1 mM. In suboptimal [Ca 2+ ] i , jumps of [Ca 2+ ] ER (70 nM to 300 µM) enhanced channel activity. Thus, [Ca 2+ ] ER effects on channel activity exhibited a biphasic dependence on [Ca 2+ ] i . In addition, the effect of high [Ca 2+ ] ER was attenuated when a voltage was applied to oppose Ca 2+ flux through the channel. These observations can be accounted for by Ca 2 + flux driven through the open InsP 3 R channel by [Ca 2+ ] ER , raising local [Ca 2+ ] i around the channel to regulate its activity through its cytoplasmic regulatory Ca 2+ -binding sites. Importantly, [Ca 2+ ] ER regulation of InsP 3 R channel activity depended on cytoplasmic Ca 2+ -buffering conditions: it was more pronounced when [Ca2+] i was weakly buffered but completely abolished in strong Ca 2+ -buffering conditions. With strong cytoplasmic buffering and Ca 2+ flux sufficiently reduced by applied voltage, both activation and inhibition of InsP 3 R channel gating by physiological levels of [Ca 2+ ] ER were completely abolished. Collectively, these results rule out Ca 2+ regulation of channel activity by direct binding to the luminal aspect of the channel.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2011

MAXIMALLY STAR-FORMING GALACTIC DISKS. I. STARBURST REGULATION VIA FEEDBACK-DRIVEN TURBULENCE

Star formation rates in the centers of disk galaxies often vastly exceed those at larger radii, whether measured by the surface density of star formation {Sigma}{sub SFR}, by the star formation rate per unit gas mass, {Sigma}{sub SFR}/{Sigma}, or even by total output. In this paper, we investigate the idea that central starbursts are self-regulated systems in which the momentum flux injected to the interstellar medium (ISM) by star formation balances the gravitational force confining the ISM gas in the disk. For most starbursts, supernovae are the largest contributor to the momentum flux, and turbulence provides the main pressure support for the predominantly molecular ISM. If the momentum feedback per stellar mass formed is p{sub *}/m{sub *} {approx} 3000 km s{sup -1}, the predicted star formation rate is {Sigma}{sub SFR} {approx} 2{pi}G{Sigma}{sup 2} m{sub *}/p{sub *} {approx} 0.1 M{sub sun} kpc{sup -2} yr{sup -1}({Sigma}/100 M{sub sun} pc{sup -2}){sup 2} in regions where gas dominates the vertical gravity. We compare this prediction with numerical simulations of vertically resolved disks that model star formation including feedback, finding good agreement for gas surface densities in the range {Sigma} {approx} 10{sup 2}-10{sup 3} M{sub sun} pc{sup -2}. We also compare to a compilation of star formation rates and gas contents from local and high-redshift galaxies (both mergers and normal galaxies), finding good agreement provided that the conversion factor X{sub CO} from integrated CO emission to H{sub 2} surface density decreases modestly as {Sigma} and {Sigma}{sub SFR} increase. Star formation rates in dense, turbulent gas are also expected to depend on the gravitational free-fall time at the corresponding mean ISM density {rho}{sub 0}; if the star formation efficiency per free-fall time is {epsilon}{sub ff}({rho}{sub 0}) {approx} 0.01, the turbulent velocity dispersion driven by feedback is expected to be v{sub z} = 0.4 {epsilon}{sub ff}({rho}{sub 0})p{sub *}/m{sub *} {approx} 10 km s{sup -1}, relatively independent of {Sigma} or {Sigma}{sub SFR}. Turbulence-regulated starbursts (controlled by kinetic momentum feedback) are part of the larger scheme of self-regulation; primarily atomic low-{Sigma} outer disks may have star formation regulated by ultraviolet heating feedback, whereas regions at extremely high {Sigma} may be regulated by feedback of stellar radiation that is reprocessed into trapped infrared.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2013

DWARF GALAXY FORMATION WITH H{sub 2}-REGULATED STAR FORMATION. II. GAS-RICH DARK GALAXIES AT REDSHIFT 2.5

We present a cosmological hydrodynamic simulation of the formation of dwarf galaxies at redshifts z ∼> 2.5 using a physically motivated model for H{sub 2}-regulated star formation. Our simulation, performed using the Enzo code and reaching a peak resolution of 109 proper parsecs at z = 2.5, extends the results of Kuhlen et al. to significantly lower redshifts. We show that a star formation prescription regulated by the local H{sub 2} abundance leads to the suppression of star formation in dwarf galaxy halos with M{sub h} ∼< 10{sup 10} M{sub ☉} and to a large population of gas-rich 'dark galaxies' at z = 2.5 with low star formation efficiencies and gas depletion timescales >20 Gyr. The fraction of dark galaxies is 60% at M{sub h} ≅ 10{sup 10} M{sub ☉} and increases rapidly with decreasing halo mass. Dark galaxies form late and their gaseous disks never reach the surface densities, ∼> 5700 M{sub ☉} pc{sup –2} (Z/10{sup –3} Z{sub ☉}){sup –0.88}, that are required to build a substantial molecular fraction. Despite this large population of dark galaxies, we show that our H{sub 2}-regulated simulation is consistent with both the observed luminosity function of galaxies and the cosmological mass density of neutral gas at z ∼> 2.5. Moreover, our results provide a theoretical explanation for the recent detection in fluorescent Lyα emission of gaseous systems at high redshift with little or no associated star formation. We further propose that H{sub 2}-regulation may offer a fresh solution to a number of outstanding 'dwarf galaxy problems' in ΛCDM. In particular, H{sub 2}-regulation leads galaxy formation to become effectively stochastic on mass scales of M{sub h} ∼ 10{sup 10} M{sub ☉}, and thus these massive dwarfs are not 'too big to fail'.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2020

Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1

UHRF1 is an important epigenetic regulator associated with apoptosis and tumour development. It is a multidomain protein that integrates readout of different histone modification states and DNA methylation with enzymatic histone ubiquitylation activity. Emerging evidence indicates that the chromatin-binding and enzymatic modules of UHRF1 do not act in isolation but interplay in a coordinated and regulated manner. Here, we compared two splicing variants (V1, V2) of murine UHRF1 (mUHRF1) with human UHRF1 (hUHRF1). We show that insertion of nine amino acids in a linker region connecting the different TTD and PHD histone modification-binding domains causes distinct H3K9me3-binding behaviour of mUHRF1 V1. Structural analysis suggests that in mUHRF1 V1, in contrast to V2 and hUHRF1, the linker is anchored in a surface groove of the TTD domain, resulting in creation of a coupled TTD-PHD module. This establishes multivalent, synergistic H3-tail binding causing distinct cellular localization and enhanced H3K9me3-nucleosome ubiquitylation activity. In contrast to hUHRF1, H3K9me3-binding of the murine proteins is not allosterically regulated by phosphatidylinositol 5-phosphate that interacts with a separate less-conserved polybasic linker region of the protein. Our results highlight the importance of flexible linkers in regulating multidomain chromatin binding proteins and point to divergent evolution of their regulation.

60 APPLIED LIFE SCIENCES↗