scholarly journals Metabolic resilience is encoded in genome plasticity

2021 ◽  
Author(s):  
Leandro Agudelo ◽  
Remy Tuyeras ◽  
Claudia Llinares ◽  
Alvaro Morcuende ◽  
Yongjin Park ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Functional Divergence ◽  
Resource Conservation ◽  
Genome Plasticity ◽  
Amino Acid Residues ◽  
Functional Relationships ◽  
Evolutionary Innovation ◽  
Disease Variant ◽  
Burst Kinetics

Abstract Metabolism plays a central role in evolution, as resource conservation is a selective pressure for fitness and survival. Resource-driven adaptations offer a good model to study evolutionary innovation more broadly. It remains unknown how resource-driven optimization of genome function integrates chromatin architecture with transcriptional phase transitions. Here we show that tuning of genome architecture and heterotypic transcriptional condensates mediate resilience to nutrient limitation. Network genomic integration of phenotypic, structural, and functional relationships reveals that fat tissue promotes organismal adaptations through metabolic acceleration chromatin domains and heterotypic PGC1A condensates. We find evolutionary adaptations in several dimensions; low conservation of amino acid residues within protein disorder regions, nonrandom chromatin location of metabolic acceleration domains, condensate-chromatin stability through cis-regulatory anchoring and encoding of genome plasticity in radial chromatin organization. We show that environmental tuning of these adaptations leads to fasting endurance, through efficient nuclear compartmentalization of lipid metabolic regions, and, locally, human-specific burst kinetics of lipid cycling genes. This process reduces oxidative stress, and fatty-acid mediated cellular acidification, enabling endurance of condensate chromatin conformations. Comparative genomics of genetic and diet perturbations reveal mammalian convergence of phenotype and structural relationships, along with loss of transcriptional control by diet-induced obesity. Further, we find that radial transcriptional organization is encoded in functional divergence of metabolic disease variant-hubs, heterotypic condensate composition, and protein residues sensing metabolic variation. During fuel restriction, these features license the formation of large heterotypic condensates that buffer proton excess, and shift viscoelasticity for condensate endurance. This mechanism maintains physiological pH, reduces pH-resilient inflammatory gene programs, and enables genome plasticity through transcriptionally driven cell-specific chromatin contacts. In vivo manipulation of this circuit promotes fasting-like adaptations with heterotypic nuclear compartments, metabolic and cell-specific homeostasis. In sum, we uncover here a general principle by which transcription uses environmental fluctuations for genome function, and demonstrate how resource conservation optimizes transcriptional self-organization through robust feedback integrators, highlighting obesity as an inhibitor of genome plasticity relevant for many diseases.

scholarly journals Metabolic resilience is encoded in genome plasticity

2021 ◽  
Author(s):  
Leandro Z. Agudelo ◽  
Rémy V Tuyéras ◽  
Claudia Llinares ◽  
Alvaro Morcuende ◽  
Yongjin Park ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Functional Divergence ◽  
Resource Conservation ◽  
Genome Plasticity ◽  
Amino Acid Residues ◽  
Functional Relationships ◽  
Evolutionary Innovation ◽  
Disease Variant ◽  
Burst Kinetics

Metabolism plays a central role in evolution, as resource conservation is a selective pressure for fitness and survival. Resource-driven adaptations offer a good model to study evolutionary innovation more broadly. It remains unknown how resource-driven optimization of genome function integrates chromatin architecture with transcriptional phase transitions. Here we show that tuning of genome architecture and heterotypic transcriptional condensates mediate resilience to nutrient limitation. Network genomic integration of phenotypic, structural, and functional relationships reveals that fat tissue promotes organismal adaptations through metabolic acceleration chromatin domains and heterotypic PGC1A condensates. We find evolutionary innovation in several dimensions; low conservation of amino acid residues within protein disorder regions, nonrandom chromatin location of metabolic acceleration domains, condensate-chromatin stability through cis-regulatory archoring and encoding of genome plasticity in radial chromatin organization. We show that environmental tuning of these adaptations leads to fasting endurance, through efficient nuclear compartmentalization of lipid metabolic regions, and, locally, human-specific burst kinetics of lipid cycling genes. This process reduces oxidative stress, and fatty-acid mediated cellular acidification, enabling endurance of condensate chromatin conformations. Comparative genomics of genetic and diet perturbations reveal mammalian convergence of phenotype and structural relationships, along with loss of transcriptional control by diet-induced obesity. Further, we find that radial transcriptional organization is encoded in functional divergence of metabolic disease variant-hubs, heterotypic condensate composition, and evolutionary tuned protein residues sensing metabolic variation. During fuel restriction, these features license the formation of large heterotypic condensates that buffer proton excess, and shift viscoelasticity for condensate endurance. This mechanism maintains physiological pH, reduces pH-resilient inflammatory gene programs, and enables genome plasticity through transcriptionally driven cell-specific chromatin contacts. In vivo manipulation of this circuit promotes fasting-like adaptations with heterotypic nuclear compartments, metabolic and cell-specific homeostasis. In sum, we uncover here a general principle by which transcription uses environmental fluctuations for genome function, and demonstrate how resource conservation optimizes transcriptional self-organization through robust feedback integrators, highlighting obesity as an inhibitor of genome plasticity relevant for many diseases.

Oxytocin analogues with non-coded amino acid residues in position 8: [8-Neopentylglycine]oxytocin and [8-cycloleucine]oxytocin

1987 ◽  
Vol 52 (9) ◽  
pp. 2317-2325 ◽  
Author(s):  
Jan Hlaváček ◽  
Jan Pospíšek ◽  
Jiřina Slaninová ◽  
Walter Y. Chan ◽  
Victor J. Hruby
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
The Other ◽  
Amino Acid Residues ◽  
Phase Synthesis ◽  
Other Hand ◽  
Fragment Condensation

[8-Neopentylglycine]oxytocin (II) and [8-cycloleucine]oxytocin (III) were prepared by a combination of solid-phase synthesis and fragment condensation. Both analogues exhibited decreased uterotonic potency in vitro, each being about 15-30% that of oxytocin. Analogue II also displayed similarly decreased uterotonic potency in vivo and galactogogic potency. On the other hand, analogue III exhibited almost the same potency as oxytocin in the uterotonic assay in vivo and in the galactogogic assay.

Synthesis of Fragments of the Vasoactive Intestinal Peptide (VIP) and Analysis of Their Residual Biological Activities

1995 ◽  
Vol 60 (7) ◽  
pp. 1229-1235 ◽  
Author(s):  
Ivana Zoulíková ◽  
Ivan Svoboda ◽  
Jiří Velek ◽  
Václav Kašička ◽  
Jiřina Slaninová ◽  
...  
Keyword(s):  
Amino Acid ◽  
Biological Activities ◽  
Residual Activity ◽  
Detailed Examination ◽  
Amino Acid Residues ◽  
Linear Peptide ◽  
Zone Electrophoresis ◽  
Capillary Zone

The vasoactive intestinal (poly)peptide (VIP) is a linear peptide containing 28 amino acid residues, whose primary structure indicates a low metabolic stability. The following VIP fragments, as potential metabolites, and their analogues were prepared by synthesis on a solid: [His(Dnp)1]VIP(1-10), VIP(11-14), [D-Arg12]VIP(11-14), [Lys(Pac)15,21,Arg20]VIP(15-22), and VIP(23-28). After purification, the peptides were characterized by amino acid analysis, mass spectrometry, RP HPLC, and capillary zone electrophoresis. In some tests, detailed examination of the biological activity of the substances in vivo and in vitro gave evidence of a low, residual activity of some fragments, viz. a depressoric activity in vivo for [His(Dnp)1]VIP(1-10) and a stimulating activity for the release of α-amylase in vitro and in vivo for [Lys(Pac)15,21,Arg20]VIP(15-22) and VIP(23-28).

scholarly journals Osteocytes as main responders to low-intensity pulsed ultrasound treatment during fracture healing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tatsuya Shimizu ◽  
Naomasa Fujita ◽  
Kiyomi Tsuji-Tamura ◽  
Yoshimasa Kitagawa ◽  
Toshiaki Fujisawa ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Transcriptional Control ◽  
Target Genes ◽  
Pulsed Ultrasound ◽  
Activated T Cells ◽  
In Vivo Models ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Ultrasound Stimulation

AbstractUltrasound stimulation is a type of mechanical stress, and low-intensity pulsed ultrasound (LIPUS) devices have been used clinically to promote fracture healing. However, it remains unclear which skeletal cells, in particular osteocytes or osteoblasts, primarily respond to LIPUS stimulation and how they contribute to fracture healing. To examine this, we utilized medaka, whose bone lacks osteocytes, and zebrafish, whose bone has osteocytes, as in vivo models. Fracture healing was accelerated by ultrasound stimulation in zebrafish, but not in medaka. To examine the molecular events induced by LIPUS stimulation in osteocytes, we performed RNA sequencing of a murine osteocytic cell line exposed to LIPUS. 179 genes reacted to LIPUS stimulation, and functional cluster analysis identified among them several molecular signatures related to immunity, secretion, and transcription. Notably, most of the isolated transcription-related genes were also modulated by LIPUS in vivo in zebrafish. However, expression levels of early growth response protein 1 and 2 (Egr1, 2), JunB, forkhead box Q1 (FoxQ1), and nuclear factor of activated T cells c1 (NFATc1) were not altered by LIPUS in medaka, suggesting that these genes are key transcriptional regulators of LIPUS-dependent fracture healing via osteocytes. We therefore show that bone-embedded osteocytes are necessary for LIPUS-induced promotion of fracture healing via transcriptional control of target genes, which presumably activates neighboring cells involved in fracture healing processes.

scholarly journals Brown Spiders’ Phospholipases-D with Potential Therapeutic Applications: Functional Assessment of Mutant Isoforms

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 320
Author(s):  
Thaís Pereira da Silva ◽  
Fernando Jacomini de Castro ◽  
Larissa Vuitika ◽  
Nayanne Louise Costacurta Polli ◽  
Bruno César Antunes ◽  
...  
Keyword(s):  
Structural Changes ◽  
Capillary Permeability ◽  
Structural Data ◽  
Histopathological Analysis ◽  
Amino Acid Residues ◽  
Wild Type ◽  
Antigenic Properties ◽  
Harmful Effects

Phospholipases-D (PLDs) found in Loxosceles spiders’ venoms are responsible for the dermonecrosis triggered by envenomation. PLDs can also induce other local and systemic effects, such as massive inflammatory response, edema, and hemolysis. Recombinant PLDs reproduce all of the deleterious effects induced by Loxosceles whole venoms. Herein, wild type and mutant PLDs of two species involved in accidents—L. gaucho and L. laeta—were recombinantly expressed and characterized. The mutations are related to amino acid residues relevant for catalysis (H12-H47), magnesium ion coordination (E32-D34) and binding to phospholipid substrates (Y228 and Y228-Y229-W230). Circular dichroism and structural data demonstrated that the mutant isoforms did not undergo significant structural changes. Immunoassays showed that mutant PLDs exhibit conserved epitopes and kept their antigenic properties despite the mutations. Both in vitro (sphingomyelinase activity and hemolysis) and in vivo (capillary permeability, dermonecrotic activity, and histopathological analysis) assays showed that the PLDs with mutations H12-H47, E32-D34, and Y228-Y229-W230 displayed only residual activities. Results indicate that these mutant toxins are suitable for use as antigens to obtain neutralizing antisera with enhanced properties since they will be based on the most deleterious toxins in the venom and without causing severe harmful effects to the animals in which these sera are produced.

scholarly journals Cloning and characterization of four SIR genes of Saccharomyces cerevisiae.

1986 ◽  
Vol 6 (2) ◽  
pp. 688-702 ◽  
Author(s):  
J M Ivy ◽  
A J Klar ◽  
J B Hicks
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mating Type ◽  
Blot Analysis ◽  
Transcriptional Control ◽  
Genomic Library ◽  
Yeast Saccharomyces Cerevisiae ◽  
Mating Type Genes ◽  
Rna Blots

Mating type in the yeast Saccharomyces cerevisiae is determined by the MAT (a or alpha) locus. HML and HMR, which usually contain copies of alpha and a mating type information, respectively, serve as donors in mating type interconversion and are under negative transcriptional control. Four trans-acting SIR (silent information regulator) loci are required for repression of transcription. A defect in any SIR gene results in expression of both HML and HMR. The four SIR genes were isolated from a genomic library by complementation of sir mutations in vivo. DNA blot analysis suggests that the four SIR genes share no sequence homology. RNA blots indicate that SIR2, SIR3, and SIR4 each encode one transcript and that SIR1 encodes two transcripts. Null mutations, made by replacement of the normal genomic allele with deletion-insertion mutations created in the cloned SIR genes, have a Sir- phenotype and are viable. Using the cloned genes, we showed that SIR3 at a high copy number is able to suppress mutations of SIR4. RNA blot analysis suggests that this suppression is not due to transcriptional regulation of SIR3 by SIR4; nor does any SIR4 gene transcriptionally regulate another SIR gene. Interestingly, a truncated SIR4 gene disrupts regulation of the silent mating type loci. We propose that interaction of at least the SIR3 and SIR4 gene products is involved in regulation of the silent mating type genes.

scholarly journals Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Prasanna A. Datar ◽  
Sonali R. Jadhav
Keyword(s):  
Amino Acid ◽  
Docking Studies ◽  
Diabetic Rats ◽  
Hypoglycemic Activity ◽  
Amino Acid Residues ◽  
Docking Score ◽  
Design And Synthesis ◽  
Hypoglycaemic Agents ◽  
Standard Compound

Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series.

Bistability of somatic pattern memories: stochastic outcomes in bioelectric circuits underlying regeneration

2021 ◽  
Vol 376 (1821) ◽  
pp. 20190765 ◽  
Author(s):  
Giovanni Pezzulo ◽  
Joshua LaPalme ◽  
Fallon Durant ◽  
Michael Levin
Keyword(s):  
Large Scale ◽  
Computational Models ◽  
State Of The Art ◽  
Memory Representation ◽  
Theme Issue ◽  
Evolutionary Innovation ◽  
New Interpretation ◽  
The Brain

Nervous systems’ computational abilities are an evolutionary innovation, specializing and speed-optimizing ancient biophysical dynamics. Bioelectric signalling originated in cells' communication with the outside world and with each other, enabling cooperation towards adaptive construction and repair of multicellular bodies. Here, we review the emerging field of developmental bioelectricity, which links the field of basal cognition to state-of-the-art questions in regenerative medicine, synthetic bioengineering and even artificial intelligence. One of the predictions of this view is that regeneration and regulative development can restore correct large-scale anatomies from diverse starting states because, like the brain, they exploit bioelectric encoding of distributed goal states—in this case, pattern memories. We propose a new interpretation of recent stochastic regenerative phenotypes in planaria, by appealing to computational models of memory representation and processing in the brain. Moreover, we discuss novel findings showing that bioelectric changes induced in planaria can be stored in tissue for over a week, thus revealing that somatic bioelectric circuits in vivo can implement a long-term, re-writable memory medium. A consideration of the mechanisms, evolution and functionality of basal cognition makes novel predictions and provides an integrative perspective on the evolution, physiology and biomedicine of information processing in vivo . This article is part of the theme issue ‘Basal cognition: multicellularity, neurons and the cognitive lens’.

Protein synthesis is required for rapid degradation of tubulin mRNA and other deflagellation-induced RNAs in Chlamydomonas reinhardi

1986 ◽  
Vol 6 (1) ◽  
pp. 54-61
Author(s):  
E J Baker ◽  
L R Keller ◽  
J A Schloss ◽  
J L Rosenbaum
Keyword(s):  
Protein Synthesis ◽  
Transcriptional Control ◽  
Protein S ◽  
Protein Synthesis Inhibitors ◽  
Control Factors ◽  
Flagellar Proteins ◽  
The Stability ◽  
And Control

After flagellar detachment in Chlamydomonas reinhardi, there is a rapid synthesis and accumulation of mRNAs for tubulin and other flagellar proteins. Maximum levels of these mRNAs (flagellar RNAs) are reached within 1 h after deflagellation, after which they are rapidly degraded to their predeflagellation levels. The degradation of alpha- and beta-tubulin RNAs was shown to be due to the shortening of their half-lives after accumulation (Baker et al., J. Cell Biol. 99:2074-2081, 1984). Deflagellation in the presence of protein synthesis inhibitors results in the accumulation of tubulin and other flagellar mRNAs by kinetics similar to those of controls. However, unlike controls, in which the accumulated mRNAs are rapidly degraded, these mRNAs are stabilized in cycloheximide. The stabilization by cycloheximide is specific for the flagellar mRNAs accumulated after deflagellation, since there is no change in the levels of flagellar mRNAs in nondeflagellated (uninduced) cells in the presence of cycloheximide. The kinetics of flagellar mRNA synthesis after deflagellation are shown to be the same in cycloheximide-treated and control cells by in vivo labeling and in vitro nuclear runoff experiments. These results show that protein synthesis is not required for the induced synthesis of flagellar mRNAs, and that all necessary transcriptional control factors are present in the cell before deflagellation, but that protein synthesis is required for the accelerated degradation of the accumulated flagellar mRNAs. Since cycloheximide prevents the induced synthesis and accumulation of flagellar proteins, it is possible that the product(s) of protein synthesis required for the accelerated decay of these mRNAs is a flagellar protein(s). The possibility that one or more flagellar proteins autoregulate the stability of the flagellar mRNAs is discussed.

scholarly journals Species-specific rDNA transcription is due to promoter-specific binding factors.

1984 ◽  
Vol 4 (2) ◽  
pp. 221-227 ◽  
Author(s):  
R Miesfeld ◽  
N Arnheim
Keyword(s):  
Rna Polymerase ◽  
Transcriptional Control ◽  
Specific Binding ◽  
Rna Polymerase I ◽  
Rdna Transcription ◽  
Nucleolar Dominance ◽  
Cell Extracts ◽  
Species Specific ◽  
Polymerase I

RNA polymerase I transcription factors were purified from HeLa and mouse L cell extracts by phosphocellulose chromatography. Three fractions from each species were found to be required for transcription. One of these fractions, virtually devoid of RNA polymerase I activity, was found to form a stable preinitiation complex with small DNA fragments containing promoter sequences from the homologous but not the heterologous species. These species-specific DNA-binding factors can explain nucleolar dominance in vivo in mouse-human hybrid somatic cells and species specificity in cell-free, RNA polymerase I-dependent transcription systems. The evolution of species-specific transcriptional control signals may be the natural outcome of a special relationship that exists between the RNA polymerase I transcription machinery and the multigene family coding for rRNA.

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