Papers by Evgenii Tretiakov
The EMBO Journal, Sep 12, 2018
Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neu... more Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropinreleasing hormone-releasing neurons innervate ependymal cells of the 3 rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal-regulated kinase 1 and tyrosine hydroxylase with the Ca 2+-sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress-induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate-limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long-lasting cortical excitability following acute stress.
bioRxiv (Cold Spring Harbor Laboratory), Dec 26, 2020
Dopa-responsive dystonia (DRD) and Parkinson’s disease (PD) are movement disorders caused by the ... more Dopa-responsive dystonia (DRD) and Parkinson’s disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency. We also show that BH4 deficiency increases sensitivities to several PD-related stressors in mice and PD human cells, resulting in worse behavioral and physiological outcomes. Conversely, genetic and pharmacological augmentation of BH4 prote...
BMC Biology
Background Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondr... more Background Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions. Results By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6–9 kb and another within 13–16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major a...
The process of domestication is associated with decrease in effective population size, which in t... more The process of domestication is associated with decrease in effective population size, which in turn leads to accumulation of slightly-deleterious mutations due to genetic drift. To maintain genome quality at a high level, we propose to use a stress-induced strong purifying selection, which based on negative epistasis, can effectively eliminate organisms with an excess of deleterious variants. Here, to identify stress factors, which interact with the effect of deleterious mutations we performed a proof-of-principle experiment with several regimes of a heat shock. We observed that fitness of mutated versus wild-type carp lines drops stronger after heat shock, which is a signature of a negative epistasis. Although the observed trend is promising, the effect of the epistasis is weak and unstable from family to family. Thus, more deep tuning of heat shock regimes is needed to uncover the most efficient combination of factors (absolute temperature, duration, stage of the embryo developme...
bioRxiv (Cold Spring Harbor Laboratory), Nov 14, 2022
Heat shock proteins in parallel with their main and originally discovered functionmaintenance of ... more Heat shock proteins in parallel with their main and originally discovered functionmaintenance of folded proteins under stressful conditions, can play also background buffering role-by folding proteins with an excess of slightly-deleterious nonsynonymous variants (SDNV). Here we tested several scenarios of this buffering role. On the comparative species scale, we demonstrated that low-Ne species are characterized by a higher expression level of hsp90 which can be explained by the excess of SDNV. On the comparative tissue level, we showed that long-lived tissues have also a higher hsp90 expression level, which can be advantageous to maintain the functionality of proteins. On the comparative gene level, we demonstrated that purifying selection of hsp90 in low-Ne-species did not relax as strongly as it happens for control genes, similar to hsp90. Additionally, we demonstrated that hsp clients versus non-clients are characterised by decreased level of selective constraints; demonstrate stronger relaxation of purifying selection in low-Ne species; have an excess of slightly-deleterious variants associated with complex disease phenotypes in humans; have an excess of pathological variants associated with clinical phenotypes in humans, suggesting that clients, being buffered by hsp90 can degenerate a bit more as compared to non-clients. Altogether, our results show that the secondary role of hsp, buffering of SDNV, is widespread and universal affecting properties of species, tissues and genes. A deep understanding of the buffering role of hsp90 will help to predict the deleterious effect of each variant in the human genome more precisely as well as will extend the application of the effectively-neutral theory of molecular evolution.
Proceedings of the National Academy of Sciences
Augmentor α and β (Augα and Augβ) are newly discovered ligands of the receptor tyrosine kinases A... more Augmentor α and β (Augα and Augβ) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Augα functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Augα fragment and monomeric Augβ also bind to Alk and potently stimulate cellular responses. While previous studies demonstrated that oncogenic Alk mutants function as important drivers of a variety of human cancers, the physiological roles of Augα and Augβ are poorly understood. Here, we investigate the physiological roles of Augα and Augβ by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Augα single knockout and double knockout of Augα and Augβ exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Augα-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Augβ-knockout mice showed similar weight curves as the littermate controls. Experiments ...
Supplementary files and Code for the article (Molecular design of hypothalamus development).<b... more Supplementary files and Code for the article (Molecular design of hypothalamus development).<br>Raw sequencing data and experimental design description were deposited in Gene Expression Omnibus (accession number: GSE132730). <br>Legends to Supplementary Files mentioned in the article<br>S1. Differentially expressed genes identified by MAST for clusters presented in Figure 1a and for the branching nodes in the dendrogram of Extended data 1a:"Data_and_Code\EDA_Integration_Annotation\DGE_and_Dend.xlsx".<br>S2.A list of genes that are specifically expressed in hypothalamic sub-regions (according to the Allen brain atlas database; www.brain-map.org) and used as positional marks:"Data_and_Code\EDA_Integration_Annotation\nuclei.xlsx".<br>S3. AUCell matrix showing the distribution of the activity of all regulons:"Data_and_Code\Developmental Regulons\auc_cell.tsv".<br>S4. A list of genes used for the manual annotation and expl...
The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutat... more The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra is affected by the oxidative damage. Assuming that oxidative damage increases with age, we analyze mtDNA mutagenesis of different species. Analysing (i) dozens thousands of somatic mtDNA mutations in samples of different age (ii) 70053 polymorphic synonymous mtDNA substitutions, reconstructed in 424 mammalian species with different generation length and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH>GH substitutions (H - heavy chain notation) is twice higher in species with high versus low generation length making their mtDNA more AH poor and GH rich. Cons...
Nature, 2020
A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus contr... more A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs 1,2. Nevertheless, a developmental blueprint integrating molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development remains unresolved 3. Here, we combine single-cell RNA-seq on 51,199 cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with GWAS-based disease phenotyping and genetic lineage reconstruction to show that 9 glial and 33 neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes arising from neurotransmitters, neuropeptides and transcription Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
ABSTRACTMutational spectrum of the mitochondrial genome (mtDNA) fluctuates between species, howev... more ABSTRACTMutational spectrum of the mitochondrial genome (mtDNA) fluctuates between species, however, factors responsible for this variation are mainly unknown. Recently, we demonstrated that the mammalian mtDNA mutational spectrum is associated with age-related oxidative damage by means of A>G substitutions on a heavy chain (hereafter Ah>Gh). Here we extend this logic hypothesizing that oxidative damage can also depend on a species-specific level of aerobic metabolism. Using body temperature of endotherms and the environmental temperature of ectotherms as a proxy for their levels of aerobic metabolism, we reconstructed and analyzed 1350 species-specific mtDNA mutational spectra of vertebrate species. First, within ray-finned fishes, we observed that temperature is associated with increased asymmetry of Ah>Gh substitution, estimated as a ratio Ah>Gh/Th>Ch. Second, comparing within-species geographically distinct clades of widely distributed European anchovy, we observe...
The EMBO Journal, 2019
Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, ... more Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic b cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.
Aging is often associated with clonal expansion of somatic mitochondrial deletions, while their o... more Aging is often associated with clonal expansion of somatic mitochondrial deletions, while their origin is still poorly understood. Deletions are often flanked by direct nucleotide repeats, however, repeats alone do not provide an exhaustive explanation of deletion distribution. Here, we hypothesized that spatial proximity of repeats alters the rate of conversion into deletions. Analyzing distribution of human deletions, we observed a hot spot of deletions with one breakpoint located within the region of 6-9kb and another within 13-16kb of the mitochondrial genome. This deletion hot spot is not explained by the distribution of the direct repeats and might be driven by close contacts of these two regions during mtDNA replication. Using Hi-C data derived from several samples of two different human tissues we observed the increased density of contacts in the potential contact zone. Using several in silico approaches we reconstructed the secondary structure of mitochondrial DNA and confi...
Mutational spectrum of the mitochondrial genome (mtDNA) does not resemble signatures of any known... more Mutational spectrum of the mitochondrial genome (mtDNA) does not resemble signatures of any known mutagens and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra may be affected by the oxidative damage which is increasing with cellular and organismal aging. However, the well-documented mutational signature of the oxidative damage, G>T substitutions, is typical only for the nuclear genome while it is extremely rare and age-independent in mtDNA. Thus it is still unclear if there is a mitochondria - specific mutational signature of the oxidative damage. Here, reconstructing mtDNA mutational spectra for human cancers originated from 21 tissues with various cell turnover rate, human oocytes fertilized at different ages, and 424 mammalian species with variable generation length which is a proxy for oocyte age, we observe...
The EMBO journal, Jan 12, 2018
Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neu... more Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin-releasing hormone-releasing neurons innervate ependymal cells of the 3 ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal-regulated kinase 1 and tyrosine hydroxylase with the Ca-sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress-induced cortical norepinephrine synthesis, ensuing neuronal excitation and behav...
Cell, 2020
Highlights d GWAS in the EGCUT biobank identifies ALK as a candidate thinness gene d Knockdown of... more Highlights d GWAS in the EGCUT biobank identifies ALK as a candidate thinness gene d Knockdown of Alk in Drosophila results in reduced triglyceride levels d Alk mutant mice exhibit resistance to diet-and leptinmutation-induced obesity d ALK controls energy expenditure via sympathetic tone to the adipose organ
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Papers by Evgenii Tretiakov