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Project description:In acute cold stress in mammals, JMJD1A, a histone H3 lysine 9 (H3K9) demethylase, upregulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals have another mechanism to cope with long-term cold stress by inducing the browning of the subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation-independent acute Ucp1 induction in BAT and demethylation-dependent chronic Ucp1 expression in beige scWAT provides complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namely, β-adrenergic receptor and peroxisome proliferator-activated receptor-γ (PPARγ) activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis. S265 phosphorylation of JMJD1A, and the following demethylation of H3K9me2 might prove to be a novel molecular target for the treatment of metabolic disorders, via promoting beige adipogenesis.
| S-EPMC5908789 | biostudies-literature
Project description:Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch
| PRJNA421896 | ENA
Project description:Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat "browning". This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.
| S-EPMC6567243 | biostudies-literature
Project description:After cold exposure, cytochrome c oxidase (COX) activity increased about 2.5-fold within 2 weeks in the brown adipose tissue (BAT) of Djungarian hamsters. The mRNAs for COX subunits I and III and the 12 S rRNA, encoded on mitochondrial DNA (mtDNA), as well as mRNAs for COX subunits IV, Va and mitochondrial transcription factor A, encoded in the nucleus, were unchanged when expressed per unit of total tissue RNA. However, since total tissue RNA doubled per BAT depot, while total DNA remained unchanged, the actual levels of these transcripts were increased within BAT cells. In contrast, the abundance of mRNA for uncoupling protein was increased 10-fold, indicating specific activation of this gene. In addition, the maximal rate of protein synthesis analysed in a faithful in organello system was increased 2.5-fold in mitochondria isolated from BAT after 7 days of cold exposure. We conclude from these data that the biogenesis of thermogenic mitochondria in BAT following cold adaptation is achieved by increasing the overall capacity for synthesis of mitochondrial proteins in both compartments, by increasing their mRNAs as well as the ribosomes needed for their translation. In addition, the translational rate for COX subunits as well as all other proteins encoded on mtDNA is increased. Thus the pool of subunits encoded on mtDNA required for assembly of respiratory chain complexes is provided. By comparison with other models of increased mitochondrial biogenesis, we propose that thyroid hormone (generated within BAT cells by 5'-deiodinase, and induced upon sympathetic stimulation), which is a well known regulator of the biogenesis of mitochondria in many tissues, is also the major effector of these adaptive changes in BAT.
| S-EPMC1217391 | biostudies-other
Project description:Plants modify their development to adapt to their environment, protecting themselves from detrimental conditions such as chilling stress by triggering a variety of signaling pathways; however, little is known about how plants coordinate developmental patterns and stress responses at the molecular level. Here, we demonstrate that interacting transcription factors OsMADS57 and OsTB1 directly target the defense gene OsWRKY94 and the organogenesis gene D14 to trade off the functions controlling/moderating rice tolerance to cold. Overexpression of OsMADS57 maintains rice tiller growth under chilling stress. OsMADS57 binds directly to the promoter of OsWRKY94, activating its transcription for the cold stress response, while suppressing its activity under normal temperatures. In addition, OsWRKY94 was directly targeted and suppressed by OsTB1 under both normal and chilling temperatures. However, D14 transcription was directly promoted by OsMADS57 for suppressing tillering under the chilling treatment, whereas D14 was repressed for enhancing tillering under normal condition.We demonstrated that OsMADS57 and OsTB1 conversely affect rice chilling tolerance via targeting OsWRKY94. Our findings highlight a molecular genetic mechanism coordinating organogenesis and chilling tolerance in rice, which supports and extends recent work suggesting that chilling stress environments influence organ differentiation.
| S-EPMC5873253 | biostudies-literature
Project description:The genus Symplocarpus in basal Araceae includes both thermogenic and non/slightly thermogenic species that prefer cold environments. If floral thermogenesis of Symplocarpus contributes to cold adaptation, it would be expected that thermogenic species have a larger habitat than non/slightly thermogenic species during an ice age, leading to increased genetic diversity in the current population. To address this question, potential distribution in past environment predicted by ecological niche modeling (ENM), genetic diversity, and population structure of chloroplast and genome-wide single nucleotide polymorphisms were compared between thermogenic Symplocarpus renifolius and non/slightly thermogenic Symplocarpus nipponicus. ENM revealed that the distribution of S. nipponicus decreased, whereas that of S. renifolius expanded in the Last Glacial Maximum. Phylogeographic analyses have shown that the population structures of the two species were genetically segmented and that the genetic diversity of S. renifolius was higher than that of S. nipponicus. The phylogenetic relationship between chloroplast and nuclear DNA is topologically different in the two species, which may be due to the asymmetric gene flow ubiquitously observed in plants. The results of this study imply that floral thermogenesis of Symplocarpus contributes to expanding the distribution during an ice age, resulting in increased genetic diversity due to cold adaptation.
| S-EPMC10349278 | biostudies-literature
Project description:Transcriptomic analysis on white adipose tissues (WAT), brown adipose tissues (BAT), skeletal muscles and liver from cold-exposed obese mice treated with KPT-330 or DMSO, and those from obese mice housed at ambient temperature indicated that KPT-330 profoundly modulates immune responses in these thermogenic tissues and organs.
2024-03-01 | GSE246327 | GEO
Project description:AimValuable studies have tested the role of UCP1 on body temperature maintenance in mice, and we sought to knockout Ucp1 in rats (Ucp1-/- ) to provide insight into thermogenic mechanisms in larger mammals.MethodsWe used CRISPR/Cas9 technology to create Ucp1-/- rats. Body weight and adiposity were measured, and rats were subjected to indirect calorimetry. Rats were maintained at room temperature or exposed to 4°C for either 24 h or 14 days. Analyses of brown and white adipose tissue and skeletal muscle were conducted via histology, western blot comparison of oxidative phosphorylation proteins, and qPCR to compare mitochondrial DNA levels and mRNA expression profiles. RNA-seq was performed in skeletal muscle.ResultsUcp1-/- rats withstood 4°C for 14 days, but core temperature steadily declined. All rats lost body weight after 14 days at 4°C, but controls increased food intake more robustly than Ucp1-/- rats. Brown adipose tissue showed signs of decreased activity in Ucp1-/- rats, while mitochondrial lipid metabolism markers in white adipose tissue and skeletal muscle were increased. Ucp1-/- rats displayed more visible shivering and energy expenditure than controls at 4°C. Skeletal muscle transcriptomics showed more differences between genotypes at 23°C than at 4°C.ConclusionRoom temperature presented sufficient cold stress to rats lacking UCP1 to activate compensatory thermogenic mechanisms in skeletal muscle, which were only activated in control rats following exposure to 4°C. These results provide novel insight into thermogenic responses to UCP1 deficiency; and highlight Ucp1-/- rats as an attractive translational model for the study of thermogenesis.
| S-EPMC11318575 | biostudies-literature
Project description:ETS variant 1 (ETV1) is an oncogenic transcription factor. However, its role in colorectal cancer has remained understudied. The present study demonstrated that ETV1 downregulation led to reduced HCT116 colorectal cancer cell growth and clonogenic activity. Furthermore, the ETV1 mRNA levels were enhanced in colorectal tumors and were associated with disease severity. In addition, ETV1 directly bound to Jumonji C domain‑containing (JMJD) 1A, a histone demethylase known to promote colon cancer. ETV1 and JMJD1A, but not a catalytically inactive mutant thereof, cooperated in inducing the matrix metalloproteinase (MMP)1 gene promoter that was similar to the cooperation between ETV1 and another histone demethylase, JMJD2A. RNA‑sequencing revealed multiple potential ETV1 target genes in HCT116 cells, including the FOXQ1 and TBX6 transcription factor genes. Moreover, JMJD1A co‑regulated FOXQ1 and other ETV1 target genes, but not TBX6, whereas JMJD2A downregulation had no impact on FOXQ1 as well as TBX6 transcription. Accordingly, the FOXQ1 gene promoter was stimulated by ETV1 and JMJD1A in a cooperative manner, and both ETV1 and JMJD1A bound to the FOXQ1 promoter. Notably, the overexpression of FOXQ1 partially reversed the growth inhibitory effects of ETV1 ablation on HCT116 cells, whereas TBX6 impaired HCT116 cell growth and may thereby dampen the oncogenic activity of ETV1. The latter also revealed for the first time, to the best of our knowledge, a potential tumor suppressive function of TBX6. Taken together, the present study uncovered a ETV1/JMJD1A‑FOXQ1 axis that may drive colorectal tumorigenesis.
| S-EPMC7646594 | biostudies-literature
Project description:In species that are distributed across steep environmental gradients, adaptive variation in physiological performance may be attributable to transcriptional plasticity in underlying regulatory networks. Here we report the results of common-garden experiments that were designed to elucidate the role of regulatory plasticity in evolutionary adaptation to hypoxic cold-stress in deer mice (Peromyscus maniculatus). We integrated genomic transcriptional profiles with measures of metabolic enzyme activities and whole-animal thermogenic performance under hypoxia in highland (4350 m) and lowland (430 m) mice from three experimental groups: (1) wild-caught mice that were sampled at their native elevations; (2) wild-caught/lab-reared mice that were deacclimated to low-elevation conditions in a common-garden lab environment; and (3) the F(1) progeny of deacclimated mice that were maintained under the same low-elevation common-garden conditions. In each experimental group, highland mice exhibited greater thermogenic capacities than lowland mice, and this enhanced performance was associated with upregulation of transcriptional modules that influence several hierarchical steps in the O(2) cascade, including tissue O(2) diffusion (angiogenesis) and tissue O(2) utilization (metabolic fuel use and cellular oxidative capacity). Most of these performance-related transcriptomic changes occurred over physiological and developmental timescales, suggesting that regulatory plasticity makes important contributions to fitness-related physiological performance in highland deer mice.
| S-EPMC4399701 | biostudies-literature