Brain histone beta-hydroxy-butyrylation couples metabolism with gene expression

The metabolic status has a well-documented influence on peripheral organs' physiology and pathology, however mounting evidence suggests that it can also affect brain function. For example, brain resilience to aging is enhanced by caloric restriction, and ketogenic diets have been used to treat neurological diseases. Unfortunately, little is known about the impact of metabolic stimuli on brain tissue at a molecular level. Recent data obtained in liver tissue suggest that beta-hydroxybutyrate (BHB) can also be a key signaling molecule regulating gene transcription. Thus, we adopted a ketogenic metabolic challenge, based on 48 hrs of fasting, and then assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex. We found that fasting enhanced K-bhb in a variety of proteins and on histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. Since one of the most enriched functional annotations both at the epigenetic and transcriptional level was circadian rhythms, we studied the expression of core-clock genes in the cortex during fasting. We found that the diurnal oscillation of specific transcripts was modulated at distinct times of the day along the circadian cycle. Thus, our results suggest that fasting dramatically impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodelling in neural tissue cells.

Download Full-text

Transcriptomic Modification in the Cerebral Cortex following Noninvasive Brain Stimulation: RNA-Sequencing Approach

Neural Plasticity ◽

10.1155/2016/5942980 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 2

Author(s):

Ben Holmes ◽

Seung Ho Jung ◽

Jing Lu ◽

Jessica A. Wagner ◽

Liudmilla Rubbi ◽

...

Keyword(s):

Gene Expression ◽

Cerebral Cortex ◽

Rna Sequencing ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Current Intensity ◽

Beneficial Effects ◽

Group A ◽

The Impact

Transcranial direct current stimulation (tDCS) has been shown to modulate neuroplasticity. Beneficial effects are observed in patients with psychiatric disorders and enhancement of brain performance in healthy individuals has been observed following tDCS. However, few studies have attempted to elucidate the underlying molecular mechanisms of tDCS in the brain. This study was conducted to assess the impact of tDCS on gene expression within the rat cerebral cortex. Anodal tDCS was applied at 3 different intensities followed by RNA-sequencing and analysis. In each current intensity, approximately 1,000 genes demonstrated statistically significant differences compared to the sham group. A variety of functional pathways, biological processes, and molecular categories were found to be modified by tDCS. The impact of tDCS on gene expression was dependent on current intensity. Results show that inflammatory pathways, antidepressant-related pathways (GTP signaling, calcium ion binding, and transmembrane/signal peptide pathways), and receptor signaling pathways (serotonergic, adrenergic, GABAergic, dopaminergic, and glutamate) were most affected. Of the gene expression profiles induced by tDCS, some changes were observed across multiple current intensities while other changes were unique to a single stimulation intensity. This study demonstrates that tDCS can modify the expression profile of various genes in the cerebral cortex and that these tDCS-induced alterations are dependent on the current intensity applied.

Download Full-text

Sperm and seminal plasma RNAs: what roles do they play beyond fertilization?

Reproduction ◽

10.1530/rep-18-0639 ◽

2019 ◽

Vol 158 (4) ◽

pp. R113-R123 ◽

Cited By ~ 6

Author(s):

Meritxell Jodar

Keyword(s):

Gene Expression ◽

Embryo Development ◽

Seminal Plasma ◽

Preimplantation Embryo ◽

Epigenetic Inheritance ◽

Early Embryo ◽

Female Reproductive Tract ◽

Transcriptional Level ◽

Preimplantation Embryo Development ◽

The Impact

The paternal contribution to the new individual is not just limited to half the diploid genome. Recent findings have shown that sperm delivers to the oocyte several components, including a complex population of RNAs, which may influence early embryo development and the long-term phenotype of the offspring. Although the majority of sperm RNAs may only represent spermatogenic leftovers with no further function, the male gamete provides a specific set of RNAs to the oocyte that is able to modulate gene expression in the preimplantation embryo. Those sperm transcripts include coding and non-coding RNAs that might either be translated by the oocyte machinery or directly regulate embryo gene expression at the transcriptional or post-transcriptional level. Interestingly, some sperm RNAs seem to be acquired during post-testicular maturation through active communication between sperm and epididymal and seminal exosomes released by the epididymis and the male accessory sex glands, respectively. Exosomes contained in the seminal plasma seem to not only interact with the spermatozoa but also with cells from the female reproductive tract, modulating their gene expression and influencing female immune response triggered by the semen. This review also considers the findings that indicate the role of semen RNAs in preimplantation embryo development and offspring phenotypes. In this regard, different studies supporting the hypothesis of paternal epigenetic inheritance of altered metabolic phenotypes associated with environmental exposures are discussed. Lastly, potential mechanisms that could explain the impact of semen RNAs to both early embryogenesis and paternal epigenetic inheritance are suggested.

Download Full-text

Shift Work, Jet Lag, and Female Reproduction

International Journal of Endocrinology ◽

10.1155/2010/813764 ◽

2010 ◽

Vol 2010 ◽

pp. 1-9 ◽

Cited By ~ 93

Author(s):

Megan M. Mahoney

Keyword(s):

Gene Expression ◽

Shift Work ◽

Clock Gene ◽

Clock Genes ◽

Reproductive Function ◽

Jet Lag ◽

Female Reproduction ◽

Clock Gene Expression ◽

Increased Risk ◽

The Impact

Circadian rhythms and “clock gene” expression are involved in successful reproductive cycles, mating, and pregnancy. Alterations or disruptions of biological rhythms, as commonly occurs in shift work, jet lag, sleep deprivation, or clock gene knock out models, are linked to significant disruptions in reproductive function. These impairments include altered hormonal secretion patterns, reduced conception rates, increased miscarriage rates and an increased risk of breast cancer. Female health may be particularly susceptible to the impact of desynchronizing work schedules as perturbed hormonal rhythms can further influence the expression patterns of clock genes. Estrogen modifies clock gene expression in the uterus, ovaries, and suprachiasmatic nucleus, the site of the primary circadian clock mechanism. Further work investigating clock genes, light exposure, ovarian hormones, and reproductive function will be critical for indentifying how these factors interact to impact health and susceptibility to disease.

Download Full-text

Compared to Australian Cultivars, European Summer Wheat (Triticum aestivum) Overreacts When Moderate Heat Stress Is Applied at the Pollen Development Stage

Agronomy ◽

10.3390/agronomy8070099 ◽

2018 ◽

Vol 8 (7) ◽

pp. 99 ◽

Cited By ~ 6

Author(s):

Kevin Begcy ◽

Anna Weigert ◽

Andrew Egesa ◽

Thomas Dresselhaus

Keyword(s):

Gene Expression ◽

Heat Stress ◽

Heat Waves ◽

Negative Impact ◽

Pollen Viability ◽

Wheat Yield ◽

Gene Expression Pattern ◽

Type A ◽

Transcriptional Level ◽

The Impact

Heat stress frequently imposes a strong negative impact on vegetative and reproductive development of plants leading to severe yield losses. Wheat, a major temperate crop, is more prone to suffer from increased temperatures than most other major crops. With heat waves becoming more intense and frequent, as a consequence of global warming, a decrease in wheat yield is highly expected. Here, we examined the impact of a short-term (48 h) heat stress on wheat imposed during reproduction at the pollen mitosis stage both, at the physiological and molecular level. We analyzed two sets of summer wheat germplasms from Australia (Kukri, Drysdale, Gladius, and RAC875) and Europe (Epos, Cornetto, Granny, and Chamsin). Heat stress strongly affected gas exchange parameters leading to reduced photosynthetic and transpiration rates in the European cultivars. These effects were less pronounced in Australian cultivars. Pollen viability was also reduced in all European cultivars. At the transcriptional level, the largest group of heat shock factor genes (type A HSFs), which trigger molecular responses as a result of environmental stimuli, showed small variations in gene expression levels in Australian wheat cultivars. In contrast, HSFs in European cultivars, including Epos and Granny, were strongly downregulated and partly even silenced, while the high-yielding variety Chamsin displayed a strong upregulation of type A HSFs. In conclusion, Australian cultivars are well adapted to moderate heat stress compared to European summer wheat. The latter strongly react after heat stress application by downregulating photosynthesis and transpiration rates as well as differentially regulating HSFs gene expression pattern.

Download Full-text

Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.732120 ◽

2021 ◽

Vol 14 ◽

Author(s):

Darío García-Rodríguez ◽

Alfredo Giménez-Cassina

Keyword(s):

Gene Expression ◽

Neuronal Excitability ◽

Ketone Bodies ◽

Biological Effects ◽

Epileptic Seizures ◽

Ketogenic Diets ◽

Infantile Seizures ◽

Neuronal Physiology ◽

The Impact ◽

The Brain

Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called “ketogenic diets,” which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis. The fact that ketogenic diets have such a profound effect on epileptic seizures points to complex biological effects of ketone bodies in addition to their role as a source of ATP. In this review, we specifically focus on the ability of ketone bodies to regulate neuronal excitability and their effects on gene expression to respond to oxidative stress. Finally, we also discuss their capacity as signaling molecules in brain cells.

Download Full-text

Intermittent Hypoxia Alters the Circadian Expression of Clock Genes in Mouse Brain and Liver

Genes ◽

10.3390/genes12101627 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1627

Author(s):

Bala S. C. Koritala ◽

Yin Yeng Lee ◽

Shweta S. Bhadri ◽

Laetitia S. Gaspar ◽

Corinne Stanforth ◽

...

Keyword(s):

Gene Expression ◽

Circadian Clock ◽

Intermittent Hypoxia ◽

Clock Genes ◽

The United States ◽

Circadian Expression ◽

Polymerase Chain ◽

States Experience ◽

The Impact ◽

The Brain

At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is not well characterized. In the current study, we used an IH mouse model to understand the impact of IH on the circadian gene expression of the canonical clock genes in the central (the brain) and peripheral (the liver) tissues. Gene expression was measured using a Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). CircaCompare was used to evaluate the differential rhythmicity between normoxia and IH. Our observations suggested that the circadian clock in the liver was less sensitive to IH compared to the circadian clock in the brain.

Download Full-text

Gene expression profiling of the SCN in young and old rhesus macaques

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0062 ◽

2018 ◽

Vol 61 (2) ◽

pp. 57-67 ◽

Cited By ~ 5

Author(s):

Dominique H Eghlidi ◽

Selva L Luna ◽

Donald I Brown ◽

Vasilios T Garyfallou ◽

Steven G Kohama ◽

...

Keyword(s):

Gene Expression ◽

Clock Genes ◽

Rhesus Macaques ◽

The Body ◽

Transcriptional Level ◽

Activity Levels ◽

Age Related ◽

Reverse Strand ◽

Or Genes ◽

Group D

In mammals, the suprachiasmatic nucleus (SCN) is the location of a master circadian pacemaker. It receives photic signals from the environment via the retinal hypothalamic tract, which play a key role in synchronizing the body’s endogenously generated circadian rhythms with the 24-h rhythm of the environment. Therefore, it is plausible that age-related changes within the SCN contribute to the etiology of perturbed activity–rest cycles that become prevalent in humans during aging. To test this hypothesis, we used gene arrays and quantitative RT-PCR to profile age-related gene expression changes within the SCN of male rhesus macaques – a pragmatic translational animal model of human aging, which similarly displays an age-related attenuation of daytime activity levels. As expected, the SCN showed high expression of arginine vasopressin, vasoactive intestinal polypeptide, calbindin and nuclear receptor subfamily 1, group D, member 1 (NR1D1) (also known as reverse strand of ERBA (REV-ERBα), both at the mRNA and protein level. However, no obvious difference was detected between the SCNs of young (7–12 years) and old animals (21–26 years), in terms of the expression of core clock genes or genes associated with SCN signaling and neurotransmission. These data demonstrate the resilience of the primate SCN to normal aging, at least at the transcriptional level and, at least in males, suggest that age-related disruption of activity–rest cycles in humans may instead stem from changes within other components of the circadian system, such as desynchronization of subordinate oscillators in other parts of the body.

Download Full-text

Differences between Cerebral Organoids Derived from a non-PD and a Parkinson’s Patient: A Potential Vulnerability for Neuroinvasive Viruses

10.20944/preprints202101.0480.v1 ◽

2021 ◽

Author(s):

Emily Schultz ◽

Tyanthony Jones ◽

Sibei Xu ◽

Dana Dean ◽

Bernd Zechmann ◽

...

Keyword(s):

Gene Expression ◽

Innate Immunity ◽

Neurodegenerative Diseases ◽

Viral Infection ◽

Genetic Background ◽

Neurological Diseases ◽

Muscarinic Acetylcholine Receptors ◽

Cns Infection ◽

Significant Difference ◽

The Impact

The development of 3D cerebral brain organoids which accurately resemble aspects of the human brain permits a more accurate characterization of physiological processes and neurological diseases. Cerebral organoids can be grown from stem cell lines with various genetic backgrounds allowing multiple neurodegenerative diseases to be modeled. While dysfunction in neurotransmission of patients with neurodegenerative diseases is expected, the impact of chronic neurodegeneration on the response to viral infection of the CNS is poorly understood. For instance, several mosquito-borne viruses like Dengue virus and West Nile Virus cause post-viral parkinsonism. How CNS infection might impact a host with inherent CNS dysfunction such as Parkinson’s Disease in poorly understood. This preliminary, observational study aimed to understand dysfunction in intrinsic and innate expression of a patient with a neurodegenerative disease and a non-affected individual in relation to potential viral infection in the CNS. Cerebral organoids were generated from human induced pluripotent stem cells with a normal genetic background or with idiopathic Parkinson’s Disease. After differentiation and maturation, organoid size, gene expression and immunofluorescence were evaluated to assess neurotransmission and innate immunity. While there was no significant difference in size of the organoids with a normal or Parkinson’s genetic background, gene expression studies identified multiple differences in innate immunity and neurotransmission. Immunofluorescence also identified differences in protein expression related to neurotransmission and innate immunity. Of note, organoids derived from a Parkinson’s patient exhibited endogenous up-regulation of dopamine and muscarinic acetylcholine receptors, GABA, glycine, and glutamate targets, and the majority of cytokines. This expression pattern suggests a chronic state of neuroexcitation and neuroinflammation in this population of organoids.

Download Full-text

Every cloud has a silver lining: how abiotic stresses affect gene expression in plant pathogen-interactions

Journal of Experimental Botany ◽

10.1093/jxb/eraa531 ◽

2020 ◽

Author(s):

Marco Zarattini ◽

Mahsa Farjad ◽

Alban Launay ◽

David Cannella ◽

Marie-Christine Soulié ◽

...

Keyword(s):

Gene Expression ◽

Plant Defense ◽

Plant Pathogen ◽

Abiotic Stresses ◽

Biotic Interactions ◽

Mineral Nutrient ◽

Transcriptional Level ◽

Tissue Organization ◽

Plant Pathogen Interactions ◽

The Impact

Abstract The current context of environmental and climate changes deeply influences the outcome of plant-pathogen interactions. Indeed, nowadays it is clear that abiotic stresses strongly affect biotic interactions at various levels. For instance, physiological parameters such as plant architecture and tissue organization along with primary and specialized metabolism are affected by environmental constraints, thus making the plant a more or less worthy host for a given pathogen. Moreover, abiotic stresses can affect the timely expression of plant defense and pathogen virulence. Indeed, several studies have shown that variations in temperature, water and mineral nutrient availability impact plant defense gene expression. Virulence gene expression, known to be crucial for disease outbreak, is also affected by environmental conditions, potentially modifying existing pathosystems and paving the way for emerging pathogens. The present review summarizes the current knowledge on the impact of abiotic stress on biotic interactions at the transcriptional level in both the plant and the pathogen side of the interaction. We performed a meta-data analysis of four different combinations of abiotic and biotic stresses. 197 modulated genes were common to all four combinations, with a strong defense-related GO term enrichment. We also describe the multistress-specific responses of selected defense-related genes.

Download Full-text