1805-P: Insulin Regulates a Broad Network of Gene Expression in the Brain to Regulated Brain Metabolism and Neurotransmission

WEIKANG CAI; THIAGO M. BATISTA; RUBEN GARCIA MARTIN; ALFRED RAMIREZ; MASAHIRO KONISHI; O'NEILL BRIAN T.; JASON K. KIM; C. RONALD KAHN

doi:10.2337/db19-1805-p

Alternative splicing during mammalian organ development

Nature Genetics ◽

10.1038/s41588-021-00851-w ◽

2021 ◽

Author(s):

Pavel V. Mazin ◽

Philipp Khaitovich ◽

Margarida Cardoso-Moreira ◽

Henrik Kaessmann

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Regulatory Networks ◽

Organ Development ◽

Functional Diversification ◽

Mammalian Genomes ◽

Species Comparisons ◽

Time Specific ◽

The Brain ◽

Gene Expression Levels

AbstractAlternative splicing (AS) is pervasive in mammalian genomes, yet cross-species comparisons have been largely restricted to adult tissues and the functionality of most AS events remains unclear. We assessed AS patterns across pre- and postnatal development of seven organs in six mammals and a bird. Our analyses revealed that developmentally dynamic AS events, which are especially prevalent in the brain, are substantially more conserved than nondynamic ones. Cassette exons with increasing inclusion frequencies during development show the strongest signals of conserved and regulated AS. Newly emerged cassette exons are typically incorporated late in testis development, but those retained during evolution are predominantly brain specific. Our work suggests that an intricate interplay of programs controlling gene expression levels and AS is fundamental to organ development, especially for the brain and heart. In these regulatory networks, AS affords substantial functional diversification of genes through the generation of tissue- and time-specific isoforms from broadly expressed genes.

Download Full-text

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Science Advances ◽

10.1126/sciadv.aba1187 ◽

2021 ◽

Vol 7 (11) ◽

pp. eaba1187

Author(s):

Rina Baba ◽

Satoru Matsuda ◽

Yuuichi Arakawa ◽

Ryuji Yamada ◽

Noriko Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Neurodevelopmental Disorders ◽

Neurodevelopmental Disorder ◽

Specific Inhibitor ◽

Autism Spectrum ◽

Poly I:C ◽

Control Of Gene Expression ◽

Epigenetic Machinery ◽

The Brain

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

Download Full-text

A gene expression atlas for different kinds of stress in the mouse brain

Scientific Data ◽

10.1038/s41597-020-00772-z ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Tiziano Flati ◽

Silvia Gioiosa ◽

Giovanni Chillemi ◽

Andrea Mele ◽

Alberto Oliverio ◽

...

Keyword(s):

Gene Expression ◽

Coping With Stress ◽

Gene Expression Atlas ◽

Sequence Read Archive ◽

Brain Transcriptome ◽

Expression Atlas ◽

Differential Gene ◽

Stress Related Genes ◽

Public Repositories ◽

The Brain

AbstractStressful experiences are part of everyday life and animals have evolved physiological and behavioral responses aimed at coping with stress and maintaining homeostasis. However, repeated or intense stress can induce maladaptive reactions leading to behavioral disorders. Adaptations in the brain, mediated by changes in gene expression, have a crucial role in the stress response. Recent years have seen a tremendous increase in studies on the transcriptional effects of stress. The input raw data are freely available from public repositories and represent a wealth of information for further global and integrative retrospective analyses. We downloaded from the Sequence Read Archive 751 samples (SRA-experiments), from 18 independent BioProjects studying the effects of different stressors on the brain transcriptome in mice. We performed a massive bioinformatics re-analysis applying a single, standardized pipeline for computing differential gene expression. This data mining allowed the identification of novel candidate stress-related genes and specific signatures associated with different stress conditions. The large amount of computational results produced was systematized in the interactive “Stress Mice Portal”.

Download Full-text

The brain transcriptome of the wolf spider, Schizocosa ocreata

BMC Research Notes ◽

10.1186/s13104-021-05648-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Daniel Stribling ◽

Peter L. Chang ◽

Justin E. Dalton ◽

Christopher A. Conow ◽

Malcolm Rosenthal ◽

...

Keyword(s):

Gene Expression ◽

De Novo ◽

Transcriptome Assembly ◽

Model Organisms ◽

De Novo Transcriptome Assembly ◽

De Novo Transcriptome ◽

Wolf Spiders ◽

Schizocosa Ocreata ◽

Genomic Studies ◽

The Brain

Abstract Objectives Arachnids have fascinating and unique biology, particularly for questions on sex differences and behavior, creating the potential for development of powerful emerging models in this group. Recent advances in genomic techniques have paved the way for a significant increase in the breadth of genomic studies in non-model organisms. One growing area of research is comparative transcriptomics. When phylogenetic relationships to model organisms are known, comparative genomic studies provide context for analysis of homologous genes and pathways. The goal of this study was to lay the groundwork for comparative transcriptomics of sex differences in the brain of wolf spiders, a non-model organism of the pyhlum Euarthropoda, by generating transcriptomes and analyzing gene expression. Data description To examine sex-differential gene expression, short read transcript sequencing and de novo transcriptome assembly were performed. Messenger RNA was isolated from brain tissue of male and female subadult and mature wolf spiders (Schizocosa ocreata). The raw data consist of sequences for the two different life stages in each sex. Computational analyses on these data include de novo transcriptome assembly and differential expression analyses. Sample-specific and combined transcriptomes, gene annotations, and differential expression results are described in this data note and are available from publicly-available databases.

Download Full-text

Bile Acids in Dementia: Brain Amyloid, White Matter Lesions, and Atrophy

Innovation in Aging ◽

10.1093/geroni/igaa057.2772 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 767-768

Author(s):

Vijay Varma ◽

Youjin Wang ◽

Yang An ◽

Sudhir Varma ◽

Murat Bilgel ◽

...

Keyword(s):

Gene Expression ◽

Bile Acids ◽

White Matter Lesions ◽

Pharmacological Modulation ◽

Dementia Risk ◽

The Brain ◽

Step Study ◽

Brain Amyloid Deposition ◽

Gene Expression Levels

Abstract While Alzheimer’s disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association is unclear. Using a novel, 3-step study design we examined the role of cholesterol catabolism in dementia by testing whether 1) the synthesis of the primary cholesterol breakdown products (bile acids (BA)) were associated with neuroimaging markers of dementia; 2) pharmacological modulation of BAs alters dementia risk; and 3) brain BA concentrations and gene expression were associated with AD. We found that higher serum concentrations of BAs are associated with lower brain amyloid deposition, slower WML accumulation, and slower brain atrophy in males. Opposite effects were observed in females. Modulation of BA levels alters risk of incident VaD in males. Altered brain BA signaling at the metabolite and gene expression levels occurs in AD. Dysregulation of peripheral cholesterol catabolism and BA synthesis may impact dementia pathogenesis through signaling pathways in the brain.

Download Full-text

Interaction of clozapine with metformin in a schizophrenia rat model

Scientific Reports ◽

10.1038/s41598-021-96478-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

G. Horvath ◽

G. Kis ◽

G. Kekesi ◽

A. Büki ◽

L. G. Adlan ◽

...

Keyword(s):

Gene Expression ◽

Cognitive Function ◽

Negative Symptoms ◽

Antipsychotic Drugs ◽

D1 Receptor ◽

Antidiabetic Drug ◽

Beneficial Effects ◽

Adjuvant Therapies ◽

Behavioral Parameters ◽

The Brain

AbstractThe low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D1R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D1R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D1R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D1R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D1R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D1R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

Download Full-text

Characterization of microglial transcriptomes in the brain and spinal cord of mice in early and late experimental autoimmune encephalomyelitis using a RiboTag strategy

Scientific Reports ◽

10.1038/s41598-021-93590-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shaona Acharjee ◽

Paul M. K. Gordon ◽

Benjamin H. Lee ◽

Justin Read ◽

Matthew L. Workentine ◽

...

Keyword(s):

Gene Expression ◽

Spinal Cord ◽

Experimental Autoimmune Encephalomyelitis ◽

Expression Patterns ◽

Immune Functions ◽

Autoimmune Encephalomyelitis ◽

Transcriptional Changes ◽

Brain And Spinal Cord ◽

The Brain ◽

Experimental Autoimmune

AbstractMicroglia play an important role in the pathogenesis of multiple sclerosis and the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). To more fully understand the role of microglia in EAE we characterized microglial transcriptomes before the onset of motor symptoms (pre-onset) and during symptomatic EAE. We compared the transcriptome in brain, where behavioral changes are initiated, and spinal cord, where damage is revealed as motor and sensory deficits. We used a RiboTag strategy to characterize ribosome-bound mRNA only in microglia without incurring possible transcriptional changes after cell isolation. Brain and spinal cord samples clustered separately at both stages of EAE, indicating regional heterogeneity. Differences in gene expression were observed in the brain and spinal cord of pre-onset and symptomatic animals with most profound effects in the spinal cord of symptomatic animals. Canonical pathway analysis revealed changes in neuroinflammatory pathways, immune functions and enhanced cell division in both pre-onset and symptomatic brain and spinal cord. We also observed a continuum of many pathways at pre-onset stage that continue into the symptomatic stage of EAE. Our results provide additional evidence of regional and temporal heterogeneity in microglial gene expression patterns that may help in understanding mechanisms underlying various symptomology in MS.

Download Full-text

Resilience, plasticity and robustness in gene expression during aging in the brain of outbred deer mice

BMC Genomics ◽

10.1186/s12864-021-07613-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

E Soltanmohammadi ◽

Y Zhang ◽

I Chatzistamou ◽

H. Kiaris

Keyword(s):

Gene Expression ◽

Cholesterol Metabolism ◽

Expression Profiles ◽

Deer Mice ◽

Abrupt Changes ◽

Transcriptional Changes ◽

Thrombospondin 4 ◽

Whole Transcriptome ◽

The Brain ◽

Shed Light

Abstract Background Genes that belong to the same network are frequently co-expressed, but collectively, how the coordination of the whole transcriptome is perturbed during aging remains unclear. To explore this, we calculated the correlation of each gene in the transcriptome with every other, in the brain of young and older outbred deer mice (P. leucopus and P. maniculatus). Results In about 25 % of the genes, coordination was inversed during aging. Gene Ontology analysis in both species, for the genes that exhibited inverse transcriptomic coordination during aging pointed to alterations in the perception of smell, a known impairment occurring during aging. In P. leucopus, alterations in genes related to cholesterol metabolism were also identified. Among the genes that exhibited the most pronounced inversion in their coordination profiles during aging was THBS4, that encodes for thrombospondin-4, a protein that was recently identified as rejuvenation factor in mice. Relatively to its breadth, abolishment of coordination was more prominent in the long-living P. leucopus than in P. maniculatus but in the latter, the intensity of de-coordination was higher. Conclusions There sults suggest that aging is associated with more stringent retention of expression profiles for some genes and more abrupt changes in others, while more subtle but widespread changes in gene expression appear protective. Our findings shed light in the mode of the transcriptional changes occurring in the brain during aging and suggest that strategies aiming to broader but more modest changes in gene expression may be preferrable to correct aging-associated deregulation in gene expression.

Download Full-text