Back to the basics? Transcriptomics offers integrative insights into the role of space, time and the environment for gene expression and behaviour

2021 ◽  
Vol 17 (9) ◽  
pp. 20210293
Author(s):  
Eva K. Fischer ◽  
Mark E. Hauber ◽  
Alison M. Bell

Fuelled by the ongoing genomic revolution, broadscale RNA expression surveys are fast replacing studies targeting one or a few genes to understand the molecular basis of behaviour. Yet, the timescale of RNA-sequencing experiments and the dynamics of neural gene activation are insufficient to drive real-time switches between behavioural states. Moreover, the spatial, functional and transcriptional complexity of the brain (the most commonly targeted tissue in studies of behaviour) further complicates inference. We argue that a Central Dogma-like ‘back-to-basics’ assumption that gene expression changes cause behaviour leaves some of the most important aspects of gene–behaviour relationships unexplored, including the roles of environmental influences, timing and feedback from behaviour—and the environmental shifts it causes—to neural gene expression. No perfect experimental solutions exist but we advocate that explicit consideration, exploration and discussion of these factors will pave the way toward a richer understanding of the complicated relationships between genes, environments, brain gene expression and behaviour over developmental and evolutionary timescales.

2022 ◽  
Author(s):  
Daniel Felsky ◽  
Hans-Ulrich Klein ◽  
Vilas Menon ◽  
Yiyi Ma ◽  
Yanling Wang ◽  
...  

Abstract Despite a growing focus on neuroimmune mechanisms of Alzheimer’s disease (AD), the role of peripheral monocytes remains largely unknown. Circulating monocytes communicate with the brain’s resident myeloid cells, microglia, via chemical signaling and can directly infiltrate the brain parenchyma.1 Thus, molecular signatures of monocytes may serve as indicators of neuropathological events unfolding in the CNS.2–5 However, no studies have yet directly tested the association of monocyte gene expression on longitudinal cognitive decline or postmortem neuropathology and brain gene expression in aging. Here we present a resource of RNA sequencing of purified CD14+ human monocytes - including an eQTL map - from over 200 elderly individuals, most with accompanying bulk brain RNA sequencing profiles, longitudinal cognitive assessments, and detailed postmortem neuropathological examinations. We tested the direct correlation of gene expression between monocytes and bulk brain tissue, finding very few significant signals driven largely by genetic variation. However, we did identify sets of monocyte-expressed genes that were highly predictive of postmortem microglial activation, diffuse amyloid plaque deposition, and cerebrovascular disease. Our findings prioritize potential blood-based molecular biomarkers for AD; they also reveal the previously unknown architecture of shared gene expression between the CNS and peripheral immune system in aging.


2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 767-768
Author(s):  
Vijay Varma ◽  
Youjin Wang ◽  
Yang An ◽  
Sudhir Varma ◽  
Murat Bilgel ◽  
...  

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.


2016 ◽  
Vol 371 (1688) ◽  
pp. 20150114 ◽  
Author(s):  
Nancy G. Forger

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.


Biomeditsina ◽  
2019 ◽  
pp. 12-22
Author(s):  
N. V. Petrova

It is shown that the level of the Lep gene expression is a marker for B/Ks-Leprᵈᵇ/+ mice, which line serves as an optimal model for describing metabolic syndrome (MS) in preclinical studies. Mice were transplanted with cultured isogenic bone marrow cells (BMC) from heterozygous db/+ donors. The recipients were divided into two groups according to an early or advanced stage of MS development. We analyzed the expression of the Lep gene on the 3rd, 8th and 14th day following the administration of stem BMCs in the brain, liver and pancreas cells by polymerase chain reaction (PCR) in real time. The Lep gene expression was evaluated in terms of the number of cDNA copies. According to our data, leptin is a complete regulator of metabolic processes due to its effect on the hypothalamus, which, together with the hippocampus, controls the production of acetylcholine and insulin in the brain. We have proven the role of the Lep gene as a quantitative criterion for evaluating the effi cacy of a cell therapy in MS.


Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 574
Author(s):  
Marta Kaczor-Kamińska ◽  
Piotr Sura ◽  
Maria Wróbel

The investigations showed changes of the cystathionine γ-lyase (CTH), 3-mercaptopyruvate sulfurtransferase (MPST) and rhodanese (TST) activity and gene expression in the brain, heart, liver, kidney, skeletal muscles and testes in frogs Pelophylax ridibundus, Xenopus laevis and Xenopus tropicalis in response to Pb2+, Hg2+ and Cd2+ stress. The results were analyzed jointly with changes in the expression of selected antioxidant enzymes (cytoplasmic and mitochondrial superoxide dismutase, glutathione peroxidase, catalase and thioredoxin reducatase) and with the level of malondialdehyde (a product of lipid peroxidation). The obtained results allowed for confirming the role of sulfurtransferases in the antioxidant protection of tissues exposed to heavy metal ions. Our results revealed different transcriptional responses of the investigated tissues to each of the examined heavy metals. The CTH, MPST and TST genes might be regarded as heavy metal stress-responsive. The CTH gene expression up-regulation was confirmed in the liver (Pb2+, Hg2+, Cd2+) and skeletal muscle (Hg2+), MPST in the brain (Pb2+, Hg2+), kidney (Pb2+, Cd2+), skeletal muscle (Pb2+, Hg2+,Cd2+) and TST in the brain (Pb2+) and kidney (Pb2+, Hg2+, Cd2+). Lead, mercury and cadmium toxicity was demonstrated to affect the glutathione (GSH) and cysteine levels, the concentration ratio of reduced to oxidized glutathione ([GSH]/[GSSG]) and the level of sulfane sulfur-containing compounds, which in case of enhanced reactive oxygen species generation can reveal their antioxidative properties. The present report is the first to widely describe the role of the sulfane sulfur/H2S generating enzymes and the cysteine/glutathione system in Pb2+, Hg2+ and Cd2+ stress in various frog tissues, and to explore the mechanisms mediating heavy metal-related stress.


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