bims-agalsp 2023-02-12 papers

Issue of 2023–02–12
three papers selected by
Dongmeng Wang, King’s College

Fluids Barriers CNS. 2023 Feb 06. 20(1): 12

Impact of aging on meningeal gene expression.

Melanie Neutzner, Corina Kohler, Stephan Frank, Hanspeter E Killer, Albert Neutzner.

BACKGROUND: The three-layered meninges cover and protect the central nervous system and form the interface between cerebrospinal fluid and the brain. They are host to a lymphatic system essential for maintaining fluid dynamics inside the cerebrospinal fluid-filled subarachnoid space and across the brain parenchyma via their connection to glymphatic structures. Meningeal fibroblasts lining and traversing the subarachnoid space have direct impact on the composition of the cerebrospinal fluid through endocytotic uptake as well as extensive protein secretion. In addition, the meninges are an active site for immunological processes and act as gatekeeper for immune cells entering the brain. During aging in mice, lymphatic drainage from the brain is less efficient contributing to neurodegenerative processes. Aging also affects the immunological status of the meninges, with increasing numbers of T cells, changing B cell make-up, and altered macrophage complement.
METHODS: We employed RNASeq to measure gene expression and to identify differentially expressed genes in meninges isolated from young and aged mice. Using Ingenuity pathway, GO term, and MeSH analyses, we identified regulatory pathways and cellular functions in meninges affected by aging.
RESULTS: Aging had profound impact on meningeal gene expression. Pathways related to innate as well as adaptive immunity were affected. We found evidence for increasing numbers of T and B lymphocytes and altered activity profiles for macrophages and other myeloid cells. Furthermore, expression of pro-inflammatory cytokine and chemokine genes increased with aging. Similarly, the complement system seemed to be more active in meninges of aged mice. Altered expression of solute carrier genes pointed to age-dependent changes in cerebrospinal fluid composition. In addition, gene expression for secreted proteins showed age-dependent changes, in particular, genes related to extracellular matrix composition and organization were affected.
CONCLUSIONS: Aging has profound effects on meningeal gene expression; thereby affecting the multifaceted functions meninges perform to maintain the homeostasis of the central nervous system. Thus, age-dependent neurodegenerative processes and cognitive decline are potentially in part driven by altered meningeal function.

Keywords: Aging; Brain; Cerebrospinal fluid; Inflammation; Meninges; Neurodegeneration; Neuroimmunology

DOI: https://doi.org/10.1186/s12987-023-00412-9

Hum Mol Genet. 2023 Feb 08. pii: ddad024. [Epub ahead of print]

Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease.

Tina Rönn, Alexander Perfilyev, Josefine Jönsson, Karl-Fredrik Eriksson, Sine W Jørgensen, Charlotte Brøns, Linn Gillberg, Allan Vaag, Elisabet Stener-Victorin, Charlotte Ling.

BACKGROUND: Dysregulation of circulating lipids is a central element for the metabolic syndrome. However, it is not well established whether human subcutaneous adipose tissue is affected by or affect circulating lipids through epigenetic mechanisms. Hence, our aim was to investigate the association between circulating lipids and DNA methylation levels in human adipose tissue.
METHODS: DNA methylation and gene expression were analyzed genome-wide in subcutaneous adipose tissue from two different cohorts, including 85 men and 93 women, respectively. Associations between DNA methylation and circulating levels of triglycerides, LDL, HDL and total cholesterol were analysed. Causal mediation analyses tested if adipose tissue DNA methylation mediates the effects of triglycerides on gene expression or insulin resistance.
RESULTS: We found 115 novel associations between triglycerides and adipose tissue DNA methylation, e.g. in the promoter of RFS1, ARID2, and HOXA5 in the male cohort (p ≤ 1.1x10-7), and 63 associations e.g. within the gene body of PTPRN2 and COL6A3 in the female cohort. We further connected these findings to altered mRNA expression levels in adipose tissue (e.g. HOXA5, IL11 and FAM45B). Interestingly, there was no overlap between methylation sites associated with triglycerides in men and the sites found in women, which points towards sex-specific effects of triglycerides on the epigenome. Finally, a causal mediation analysis provided support for adipose tissue DNA methylation as a partial mediating factor between circulating triglycerides and insulin resistance.
CONCLUSIONS: This study identified novel epigenetic alterations in adipose tissue associated with circulating lipids. Identified epigenetic changes seem to mediate effects of triglycerides on insulin resistance.

DOI: https://doi.org/10.1093/hmg/ddad024

Oncol Lett. 2023 Feb;25(2): 76

rs77283072 influences breast cancer susceptibility by regulating CDKN2A expression.

Guang-Huan He, Shao-Dong Liu, Xiao-Qian Shi, Ying Chen, Li Su, Qiao-Na Shi, Chang Sun.

Breast cancer is the cancer type with the highest morbidity rates in women, and previous genome-wide association studies (GWASs) have suggested that the single nucleotide polymorphism (SNP) rs1011970 is significantly associated with this disease. An analysis of data from the 1000 Genomes Project demonstrated that there is an SNP, rs77283072, in almost complete linkage disequilibrium with rs1011970, which should therefore present the same signal in a GWAS. However, the actual causal SNP and its associated underlying mechanism have yet to be elucidated. Therefore, the present study evaluated the role of rs77283072 in terms of its association with breast cancer. A dual-luciferase assay was performed, which demonstrated that the two alleles of rs1011970 did not exhibit significantly different reporter gene activity. However, the A allele of rs77283072 exhibited a significant increase in relative luciferase activity compared with the G allele, which suggested that rs77283072 was the causal SNP for breast cancer. Chromosome conformation capture demonstrated that the enhancer containing rs77283072 interacted with the promoter of cyclin-dependent kinase inhibitor 2A (CDKN2A). Furthermore, expression quantitative trait locus analysis demonstrated that the expression of CDKN2A was dependent on the genotype of rs77283072. Taken together, the findings of the present study provided novel insights into the mechanism underlying how the genetic variation in this locus was able to influence breast cancer susceptibility and further the treatment for this disease.

Keywords: CDKN2A; breast cancer; rs1011970; rs77283072; susceptibility

DOI: https://doi.org/10.3892/ol.2023.13662