Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

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Abstract

Preterm infants are vulnerable to inflammation‐induced white matter injury (WMI), which is associated with neurocognitive impairment and increased risk of neuropsychiatric diseases in adulthood. Epigenetic mechanisms, particularly DNA methylation, play a role in normal development and modulate the response to pathological challenges. Our aims were to determine how WMI triggered DNA methylation alterations in brains of neonatal rats and if such changes persisted over time. We used a robust model of WMI by injecting lipopolysaccharide (LPS) or sterile saline in the corpus callosum of 3‐day‐old (P3) rat pups. Brains were collected 24 hours (P4) and 21 days post‐injection (P24). We extracted genomic DNA from the brain to establish genome‐wide quantitative DNA methylation profiles using reduced representation bisulfite sequencing. Neonatal LPS exposure induced a persistent increased methylation of genes related to nervous system development and a reduced methylation of genes associated with inflammatory pathways. These findings suggest that early‐life neuroinflammatory exposure impacts the cerebral methylation landscape with determining widespread epigenetic modifications especially in genes related to neurodevelopment.

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Inflammation and Alzheimer's disease.

H Akiyama, S. Barger, S Barnum … (2000)

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

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Obesity accelerates epigenetic aging of human liver.

S Horvath, W Erhart, M Brosch … (2014)

Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an "epigenetic clock") to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10(-4) in dataset 1 and r = 0.42, P = 1.2 × 10(-4) in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10(-9)) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.

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Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome.

Marina Bibikova, Sebastian Moran, Juan Sandoval … (2011)

DNA methylation is the most studied epigenetic mark and CpG methylation is central to many biological processes and human diseases. Since cancer has highlighted the contribution to disease of aberrant DNA methylation patterns, such as the presence of promoter CpG island hypermethylation-associated silencing of tumor suppressor genes and global DNA hypomethylation defects, their importance will surely become apparent in other pathologies. However, advances in obtaining comprehensive DNA methylomes are hampered by the high cost and time-consuming aspects of the single nucleotide methods currently available for whole genome DNA methylation analyses. Following the success of the standard CpG methylation microarrays for 1,505 CpG sites and 27,000 CpG sites, we have validated in vivo the newly developed 450,000 (450K) cytosine microarray (Illumina). The 450K microarray includes CpG and CNG sites, CpG islands/shores/shelves/open sea, non-coding RNA (microRNAs and long non-coding RNAs) and sites surrounding the transcription start sites (-200 bp to -1,500 bp, 5'-UTRs and exons 1) for coding genes, but also for the corresponding gene bodies and 3'-UTRs, in addition to intergenic regions derived from GWAS studies. Herein, we demonstrate that the 450K DNA methylation array can consistently and significantly detect CpG methylation changes in the HCT-116 colorectal cancer cell line in comparison with normal colon mucosa or HCT-116 cells with defective DNA methyltransferases (DKO). The provided validation highlights the potential use of the 450K DNA methylation microarray as a useful tool for ongoing and newly designed epigenome projects.

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Author and article information

Contributors

Gregory A. Lodygensky: ga.lodygensky@umontreal.ca

Journal

Journal ID (nlm-ta): FASEB J

Journal ID (iso-abbrev): FASEB J

Journal ID (doi): 10.1096/(ISSN)1530-6860

Journal ID (publisher-id): FSB2

Title: The FASEB Journal

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0892-6638

ISSN (Electronic): 1530-6860

Publication date (Electronic): 22 November 2019

Publication date (Print): January 2020

Volume: 34

Issue: 1 ( doiID: 10.1096/fsb2.v34.1 )

Pages: 432-445

Affiliations

[ ¹ ] Department of Pediatrics Université de Montréal Research Center of the CHU Sainte‐Justine Montréal QC Canada

[ ² ] Department of Biochemistry and Molecular Medicine Université de Montréal Research Center of the CHU Sainte‐Justine Montréal QC Canada

[ ³ ] Department of Obstetrics & Gynecology Université de Montréal Research Center of the CHU Sainte‐Justine Montréal QC Canada

[ ⁴ ] Department of Pharmacology and Physiology Université de Montréal Montréal QC Canada

Author notes

[*] [* ] Correspondence

Gregory A. Lodygensky, Department of Pediatrics, NICU, Sainte‐Justine Hospital and Research Center, 3175 Chemin de la Côte Sainte‐Catherine, Montreal, QC H3T 1C5, Canada.

Email: ga.lodygensky@ 123456umontreal.ca

Article

Publisher ID: FSB220014

DOI: 10.1096/fj.201901461R

PMC ID: 6972494

PubMed ID: 31914673

SO-VID: 6e9c8b6a-44e9-4137-a346-107bc5519ddd

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 13 June 2019

Date revision received : 26 September 2019

Date accepted : 08 October 2019

Page count

Figures: 5, Tables: 1, Pages: 14, Words: 8537

Funding

Funded by: Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)

Award ID: 136908

Funded by: Centre de recherche du CHU Sainte‐Justine (CHU Sainte‐Justine Research Center) , open-funder-registry 10.13039/501100010778;

Funded by: Fonds de Recherche du Québec ‐ Santé (FRQS) , open-funder-registry 10.13039/501100000156;

Funded by: Institute of Human Development, Child and Youth Health

Funded by: Health Research , open-funder-registry 10.13039/100005622;

Custom metadata

source-schema-version-number 2.0

cover-date January 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:21.01.2020

ScienceOpen disciplines: Molecular biology

Keywords: dna methylation,epigenetics,lipopolysaccharide,periventricular leukomalacia

Data availability:

ScienceOpen disciplines: Molecular biology

Keywords: dna methylation, epigenetics, lipopolysaccharide, periventricular leukomalacia

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

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Biomarkers for Inflammatory Lung Disease

Most cited references 70

Inflammation and Alzheimer's disease.

Obesity accelerates epigenetic aging of human liver.

Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome.

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