The Placenta Epigenome–Brain Axis: Placental Epigenomic and Transcriptomic Responses that Preprogram Cognitive Impairment

Abstract

Aim: The placenta–brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied. Materials & methods: The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined. Results: Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10. Conclusion: Findings highlight key placenta epigenome–brain relationships that support the developmental origins of health and disease hypothesis.

Plain language summary

Children born extremely preterm are at increased risk for neurodevelopmental impairments such as cerebral palsy, intellectual disability and autism. The biological processes that lead to these impairments likely begin before birth and involve altered placental function. In this study, the authors analyzed placental genomic and epigenomic data from children who were born extremely preterm in relation to cognitive assessments at 10 years of age. They examined the differences between the expression of placental genes and molecules that influence the expression of placental genes, comparing children who had impaired cognition at 10 years with children who did not. The results demonstrated elevated expression levels of genes involved in inflammatory processes and molecules that control the expression of these genes within the placentas of children who had impaired cognition at age 10.

Keywords::

• cognition
• epigenetics
• epigenome
• miRNA
• mRNA
• placenta

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0061

Author contributions

M O’Shea and RC Fry conceived of the study design. All the authors interpreted the findings regarding associations with neurocognitive impairment in children born preterm. AN Freedman, LA Eaves, JE Rager, N Gavino-Lopez, L Smeester, J Bangma and HP Santos analyzed and interpreted the data-related mRNAs and miRNAs. KCK Kuban, RM Joseph, M O’Shea and RC Fry oversaw the analyses. AN Freedman drafted the manuscript, and all authors read, provided input and approved the final manuscript.

Acknowledgments

The authors would like to thank the ELGAN Study Investigators and participants for their contributions to this research.

Financial & competing interests disclosure

This research was supported by grants from the following: National Institutes of Health (http://www.nih.gov): R01 ES019315, P42 ES005948; the Office of the NIH Director: UH3OD023348; the National Institute of Child Health and Human Development: R01HD092374, R03HD101413, UG3OD023348; the National Institute of Neurologic Disorders and Stroke: U01NS040069, U01NS040069, U01NS040069; the National Institute of Nursing Research: R01NR019245; and the National Institute for Occupational Safety and Health: T42/OH-008673. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data sharing statement

All genomic data generated or analyzed in this study are included in this published article. mRNA- and miRNA-sequencing data have been deposited in Gene Expression Omnibus [GEO: GSE154829] (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154829).

Additional information

Funding

This research was supported by grants from the following: National Institutes of Health (http://www.nih.gov): R01 ES019315, P42 ES005948; the Office of the NIH Director: UH3OD023348; the National Institute of Child Health and Human Development: R01HD092374, R03HD101413, UG3OD023348; the National Institute of Neurologic Disorders and Stroke: U01NS040069, U01NS040069, U01NS040069; the National Institute of Nursing Research: R01NR019245; and the National Institute for Occupational Safety and Health: T42/OH-008673. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.