Spatiotemporal specificity of correlated DNA methylation and gene expression pairs across different human tissues and stages of brain development

ABSTRACT

DNA methylation (DNAm) that occurs on promoter regions is primarily considered to repress gene expression. Previous studies indicated that DNAm could also show positive correlations with gene expression. Both DNAm and gene expression profiles are known to be tissue- and development-specific. This study aims to investigate how DNAm and gene expression are coordinated across different human tissues and developmental stages, as well as the biological significance of such correlations. By analyzing 2,239 samples with both DNAm and gene expression data in the same human subjects obtained from six published datasets, we evaluated the correlations between gene and CpG pairs (GCPs) at cis-regions and compared significantly correlated GCPs (cGCPs) across different tissues and brains at different age groups. A total of 37,363 cGCPs was identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (>90%) of cGCPs was tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlights the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, the early developmental brain possessed a highly unique set of cGCPs that were associated with neurogenesis and psychiatric disorders. By assessing the epigenetic factors involved in cGCPs, we discovered novel regulatory mechanisms of positive cGCPs distinct from negative cGCPs, which were related to multiple factors, such as H3K27me3, CTCF, and JARD2. The catalogue of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.

KEYWORDS:

• DNA methylation
• gene expression
• tissue
• development
• gene and CpG pairs (GCPs)

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grants Nos. 82022024, 31970572, 31871276), the National Key R&D Project of China (Grants No. 2016YFC1306000 and 2017YFC0908701), Innovation-driven Project of Central South University (Grant Nos. 2020CX003), and NIH grants U01 MH122591, 1U01MH116489, 1R01MH110920. We sincerely thank Liz Kuney, Richard F. Kopp, and other colleagues for scientific and language advice that helped improve our manuscript.

Disclosure statement

The authors declare no competing interests.

Author contributions

KW, RD, YX, and CJ collected and preprocessed the datasets. KW performed the GCPs analysis. KW and JH performed the feature and GWAS enrichment analysis. KW, CC, TM, CZ, and CL participated in the revision of the manuscript. CC and CL conceived the study, participated in its design, and supervised the entire project. All authors read and approved the final manuscript.

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [82022024]; National Natural Science Foundation of China [31970572]; National Natural Science Foundation of China [31871276]; Innovation-driven Project of Central South University [2020CX003]; National Institutes of Health [1U01MH116489]; National Institutes of Health [1R01MH110920]; National Institutes of Health [U01 MH122591]; the National Key R&D Project of China [2017YFC0908701]; the National Key R&D Project of China [2016YFC1306000].