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Sudden infant death syndrome: exposure to cigarette smoke leads to hypomethylation upstream of the growth factor independent 1 (GFI1) gene promoter

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Abstract

Purpose

Smoking during pregnancy has long been known as an important risk factor for sudden infant death syndrome (SIDS). However, the precise relationship between the smoking behavior of the mother and SIDS still remains unclear. In this study, the influence of prenatal smoking exposure on the childrens’ DNA methylation state of a CpG island located upstream of the promoter of the growth factor independent 1 (GFI1) gene was analyzed.

Methods

Blood samples of well-defined SIDS cases with non-smoking mothers (n = 11), SIDS cases with smoking mothers during pregnancy (n = 11), and non-SIDS cases (n = 6) were obtained from a previous study and methylation states were determined by bisulfite sequencing.

Results

Significant hypomethylation was observed in this CpG island in SIDS cases with cigarette smoke exposure compared to non-exposed cases. The strongest effect in this CpG island was observed for 49 CpG sites located within a transcription factor binding site. Coding for a transcriptional repressor, GFI1 plays an important role in various developmental processes. Alterations in the GFI1 expression might be linked to various conditions that are known to be associated with SIDS, such as dysregulated hematopoiesis and excessive inflammatory response.

Conclusion

Data obtained in this study show that analysis of methylation states in cases of sudden infant death syndrome might provide a further important piece of knowledge toward understanding SIDS, and should be investigated in further studies.

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Acknowledgments

We would like to thank all forensic pathologists at the Institute of Legal medicine for thorough post-mortem examination, Athina Vidaki for helpful discussions on bisulfite sequencing and involved parents for consenting to molecular analyses.

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Authors and Affiliations

  1. Institute of Legal Medicine, University of Münster, Röntgenstr. 23, 48149, Münster, Germany

    Kristina Schwender, Hannah Holtkötter, Kristina Schulze Johann, Alina Glaub, Marianne Schürenkamp, Ulla Sibbing, Sabrina Banken, Mechtild Vennemann, Heidi Pfeiffer & Marielle Vennemann

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  1. Kristina Schwender
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GeSID Study Group

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Correspondence to Marielle Vennemann.

Electronic supplementary material

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12024_2016_9812_MOESM1_ESM.pdf

Primer sequences designed for bisulfite sequencing of a 2600 bp region upstream of the GFI1 promoter. Differentially methylated positions are given as Y (C or T) and R (G or A) (PDF 41 kb)

12024_2016_9812_MOESM2_ESM.pdf

Mean relative methylation (MRM) values with standard deviation (SD) for 148 successfully analyzed CpG sites and all SIDS cases. MRM and SD for CpG sites of the transcription factor binding site (CpG 58-112) for non-SIDS cases. Original data on all samples and all CpG sites are available on request (PDF 96 kb)

12024_2016_9812_MOESM3_ESM.pdf

Bisulfite converted sequence of the analyzed area upstream of the GFI1 promoter region. PCR primers were designed for 8 individual reactions to cover a total of 2600 bp containing 170 CpG positions (arrows). The area of the transcription factor binding site is highlighted in red. The following 10 CpG positions were not included in the analysis due to poor sequencing quality or incomplete bisulfite conversion: 80, 135, 136, 137, 138, 139, 140, 141, 169, 170. All CpG sites located within primer binding sites were also excluded from analyses (PDF 66 kb)

12024_2016_9812_MOESM4_ESM.pdf

Supplementary Material—Fig. S2 Extreme example of differential methylation between a SIDS case not exposed (A) and exposed (B) to cigarette smoke. Asterisks indicate CpG positions 10, 11, and 13 in GFI1 fragment 2 in reverse direction. In the sequence example B a slight background with elevated peaks is visible. This does not affect the calculation of the relative methylation state because relevant positons are not affected (PDF 113 kb)

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Schwender, K., Holtkötter, H., Johann, K.S. et al. Sudden infant death syndrome: exposure to cigarette smoke leads to hypomethylation upstream of the growth factor independent 1 (GFI1) gene promoter. Forensic Sci Med Pathol 12, 399–406 (2016). https://doi.org/10.1007/s12024-016-9812-y

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  • DOI: https://doi.org/10.1007/s12024-016-9812-y

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