Research Article: Maternal circadian disruption is associated with variation in placental DNA methylation

Date Published: April 26, 2019

Publisher: Public Library of Science

Author(s): Danielle A. Clarkson-Townsend, Todd M. Everson, Maya A. Deyssenroth, Amber A. Burt, Karen E. Hermetz, Ke Hao, Jia Chen, Carmen J. Marsit, Henrik Oster.


Circadian disruption is a common environmental and occupational exposure with public health consequences, but not much is known about whether circadian disruption affects in utero development. We investigated whether maternal circadian disruption, using night shift work as a proxy, is associated with variations in DNA methylation patterns of placental tissue in an epigenome-wide association study (EWAS) of night shift work. Here, we compared cytosine-guanosine dinucleotide (CpG) specific methylation genome-wide of placental tissue (measured with the Illumina 450K array) from participants (n = 237) in the Rhode Island Child Health Study (RICHS) who did (n = 53) and did not (n = 184) report working the night shift, using robust linear modeling and adjusting for maternal age, pre-pregnancy smoking, infant sex, maternal adversity, and putative cell mixture. Statistical analyses were adjusted for multiple comparisons and results presented with Bonferroni or Benjamini and Hochberg (BH) adjustment for false discovery rate. Night shift work was associated with differential methylation in placental tissue, including CpG sites in the genes NAV1, SMPD1, TAPBP, CLEC16A, DIP2C, FAM172A, and PLEKHG6 (Bonferroni-adjusted p<0.05). CpG sites within NAV1, MXRA8, GABRG1, PRDM16, WNT5A, and FOXG1 exhibited the most hypomethylation, while CpG sites within TDO2, ADAMTSL3, DLX2, and SERPINA1 exhibited the most hypermethylation (BH q<0.10). Functional analysis indicated GO-terms associated with cell-cell adhesion and enriched GWAS results for psoriasis. Night shift work was associated with differential methylation of the placenta, which may have implications for fetal health and development. This is the first study to examine the epigenetic impacts of night shift exposure, as a proxy for circadian disruption, on placental methylation in humans, and, while results should be interpreted with caution, suggests circadian disruption may have epigenetic impacts.

Partial Text

Disruption of circadian rhythms is associated with negative health outcomes such as cancer, metabolic disorders, and neurological disorders in epidemiologic[1] and animal studies[2]; however, the impacts of circadian disruption during pregnancy on fetal development and child health have been largely overlooked. The core circadian clock consists of feedback loops of transcription factors (TF) that generate oscillating cycles of gene transcription and translation. These endogenously generated rhythms rely on cues, such as light, to synchronize patterns of physiological activity with the external environment. Light signals the suprachiasmatic nucleus (SCN) of the hypothalamus, the “master clock”, to set the body’s peripheral clocks[3].

We identified a number of CpG sites exhibiting differential methylation associated with night shift work in newborn placental tissue. While the average absolute differences for the 298 CpG site corresponded to a roughly 1.7% change in methylation, even a small change in methylation may have physiologically-relevant effects, and these magnitudes of association are comparable to others reported for exposures including toxic trace elements and maternal smoking during pregnancy[31]. The overall trend of hypomethylation with night shift work may be due to increased TF binding to DNA, leading to chromatin changes establishing the hypomethylated state[32]. Because one of the core components of the circadian clock, CLOCK, acts as a histone acetyltransferase[33], it is also possible that circadian disruption impacts the epigenetic activity of CLOCK, affecting chromatin state and accessibility. However, there is still much to discover about circadian interactions with methylation and developmental processes.




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