Long noncoding RNA expression in the cervix mid-pregnancy is associated with the length of gestation at delivery

Abstract

Infants born preterm are at increased risk of multiple morbidities and mortality. Why some women deliver preterm remains poorly understood. Prior studies have shown that cervical microRNA expression and DNA methylation are associated with the length of gestation. However, no study has examined the role of long noncoding RNAs (lncRNAs) in the cervix during pregnancy. To determine whether expression of lncRNAs is associated with length of gestation at delivery, we analyzed RNA from cervical swabs obtained from 78 women during pregnancy (mean 15.5, SD 5.0, weeks of gestation) who were participating in the Spontaneous Prematurity and Epigenetics of the Cervix (SPEC) Study in Boston, MA, USA. We used a PCR-based platform and found that 9 lncRNAs were expressed in at least 50% of the participants. Of these, a doubling of the expression of TUG1, TINCR, and FALEC was associated with shorter lengths of gestation at delivery [2.8 (95% CI: 0.31, 5.2); 3.3 (0.22, 6.3); and 4.5 (7.3, 1.6) days shorter respectively]. Of the lncRNAs analyzed, none was statistically associated with preterm birth, but expression of FALEC was 2.6-fold higher in women who delivered preterm vs. term (P = 0.051). These findings demonstrate that lncRNAs can be measured in cervical samples obtained during pregnancy and are associated with subsequent length of gestation at delivery. Further, this study supports future work to replicate these findings in other cohorts and perform mechanistic studies to determine the role of lncRNAs in the cervix during pregnancy.

Racial and Ethnic Representation in Epigenomic Studies of Preterm Birth: A Systematic Review

“…Among excluded studies, two were excluded because they were transcriptomic [45] and metabolomic [46] studies. Five studies were epigenomic studies, but were excluded because they investigated epigenomic mechanisms other than DNA methylation including long noncoding RNA [47][48][49] and miRNA [50,51], and six analyzed candidate DNA methylation sites (<42) [52][53][54][55][56][57]. Four studies were excluded because they were methylomic studies utilizing the extreme low gestational age newborns (ELGAN) cohort or other cohorts including only samples from preterm infants and thus lacking infants born at term for comparison [58][59][60][61].…”

Epigenetic impact of long non-coding RNA lnc-ADAM9 on extracellular matrix pathway in preterm syndrome through down-regulation of mRNA-ADAM9

“…Collagen degradation reduces the physical strength of the fetal membranes and contributes to pPROM. Other studies have found that differential expression of lncRNAs in the cervix and myometrium is associated with the length of gestation [30,31] . Evidence for the epigenetic regulatory role of lncRNA in preterm labor has been provided, and this has strengthened our confidence in seeking to explore the pathogenesis of sPTB with further examination of lncRNA.…”

“…The high heterogeneity of sPTB is associated with its multifactorial etiology, whereby gene-environmental interactions are recognized as significant contributors. Aberrant transcription of lncRNA has been found in the uterus and placenta of women who have experienced premature birth [3,30,31] . We have performed a series of studies to discover and verify the regulation of lncRNA in sPTB.…”

Role of epigenetics in parturition and preterm birth

“…Therefore, the up‐regulation of these lncRNAs in foetal membranes, resulting in the suppression of collagen mRNA expression and a consequent decrease in collagen levels, may be an underlying cause of PPROM. Similarly, a doubling of the expression levels of taurine up‐regulated 1 ( TUG1 ), tissue differentiation‐inducing non‐protein encoding RNA ( TINCR ), and focally amplified lncRNA in epithelial cancer ( FALEC ) in the human cervix is correlated with a shortening of the gestation period by 2.8, 3.3, and 4.5 days, respectively (Burris et al ., 2018), implying that these lncRNAs may be involved in the occurrence of PTB. However, the latter study included only seven preterm infants, limiting the statistical strength of their conclusions.…”