(Epi)genetic variants of the sarcomere-desmosome are associated with
premature utero-contraction in spontaneous preterm labor
Abstract
Background: Spontaneous preterm birth (sPTB) is a syndrome with clinical
and genetic heterogeneity. Few studies have focused on genetic and
epigenetic defects and pathogenic mechanisms associated with premature
uterine contraction (PUC) of sPTB. Objective: To investigate the
(epi)genetic variations associated with premature uterine contraction
(PUC) of sPTB. Design: An integrated omics approach of systems biology
was employed. Genomics, transcriptomics, methylomics, and proteomics
were employed to focus on genetic loci/genes related to uterine muscle
contraction, and specifically on genes associated with sarcomeres and
desmosomes. Methods: Pregnant cohort with biobank of pregnant tissues
was subjected to multiomic studies. Results: Thirteen SNVs and
pathogenic variants were identified in the sarcomere gene, TTN, from 146
women with sPTL. DEPs of five lncRNAs were identified from loci that
overlap with four sarcomeric genes. Longitudinally, the lncRNA TPM3 was
found to significantly regulate the messenger RNA (mRNA) of TPM3 in the
placenta, compared to maternal blood. The majority of GMPs related to
PUC were also identified in the CpG promoters of sarcomeric genes/loci.
DEP of PCU mRNAs showed 22 genes associated with the sarcomere and three
with the desmosome. Conclusion: The results demonstrated that PUC was
associated mainly with pathogenic variants of the TTN gene and that
transcription of sarcomeric PUC genes is likely regulated by epigenetic
factors, including methylation and lncRNA.