Deciphering a shared transcriptomic regulation and the relative contribution of each regulator type through endometrial gene expression signatures.

Fecha de publicación: 12/09/2023 Fecha Ahead of Print: 12/09/2023

Autores de IIS La Fe

• Antonio Parraga Leo

  Autor

• Patricia Sebastián León

  Autor

• Almudena Devesa Peiró

  Autor

• Nuria Pellicer De Castellvi

  Autor

• José Remohí Giménez

  Autor

• Francisco Domínguez Hernández

  Autor

• Patricia Díaz Gimeno

  Autor

Participantes ajenos a IIS La Fe

• Marti-Garcia D

Grupos

• Biología Reproductiva y Bioingeniería en Reproducción Humana

  

  Leader

  Nicolás Garrido Puchalt

• Biomarcadores, Medicina Genómica, Estadística y Análisis masivo de datos en Reproducción humana asistida

  

  Investigador Principal

  Marcos Meseguer Escrivá

• Endocrinología Reproductiva e Infertilidad

  Leader

  José Remohí Giménez

• Medicina Reproductiva

  

  Investigador Principal

  José Morales Roselló

Abstract

BACKGORUND: While various endometrial biomarkers have been characterized at the transcriptomic and functional level, there is generally a poor overlap among studies, making it unclear to what extent their upstream regulators (e.g., ovarian hormones, transcription factors (TFs) and microRNAs (miRNAs)) realistically contribute to menstrual cycle progression and function. Unmasking the intricacies of the molecular interactions in the endometrium from a novel systemic point of view will help gain a more accurate perspective of endometrial regulation and a better explanation the molecular etiology of endometrial-factor infertility. METHODS: An in-silico analysis was carried out to identify which regulators consistently target the gene biomarkers proposed in studies related to endometrial progression and implantation failure (19 gene lists/signatures were included). The roles of these regulators, and of genes related to progesterone and estrogens, were then analysed in transcriptomic datasets compiled from samples collected throughout the menstrual cycle (n = 129), and the expression of selected TFs were prospectively validated in an independent cohort of healthy participants (n = 19). RESULTS: A total of 3,608 distinct genes from the 19 gene lists were associated with endometrial progression and implantation failure. The lists' regulation was significantly favoured by TFs (89% (17/19) of gene lists) and progesterone (47% (8 /19) of gene lists), rather than miRNAs (5% (1/19) of gene lists) or estrogen (0% (0/19) of gene lists), respectively (FDR < 0.05). Exceptionally, two gene lists that were previously associated with implantation failure and unexplained infertility were less hormone-dependent, but primarily regulated by estrogen. Although endometrial progression genes were mainly targeted by hormones rather than non-hormonal contributors (odds ratio = 91.94, FDR < 0.05), we identified 311 TFs and 595 miRNAs not previously associated with ovarian hormones. We highlight CTCF, GATA6, hsa-miR-15a-5p, hsa-miR-218-5p, hsa-miR-107, hsa-miR-103a-3p, and hsa-miR-128-3p, as overlapping novel master regulators of endometrial function. The gene expression changes of selected regulators throughout the menstrual cycle (FDR < 0.05), dually validated in-silico and through endometrial biopsies, corroborated their potential regulatory roles in the endometrium. CONCLUSIONS: This study revealed novel hormonal and non-hormonal regulators and their relative contributions to endometrial progression and pathology, providing new leads for the potential causes of endometrial-factor infertility.

© 2023. BioMed Central Ltd., part of Springer Nature.

Keywords

• CTCF; Endometrial receptivity; Estrogen; GATA6; Infertility; Menstrual cycle regulation; Progesterone; Recurrent implantation failure; TFs; miRNAs