Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus.

Fernanda Bernardi Bertonha,Carlos Alberto Moreira-Filho,Paulo Chaccur,Christiana Vinhas,Maria Claudia Nogueira Zerbini,Leandro Rodrigues Ferreira,Magda Maria Carneiro-Sampaio,Silvia Yumi Bando,Panayiotis V Benos

doi:10.1371/journal.pone.0227547

Abstract

The human thymus suffers a transient neonatal involution, recovers and then starts a process of decline between the 1st and 2nd years of life. Age-related morphological changes in thymus were extensively investigated, but the genomic mechanisms underlying this process remain largely unknown. Through Weighted Gene Co-expression Network Analysis (WGCNA) and TF-miRNA-mRNA integrative analysis we studied the transcriptome of neonate and infant thymic tissues grouped by age: 0–30 days (A); 31days-6 months (B); 7–12 months (C); 13–18 months (D); 19-31months (E). Age-related transcriptional modules, hubs and high gene significance (HGS) genes were identified, as well as TF-miRNA-hub/HGS co-expression correlations. Three transcriptional modules were correlated with A and/or E groups. Hubs were mostly related to cellular/metabolic processes; few were differentially expressed (DE) or related to T-cell development. Inversely, HGS genes in groups A and E were mostly DE. In A (neonate) one third of the hyper-expressed HGS genes were related to T-cell development, against one-twentieth in E, what may correlate with the early neonatal depletion and recovery of thymic T-cell populations. This genomic mechanism is tightly regulated by TF-miRNA-hub/HGS interactions that differentially govern cellular and molecular processes involved in the functioning of the neonate thymus and in the beginning of thymic decline.

Highlights

The human thymus grows only during the first year of life and its steady involution begins thereafter[1]
The human thymus presents some functional peculiarities in the neonatal period and along the first six months of age, i.e. during minipuberty, when a transient surge in gonadal hormones takes place[2]
The genomic analyses were centered in the identification of transcriptional modules by Weighted Gene Co-expression Network Analysis (WGCNA) and in mRNA-miRNA-Transcription Factor (TF) co-expression network analysis

Summary

Introduction

The human thymus grows only during the first year of life and its steady involution begins thereafter[1]. The human thymus presents some functional peculiarities in the neonatal period and along the first six months of age, i.e. during minipuberty, when a transient surge in gonadal hormones takes place[2]. In the neonatal thymus occurs a transient involution marked by severe depletion of double-positive (DP) thymocytes, which is later. Age-related transcriptional modules in neonatal and infant human thymus. Flagship MIKON (Project RConnected; https:// www.framcentre.com/) and the Arctic Belmont Forum Arctic Observing and Research for Sustainability The Norwegian collaboration was financed by Norwegian Research Council grant 247474 (https://www.forskningsradet.no/en). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion