Transposable Elements Continuously Remodel the Regulatory Landscape, Transcriptome, and Function of Decidual Stromal Cells

Abstract

Gene expression evolution underlies the origin, divergence, and conservation of biological characters including cell-types, tissues, and organ systems. Previously we showed that large-scale gene expression changes in decidual stromal cells contributed to the origins of pregnancy in eutherians and the divergence of pregnancy traits in primates, and that transposable elements likely contributed to these gene expression changes. Here we show that two large waves of TEs remodeled the transcriptome and regulatory landscape of decidual stromal cells, including a major wave in primates. Genes nearby TE-derived regulatory elements are among the most progesterone responsive in the genome and play essential roles in orchestrating progesterone responsiveness and the core function of decidual cells by donating progesterone receptor binding sites to the genome. We tested the regulatory abilities of 89 TE consensus sequences and found nearly all acted as repressors in mammalian cells, but treatment with a histone deacetylase inhibitor unmasked latent enhancer functions. These data indicate TEs have played an important role in the development, evolution, and function of primate decidual stromal cells and suggest a two-step model in which latent enhancer functions of TEs are unmasked after they lose primary repressors functions.

Comprehensive identification of onco-exaptation events in bladder cancer cell lines revealed L1PA2-SYT1 as a prognosis-relevant event

“…These regions contribute to the binding motif of the progesterone receptor and mediate regulatory effects on pathways like the cell cycle and ERBB signaling. 33 Furthermore, we also identified an onco-exaptation event related to SALL4 (AluJb-SALL4). This event was also identified in the pan-cancer study, although the TSS is predicted to be contributed by a different TE subfamily (MLT1J).…”

Differential selective regimes identify categories of transposable elements with regulatory function

“…1 Widespread exaptation of AmnSINE1 elements has been associated with the emergence of mammalian-specific traits, specifically in brain development 20,21 . Both AmnSINE1 and MamSINE1 were found enriched in active regulatory regions in human development 22 , and to be involved in the rewiring of the NF-κB regulome 7 , while MIR3 and MIRc were shown to contribute to gene regulation in decidual stromal cells in mammals 23 and the regulome of estrogen receptor alpha 24 .…”

Human embryo implantation

“…Haemochorial placentation coincided with the inflammatory reprogramming of endometrial stromal cells into progesterone-dependent decidual cells ( Lynch et al, 2015 ; Erkenbrack et al, 2018 ; Chavan et al, 2021 ), a process that involves massive changes in gene expression under the control of novel TE-derived regulatory elements that confer responsiveness to steroid hormones ( Mika and Lynch, 2022 ). Decidual cells are defined by their epithelioid morphology, resistance to oxidative and metabolic stress signals and secretory phenotype ( Gellersen and Brosens, 2014 ; Kajihara et al, 2014 ).…”

“…PKA signalling also activates evolutionarily conserved decidual transcription factors, including CEBPB, FOXO1, GATA2 and HAND2, which in turn leads to sequential regulation of distinct transcriptional programmes ( Erkenbrack et al, 2018 ; Gellersen and Brosens, 2014 ). Several decidual transcription factors physically engage the liganded progesterone receptor and bind as multimeric complexes to primate-specific TEs and other cis -regulatory DNA elements in promoter and enhancer regions of target genes ( Christian et al, 2002 ; Vrljicak et al, 2018 ; Mika and Lynch, 2022 ). Hence, progesterone is essential for maintaining decidual gene expression, although insufficient for initiating this differentiation process ( Brosens et al, 1999 ).…”