Retrotransposons spread potential cis-regulatory elements during mammary gland evolution.

Area of Science:

• Evolutionary biology
• Genomics
• Developmental biology

Background:

• Gene regulatory networks are rewired by acquiring cis-elements.
• Transposable elements (TEs), particularly retrotransposons, can provide sequences for regulatory elements like enhancers and promoters.
• The role of retrotransposons in spreading binding sites for master regulators of mammalian morphogenesis is largely unknown.

Purpose of the Study:

• To investigate whether retrotransposons spread binding sites for estrogen receptor α (ERα) and related pioneer factors essential for mammary gland development.
• To determine if this spreading accelerated cis-regulatory expansion contributing to mammalian morphological features.
• To identify the specific retrotransposon families involved and their expansion timing.

Main Methods:

• Bioinformatic analysis of transcription factor binding motifs.
• Identification and characterization of TE-derived cis-regulatory elements.
• Comparative genomics to trace the evolutionary history of TE insertions and regulatory element co-option.

Main Results:

• Thousands of estrogen receptor α (ERα) and pioneer factor (FoxA1, GATA3, AP2γ) binding sites originated from retrotransposon-mediated motif spreading.
• These TE-derived elements function primarily as distal enhancers, enriched near genes involved in mammary gland morphogenesis.
• The retrotransposons responsible were mainly L2/MIR in early eutherian ancestors and ERV1 in simian primates and murines.

Conclusions:

• Retrotransposons have significantly contributed to the evolution of gene regulatory networks by spreading functional cis-elements.
• The co-option of TE-derived sequences by the host genome accelerates the establishment and diversification of gene regulatory networks.
• This mechanism likely played a crucial role in driving morphological innovation in mammals.