Long non-coding RNAs transcribed by ERV-9 LTR retrotransposon act in cis to modulate long-range LTR enhancer function

Area of Science:

• Genomics
• Molecular Biology
• Epigenetics

Background:

• Long terminal repeat (LTR) retrotransposons constitute a significant portion of the human genome.
• LTR sequences are notably enriched in human long non-coding RNAs (lncRNAs).
• The biological functions of LTR lncRNAs remain largely unexplored.

Purpose of the Study:

• To investigate the functional role of ERV-9 (human endogenous retrovirus-9) LTR lncRNAs in primary human erythroblasts.
• To elucidate the mechanism by which ERV-9 lncRNAs regulate gene transcription and erythropoiesis.

Main Methods:

• Genome-wide RNA and ChIRP analyses were performed.
• Global knockdown and locus-specific deletion of ERV-9 lncRNAs were utilized.
• Experiments were conducted in human erythroblasts with numerous ERV-9 LTRs and in transgenic mouse erythroblasts with a single ERV-9 LTR within the β-globin locus.

Main Results:

• ERV-9 lncRNAs were found to activate transcription of key erythroid genes.
• These lncRNAs modulated ex vivo erythropoiesis.
• ERV-9 lncRNAs function in cis to stabilize the ERV-9 LTR enhancer complex, promoting long-range enhancer activity for downstream genes.

Conclusions:

• LTR lncRNAs, specifically from ERV-9, play a crucial role in activating cis-linked globin gene transcription.
• These findings suggest a conserved mechanism where LTR lncRNAs modulate enhancer function for critical cellular processes like erythropoiesis.