Long-range function of an intergenic retrotransposon

Area of Science:

• Genomics
• Molecular Biology
• Epigenetics

Background:

• Retrotransposons, including human endogenous retroviruses (HERVs) and their long terminal repeats (LTRs), constitute over 40% of the human genome.
• Many HERVs reside in intergenic regions, and their potential beneficial host functions remain largely unknown.

Purpose of the Study:

• To investigate the functional role of an intergenic LTR retrotransposon, specifically ERV-9, in regulating gene expression.
• To determine if ERV-9 retrotransposons located upstream of globin genes contribute to host functions, particularly globin gene switching.

Main Methods:

• Analysis of the ERV-9 LTR sequence for transcription factor binding motifs (CCAAT, GATA).
• Assessing the recruitment of transcription factors NF-Y and GATA-2 to the ERV-9 LTR in erythroid cells.
• Investigating the formation of an LTR/RNA polymerase II complex and the transcription of intergenic RNAs.
• Evaluating the effect of LTR-derived RNAs on globin promoter activity and gene switching.

Main Results:

• The ERV-9 LTR, situated 40-70 kb upstream of globin genes, possesses functional CCAAT and GATA motifs.
• This LTR competitively recruits low-abundance transcription factors NF-Y and GATA-2 in adult erythroid cells, forming an LTR/RNA polymerase II complex.
• The complex transcribes intergenic RNAs that interact with downstream globin promoters.
• This interaction modulates transcription factor binding at globin promoters, influencing globin gene switching.

Conclusions:

• Intergenic ERV-9 LTR retrotransposons can serve a long-range host function by regulating gene expression.
• A competitive mechanism involving LTR-driven transcription and RNA-mediated interactions modulates globin gene switching.
• This study reveals a novel role for endogenous retroelements in the regulation of developmental gene expression.