Co-option of retrotransposons promotes antibody diversification, 2026, Lauring et al.

[SNT Gatchaman]

Co-option of retrotransposons promotes antibody diversification

Spoiler: Authors

Max C Lauring; Ming Yang; Aditya Sarode; Jianhua Wang; Zixin Ni; Kristen A Froehlich; Wanwei Zhang; Shudipto Wahed; Sisi Zheng; Stephen P Goff; Jiguang Wang; Uttiya Basu

Activation-induced cytidine deaminase (AID) accomplishes somatic hypermutation (SHM) of VH(D)JH genes in germinal center B cells for antibody diversification and affinity maturation. How AID specifically targets VH(D)JH remains unclear.

We report the discovery of LINE-1 (L1) retrotransposons upstream to many VH genes in the immunoglobulin locus. These L1s are evolutionarily old, truncated, and retrotransposition dead. Recombined VH promoters generate long, strong antisense RNAs encoding upstream L1s, triggering the human silencing hub (HUSH) complex and AID recruitment, which we term L1-driven SHM.

We show that L1-driven SHM occurs in vivo using HUSH conditional knockout mice and engineered mice with VH genes devoid of upstream L1s. Insertion of transcriptionally active L1s at non-immunoglobulin loci endogenously lacking upstream L1s promotes off-target SHM.

We demonstrate that old retrotransposons serve physiological roles, and our findings reveal how B cells co-opted an anti-retrotransposon silencing mechanism to promote antibody diversity. In doing so, we established a new link between cell-intrinsic innate and adaptive immunity.

HIGHLIGHTS
• Many immunoglobulin VH genes possess nearby upstream LINE-1 retrotransposon sequences

• VH upstream LINE-1s promote B cell VH(D)JH somatic hypermutation in vitro and in vivo

• VH antisense RNA encoding upstream L1s recruits the HUSH complex/AID to recombined VH(D)JH

• B cells co-opted a retrotransposon silencing mechanism to enhance antibody diversity

Web | DOI | PDF | Cell | Open Access

 

[SNT Gatchaman]

To our knowledge, this is the first characterization of L1 retrotransposons in the Ig locus and the first report of L1s contributing to B cell antibody diversity. This study highlights that while we tend to view evolutionarily old, transcriptionally dead L1s as inconsequential genomic fossils, these sequences serve a surprisingly beneficial role in physiological immunity. L1-mediated antibody diversification is likely one of many cases of ancient retrotransposition events being co-opted, and further such discoveries will surely emerge across biological contexts.

In attempting to silence potentially deleterious, non-self, transcribed, L1 insertions upstream to VH genes, B cells co-opted ancestral HUSH- and AID-mediated defense to incapacitate these L1s, enhancing antibody diversity in the process. In doing so, this mechanism expands our understanding of the interconnectivity of the immune system by linking cell-intrinsic innate and adaptive immunity.

 

[SNT Gatchaman]

ME Research UK and Action for ME have funded research into retrotransposons in ME/CFS. See this article and this thread.