In humans, each of the two 3’RR located downstream of Cα1 and Cα2 contains three enhancer elements similar to mouse hs3, hs1,2 and hs4, with hs1,2 being also flanked by IRIS. The modest activity of each of the 3’RR elements in vitro, however, contributes to a synergic and potent global effect of the 3’RR in transgenes, especially when its ‘palindromic’ architecture is maintained 14. The mouse 3’RR contains four enhancer elements ( hs3a, hs1,2, hs3b and hs4) with hs1,2 flanked by inverted repeated intervening sequences ( IRIS) and the centre of a >25-kb palindrome bounded by 2 inverted copies of the hs3 enhancers ( hs3a and hs3b) refs 2, 13. The IgH 3’ regulatory region ( 3’RR), which encompasses the four transcriptional enhancers hs3a, hs1,2, hs3b and hs4, controls μ-transcription in mature B cells 5, and is the master element controlling conventional class switch recombination (CSR) 6, 7, locus suicide recombination 8 and somatic hypermutation (SHM) 9 but with little role in V(D)J recombination, except for silencing early transcription in pro-B cells 10, 11, 12. Among 5’ elements, the intronic Eμ enhancer is reported as a master control element of V(D)J recombination 3, 4. Multiple cis-regulatory elements located 5’ and 3’ of constant ( C) genes control B-cell ontogeny. Lymphopoiesis is coupled with programmed accessibility of Ig genes to transcription and to several major transcription-dependent DNA-remodelling events 1, 2. In conclusion, this work indicates that the IgH 3’RR does not simply pile up enhancer units but also optimally exposes them into a functional architecture of crucial importance. By contrast, a ‘palindromic effect’ significantly lowers V H germline transcription, AID recruitment and SHM. CSR and IgH transcription appear to be poorly dependent on the 3’RR architecture and it is more or less preserved, provided 3’RR enhancers are present. Here we report that deconstructing the palindromic IgH 3’RR strongly affects its function even when enhancers are preserved. In mammals, evolution maintained this unique palindromic arrangement, suggesting that it is functionally significant. The mouse 3’RR contains four enhancer elements with hs1,2 flanked by inverted repeated sequences and the centre of a 25-kb palindrome bounded by two hs3 enhancer inverted copies ( hs3a and hs3b). The IgH 3’ regulatory region ( 3’RR) controls class switch recombination (CSR) and somatic hypermutation (SHM) in B cells.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |