Elucidation of IgH intronic enhancer functions via germ-line deletion.

Proc Natl Acad Sci U S A 2005 Oct 26;102(40):14362-7. Epub 2005 Sep 26.

The CBR Institute for Biomedical Research, Inc., and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Studies of chimeric mice demonstrated that the core Ig heavy chain (IgH) intronic enhancer (iEmu) functions in V(D)J and class switch recombination at the IgH locus. To more fully evaluate the role of this element in these and other processes, we generated mice homozygous for germ-line mutations in which the core sequences of iEmu (cEmu) were either deleted (cEmu(Delta/Delta) mice) or replaced with a pgk-Neo(R) cassette (cEmu(N/N) mice). The cEmu(Delta/Delta) mice had reduced B cell numbers, in association with impaired D to J(H) and V(H) to DJ(H) rearrangement, whereas cEmu(N/N) mice had a complete block in IgH V(D)J(H) recombination, confirming that additional cis elements cooperate with iEmu to enforce D to J(H) recombination. In addition, developing cEmu(Delta/Delta) and cEmu(N/N) B lineage cells had correspondingly decreased levels of germ-line transcripts from the J(H) region of the IgH locus (mu0 and Imu transcripts); although both had normal levels of germ-line V(H) transcripts, suggesting that cEmu may influence IgH locus V(D)J recombination by influencing accessibility of J(H) proximal regions of the locus. Consistent with chimera studies, peripheral cEmu(Delta/Delta) B cells had normal surface Ig and relatively normal class switch recombination. However, cEmu(Delta/Delta) B cells also had relatively normal somatic hypermutation of their IgH variable region genes, showing unexpectedly that the cEmu is not required for this process. The availability of mice with the iEmu mutation in their germ line will facilitate future studies to elucidate the roles of iEmu in V(H)(D)J(H) recombination in the context of IgH chromatin structure and germ-line transcription.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0507090102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1242331PMC
October 2005
2 Reads

Publication Analysis

Top Keywords

igh locus
12
class switch
8
cells normal
8
cemun/n mice
8
cemudelta/delta mice
8
levels germ-line
8
intronic enhancer
8
germ-line transcripts
8
cemudelta/delta cells
8
igh intronic
8
switch recombination
8
igh
7
mice
7
recombination
6
germ-line
5
iemu
5
cemudelta/delta
5
mice iemu
4
consistent chimera
4
recombination confirming
4

Altmetric Statistics

References

(Supplied by CrossRef)

Jung et al.
Cell 2004

Manis et al.
Trends in immunology 2002

Li et al.
Genes & Development 2004

Dudley et al.
Advances in immunology 2005

Cell 2002

Chowdhury et al.
Immunological reviews 2004

Khamlichi et al.
Advances in immunology 2000

Corcoran et al.
Seminars in immunology 2005

Lennon et al.
Nature; Physical Science (London) 1985

Alessandrini et al.
Molecular and Cellular Biology 1991

Yancopoulos et al.
Cell 1985

Similar Publications