Targeted inhibition of V(D)J recombination by a histone methyltransferase.
The tissue- and stage-specific assembly of antigen receptor genes by V(D)J recombination is regulated by changes in the chromatin accessibility of target gene segments. This dynamic remodeling process is coordinated by cis-acting promoters and enhancers, which function as accessibility control elements. The basic epigenetic mechanisms that activate or repress chromatin accessibility to V(D)J recombinase remain unclear. We now demonstrate that a histone methyltransferase overrides accessibility control element function and cripples V(D)J recombination of chromosomal gene segments. The recruited histone methyltransferase induces extensive revisions in the local chromatin environment, including altered histone modifications and de novo methylation of DNA. These findings indicate a key function for histone methyltransferases in the tissue- and stage-specific suppression of antigen receptor gene assembly during lymphocyte development.
Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
Oleg
O
Osipovich
Robin
R
Milley
Amber
A
Meade
Makoto
M
Tachibana
Yoichi
Y
Shinkai
Michael S
MS
Krangel
Eugene M
EM
Oltz
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000201:enzymology; D019175:DNA Methylation; D005786:Gene Expression Regulation; D015329:Gene Rearrangement, T-Lymphocyte; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D007128:Immunoglobulin Fragments / Q000235:genetics*; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008780:Methyltransferases / Q000502:physiology*; D051379:Mice; D011496:Protein Methyltransferases; D014158:Transcription, Genetic; D045567:VDJ Recombinases / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D007128:Immunoglobulin Fragments; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D045567:VDJ Recombinases