Loss of CARM1 results in hypomethylation of thymocyte cyclic AMP-regulated phosphoprotein and deregulated early T cell development.
The coactivator-associated arginine methyltransferase, CARM1, is a positive regulator of transcription. Using high density protein arrays, we have previously identified in vitro substrates for CARM1. One of these substrates, TARPP (thymocyte cyclic AMP-regulated phosphoprotein), is expressed specifically in immature thymocytes. Here, we have demonstrated that TARPP is arginine-methylated at a single residue, Arg(650), both in vitro and in vivo. In addition, recombinant TARPP is not methylated by extracts from Carm1(-/-) cells, indicating that there is no redundancy in this pathway. We show that thymi from Carm1(-/-) embryos (E18.5) have a 5-10-fold reduction in cellularity compared with wild type littermates. Flow cytometric analysis of thymocytes revealed a decrease in the relative proportion of double negative thymocytes in Carm1(-/-) embryos because of a partial developmental arrest in the earliest thymocyte progenitor subset. These results demonstrate that CARM1 plays a significant role in promoting the differentiation of early thymocyte progenitors, possibly through its direct action on TARPP.
Kim
Jeesun
J
The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Lee
Jaeho
J
Yadav
Neelu
N
Wu
Qi
Q
Carter
Carla
C
Richard
Stéphane
S
Richie
Ellen
E
Bedford
Mark T
MT
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D054645:Protein Phosphatase 1; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*
D010750:Phosphoproteins; C424983:Ppp1r1c protein, mouse; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D054645:Protein Phosphatase 1