Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells.
BACKGROUND
Chromosomal aberrations of BCL11A at 2p16.1 have been reported in a variety of B-cell malignancies and its deficiency in mice leads to a profound block in B-cell development.


RESULTS
Alternative pre-mRNA splicing of BCL11A produces multiple isoforms sharing a common N-terminus. The most abundant isoform we have identified in human lymphoid samples is BCL11A-XL, the longest transcript produced at this locus, and here we report the conservation of this major isoform and its functional characterization. We show that BCL11A-XL is a DNA-sequence-specific transcriptional repressor that associates with itself and with other BCL11A isoforms, as well as with the BCL6 proto-oncogene. Western blot data for BCL11A-XL expression coupled with data previously published for BCL6 indicates that these genes are expressed abundantly in germinal-center-derived B cells but that expression is extinguished upon terminal differentiation to the plasma cell stage. Although BCL11A-XL/BCL6 interaction can modulate BCL6 DNA binding in vitro, their heteromeric association does not alter the homomeric transcriptional properties of either on model reporter activity. BCL11A-XL partitions into the nuclear matrix and colocalizes with BCL6 in nuclear paraspeckles.


CONCLUSIONS
We propose that the conserved N-terminus of BCL11A defines a superfamily of C2HC zinc-finger transcription factors involved in hematopoietic malignancies.
Liu
Hui
H
Section of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, 1 University Station, A5000, University of Texas, Austin, Texas 78712, USA. hui.liu@zimmer.com
Ippolito
Gregory C
GC
Wall
Jason K
JK
Niu
Teresa
T
Probst
Loren
L
Lee
Baeck-Seung
BS
Pulford
Karen
K
Banham
Alison H
AH
Stockwin
Luke
L
Shaffer
Arthur L
AL
Staudt
Louis M
LM
Das
Chhaya
C
Dyer
Martin J S
MJ
Tucker
Philip W
PW
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D015530:Nuclear Matrix / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins
C486563:BCL11A protein, human; D002352:Carrier Proteins; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins