Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells.
The transcription factor Pax5 represses lineage-inappropriate genes and activates B cell-specific genes in B lymphocytes. By identifying 110 Pax5-repressed genes, we now demonstrate that Pax5 downregulates diverse biological activities including receptor signaling, cell adhesion, migration, transcriptional control, and cellular metabolism at B cell commitment. The T lymphoid or myeloid expression of these genes demonstrates that Pax5(-/-) pro-B cells and common lymphoid progenitors display lymphoid and myeloid promiscuity of gene expression. These lineage-inappropriate genes require continuous Pax5 activity for their repression, as they are reactivated in committed pro-B cells and mature B cells following conditional Pax5 deletion. Pax5-repressed genes are also reexpressed in plasma cells, which depend for normal function on Cd28 and Ccr2 reactivation. The loss of Pax5 during terminal differentiation thus contributes to the plasma cell transcription program. Finally, ectopic expression of the Pax5-repressed chemokine gene Ccl3 in B cells results in increased osteoclast formation and bone loss, demonstrating that Pax5-mediated gene repression is essential for normal homeostasis of hematopoietic development.
Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Alessio
A
Delogu
Alexandra
A
Schebesta
Qiong
Q
Sun
Katharina
K
Aschenbrenner
Thomas
T
Perlot
Meinrad
M
Busslinger
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001773:Blood Cells / Q000502:physiology*; D001862:Bone Resorption / Q000209:etiology; D018106:CD28 Antigens / Q000235:genetics; D002448:Cell Adhesion; D002465:Cell Movement; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000235:genetics; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006706:Homeostasis; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000502:physiology; D051757:PAX5 Transcription Factor / Q000502:physiology*; D010950:Plasma Cells / Q000378:metabolism*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics
D018106:CD28 Antigens; C496534:Ccl3 protein, mouse; C515335:Ccr2 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine