Integrated genetic approaches identify the molecular mechanisms of Sox4 in early B-cell development: intricate roles for RAG1/2 and CK1ε.
Commitment of hematopoietic stem cells to B lineage precursors and subsequent development of B lineage precursors into mature B cells is stringently controlled by stage-specific transcription factors. In this study, we used integrated genetic approaches and systematically determined the role of Sry-related high mobility group box (Sox) 4 and the underlying molecular mechanisms in early B-cell development. We found that Sox4 coordinates multilevel controls in the differentiation of early stage B cells. At the molecular level, Sox4 orchestrates a unique gene regulatory program, and its function was predominantly mediated through a conventional Sox4-binding motif as well as an unconventional GA-binding protein α chain binding motif. Our integrated gene network and functional analysis indicated that Sox4 functions as a bimodular transcription factor and ensures B lineage precursor differentiation through 2 distinct mechanisms. It positively induces gene rearrangements at immunoglobulin heavy chain gene loci by transcriptionally activating the Rag1 and Rag2 genes and negatively regulates Wnt signaling, which is critical for self-renewal, by inducing the expression of casein kinase 1 ε. Our findings illustrate that Sox4 mediates critical fine-tuning of the 2 opposing forces in early B-cell development and also set forth a model for characterization of critical genes whose deficiency, like Sox4 deficiency, is detrimental to this process.
Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology.
Saradhi
S
Mallampati
Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology.
Baohua
B
Sun
Department of Molecular Carcinogenesis, and.
Yue
Y
Lu
Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology.
Haiqing
H
Ma
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX;
Yun
Y
Gong
Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA; and.
Donghai
D
Wang
Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Ju-Seog
JS
Lee
Department of Molecular Carcinogenesis, and.
Kevin
K
Lin
Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology.
Xiaoping
X
Sun
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D048149:Casein Kinase 1 epsilon / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055751:SOXC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse; C064658:RAG-1 protein; D048149:Casein Kinase 1 epsilon