Regulation of DNA Replication within the Immunoglobulin Heavy-Chain Locus During B Cell Commitment
| Autor: | Carl L. Schildkraut, Michel G. Gauthier, John Bechhoefer, Meinrad Busslinger, Paolo Norio, Settapong T. Kosiyatrakul, Agnieszka Demczuk, Ingrid Veras |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
DNA Replication
QH301-705.5 Cellular differentiation PAX5 Transcription Factor Immunology Locus (genetics) Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mice 0302 clinical medicine hemic and lymphatic diseases Molecular Cell Biology medicine Genetics Animals Humans Cell Lineage Biology (General) Theoretical Biology B cell 030304 developmental biology Regulation of gene expression 0303 health sciences B-Lymphocytes Stochastic Processes Binding Sites General Immunology and Microbiology General Neuroscience DNA replication Computational Biology Cell biology medicine.anatomical_structure Immunoglobulin heavy chain PAX5 General Agricultural and Biological Sciences Immunoglobulin Heavy Chains 030217 neurology & neurosurgery Research Article Developmental Biology |
| Zdroj: | PLoS Biology PLoS Biology, Vol 10, Iss 7, p e1001360 (2012) |
| Popis: | The temporal order of replication of mammalian chromosomes appears to be linked to their functional organization, but the process that establishes and modifies this order during cell differentiation remains largely unknown. Here, we studied how the replication of the Igh locus initiates, progresses, and terminates in bone marrow pro-B cells undergoing B cell commitment. We show that many aspects of DNA replication can be quantitatively explained by a mechanism involving the stochastic firing of origins (across the S phase and the Igh locus) and extensive variations in their firing rate (along the locus). The firing rate of origins shows a high degree of coordination across Igh domains that span tens to hundreds of kilobases, a phenomenon not observed in simple eukaryotes. Differences in domain sizes and firing rates determine the temporal order of replication. During B cell commitment, the expression of the B-cell-specific factor Pax5 sharply alters the temporal order of replication by modifying the rate of origin firing within various Igh domains (particularly those containing Pax5 binding sites). We propose that, within the Igh CH-3′RR domain, Pax5 is responsible for both establishing and maintaining high rates of origin firing, mostly by controlling events downstream of the assembly of pre-replication complexes. Author Summary Each time a mammalian cell duplicates its genome in preparation for cell division it activates thousands of so called “DNA origins of replication.” The timely and complete duplication of the genome depends on careful orchestration of origin activation, which is modified when cells differentiate to perform a specific function. We currently lack a universally accepted model of origin regulation that can explain the replication dynamics in complex eukaryotes. Here, we studied the mouse immunoglobulin heavy-chain locus, one of the antibody-encoding portions of the genome, where origins change activity when antibody-producing B cells differentiate in the bone marrow. We show that multiple aspects of DNA replication initiation, progression, and termination can be explained mathematically by the interplay between randomly firing origins and two independent variables: the speed of progression of replication forks and the firing rate of origins along the locus. The rate of origin firing varies extensively along the locus during B cell differentiation and, thus, is a dominant factor in establishing the temporal order of replication. A differentiation factor called Pax5 can alter the temporal order of replication by modifying the rate of origin firing across various parts of the locus. |
| Databáze: | OpenAIRE |
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