Regulation of DNA Replication Within the Immunoglobulin Heavy-chain Locus During B Cell Commitment

Overview

Journal PLoS Biol

Specialty Biology

Date 2012 Jul 19

PMID 22807655

Citations 33

Authors

Agnieszka Demczuk

Michel G Gauthier

Ingrid Veras

Settapong Kosiyatrakul

Carl L Schildkraut

Meinrad Busslinger

John Bechhoefer

Paolo Norio

Affiliations

Soon will be listed here.

Abstract

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 C(H)-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.

Citing Articles

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