Ribeiro de Almeida C, Hendriks RW, Stadhouders R
The Ig魏 locus, which is spread over 3Mb of genomic DNA and contains >100 variable (V) genes, serves as an important model system to study long-range chromatin interactions. Here, we will discuss how in developing B cells in the bone marrow the accessibility of individual V魏 segments is controlled by many lineage-specific and ubiquitously expressed transcription factors that act on various cis-regulatory elements, including promoters, enhancers, and insulators. This dynamic control furthermore involves changes in subnuclear localization, histone modification, DNA demethylation, and three-dimensional locus compaction. In pro-B cells, the Ig魏 locus adopts a poised conformation as full contraction has been achieved and many key transcription factors already occupy the locus. Subsequently, the combined activation of pre-B cell antigen receptor signaling pathways and attenuation of IL-7R signaling in small resting pre-B cells dramatically modifies the transcription factor landscape, supporting the induction of monoallelic Ig魏 gene rearrangements. Hereby, the intronic and 3' Ig魏 enhancer elements coordinately focus their activities in the V魏 region toward frequently used V魏 genes. Recent work has drawn attention to the intriguing role of the CTCF-associated regulatory elements Cer and Sis, which are located in the V魏-J魏 intervening region and control Ig魏 locus contraction and V魏 repertoire diversity. This involves CTCF-mediated locus insulation, restricting enhancer activity to the V魏 region and suppressing the preferential recombination to proximal V魏 genes. A picture emerges in which the dynamic control of long-range genomic interactions ensures correct timing of Ig魏 locus recombination and provides appropriate opportunities for individual V魏 gene segments to engage in V魏-J魏 rearrangement.
+view abstract
Advances in immunology, PMID: 26477368
2015