The IgH -MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation.

Intoduction: Two scaffold/matrix attachment regions (5'- and 3'- ) flank the intronic core enhancer (c) within the immunoglobulin heavy chain locus (). Besides their conservation in mice and humans, the physiological role of is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated.

Methods: Our study analyzed SHM and its transcriptional control in a mouse model devoid of , further combined to relevant models deficient for base excision repair and mismatch repair.

Distinct B-Cell Specific Transcriptional Contexts of the BCL2 Oncogene Impact Pre-Malignant Development in Mouse Models.

Upregulated expression of the anti-apoptotic oncogene is a common feature of various types of B-cell malignancies, from lymphoma to leukemia or myeloma. It is currently unclear how the various patterns of deregulation observed in pathology eventually impact the phenotype of malignant B cells and their microenvironment. Follicular lymphoma (FL) is the most common non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells, and its major hallmark is the t(14:18) translocation occurring in B cell progenitors and placing the gene under the control of the immunoglobulin heavy chain locus regulatory region (IgH 3'RR), thus exposing it to constitutive expression and hypermutation.

Functional anatomy of the immunoglobulin heavy chain 3΄ super-enhancer needs not only core enhancer elements but also their unique DNA context.

Cis-regulatory elements feature clustered sites for transcription factors, defining core enhancers and have inter-species homology. The mouse IgH 3΄ regulatory region (3'RR), a major B-cell super-enhancer, consists of four of such core enhancers, scattered throughout more than 25 kb of packaging 'junk DNA', the sequence of which is not conserved but follows a unique palindromic architecture which is conserved in all mammalian species. The 3'RR promotes long-range interactions and potential IgH loops with upstream promoters, controlling class switch recombination (CSR) and somatic hypermutation (SHM).