The spatial and temporal regulation of complex loci’s expression is often effected by distant regulatory elements within relatively large chromatin domains. Transcriptional and architectural factors play an important role in the establishment and maintenance of these domains and facilitate long-range interactions between regulatory elements and their target promoters.
During an immune response, antigen encounter triggers important changes in the expression pattern of B lymphocytes (specialized in antibody production) including remarkable physiological remodeling of their genome. In some yet ill-known contexts, this remodeling can implicate antibody genes in chromosomal translocations, i.e. reciprocal exchanges of portions of chromosomes, potentially leading to cancer (lymphomas, myeloma).
In the specific case of the immunoglobulin heavy chain locus (IgH locus), expression occurs in two main steps controlled by different regulatory elements. Early expression in developing B cells involves the so-called variable region whereas late expression targets the constant region that contains numerous genes. Why is expression of the constant genes restricted to late stages of B cell development?
In a recent study, Ahmed Amine Khamlichi’s team has shown that this delayed expression was largely due to a novel regulatory element within the IgH locus. This element binds an architectural factor (called CTCF) which blocks the enhancing activity of a powerful transcriptional element (3’RR) lying downstream of the IgH locus (see figure). However, following antigen encounter and B cell activation, CTCF is evicted and the 3’RR can therefore activate its target promoters. Surprisingly, upon deletion of the CTCF binding element, various constant genes normally expressed at late stages of B cell development are now expressed at early stages (see figure). These data strongly suggest that the novel element functions as an inducible switch that controls, at least in part, the temporal expression of the IgH locus by insulating the 3’RR from constant genes prior to B cell activation.
This study opens important lines of investigation. In particular, elucidation of the role of this regulatory element in the architecture of the IgH locus should enable a better understanding of the mechanisms underlying the establishment, maintenance and deregulation of large chromatin domains, the precise function of the dynamics of these domains in the activation or silencing of gene expression, as well as the timing of chromosomal translocations involving the IgH locus.
A Scheme of the mouse IgH locus. The novel regulatory element (5’hs1RI) is located within the alpha constant gene. The CTCF binding sites within the 5’hs1RI element and downstream of the powerful locus control region (3’RR, which controls IgH constant genes’ expression), are indicated in red ovals. B A simplified model of the premature action of the 3’RR on its target promoters (shown here the promoter of the gamma3 constant gene) in immature B cells in the absence of the 5’hs1RI (dotted oval).
Fatima-Zohra Braikia, Chloé Oudinet, Dania Haddad, Zeliha Oruc, Domenico Orlando, Audrey Dauba, Marc Le Bert and Ahmed Amine Khamlichi. (2017) An inducible CTCF insulator delays the IgH 3’ regulatory region-mediated activation of germline promoters and alters class switching. PNAS. 2017 May 22. pii: 201701631. doi: 10.1073/pnas.1701631114.
Researcher: Ahmed Amine Khamlichi | 05 61 17 55 22 | firstname.lastname@example.org
Press: Françoise Viala | 06 01 26 52 59 | Communication@ipbs.fr
More information HERE (in french)