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In some instances, more is better…for the IgH super-enhancer

Complex loci contain multiple genes whose regulation is developmentally regulated or induced by extracellular signals. In many cases, these genes are induced on both chromosomes, and it is still a matter of debate whether the gene promoters on the same chromosome compete for shared regulatory elements or if they are co-activated. The team of Ahmed Amine Khamlichi at the IPBS showed that the two modes, competition and co-activation, operate at an antibody locus, and that it is the nature of the inducing signal that determines which mode will prevail. This study was published in PNAS on July, 2019.

 

Expression of complex, multigenic, loci in mammals is often controlled by distant elements on the chromosome in a cell type- and developmental stage-specific manner. This long-range regulation takes place within dynamic chromatin domains and is developmentally regulated or induced by specific extracellular signals. One of the central questions in the field of transcriptional regulation of complex loci relates to the mode of activation of gene promoters. Do they compete for shared regulatory elements or are they co-activated?      
The constant region of the antibody heavy chain (IgH) locus contains multiple inducible genes whose promoters (named I promoters) are controlled by a super-enhancer, called the 3’RR (3’Regultory Region). Any attempt to elucidate the mode of activation of I promoters on the same chromosome must accommodate the fact these promoters are induced on both chromosomes. Therefore, the use of cell populations or even single cells is not conclusive (see Figure).  
Through a combination of genetic and functional analyses, Santos et al. showed that, at the single chromosome level, I promoters can either compete for, or be co-activated by, the 3’RR, regardless of their localization on the chromosome or their distance from the 3’RR. What counts in the choice of the activation mode is the nature of the inducing signal.

Upon IgH/c-Myc chromosomal translocation, the translocated  oncogene falls under the control of the 3’RR, is overexpressed, and can move to downstream constant genes (through a process called class switch recombination) during tumor progression. The capacity of the 3’RR to activate two promoters on the same chromosome could explain this process. The study also raises important questions as to the mechanisms underlying induced chromatin loops that juxtapose distant promoters and the 3’RR. 

 

Scheme of a rearranged IgH locus

Figure. Scheme of a rearranged IgH locus. The constant genes are structurally similar. Their transcription initiates at I promoters that are under the control of a super-enhancer (3’RR). I promoters are induced by different stimuli (shown on the top). B cells are diploid and have therefore two copies of the IgH locus. I promoters can be induced on both chromosomes. For clarity, only one chromosome is shown. In the figure is represented activation of Iγ2b and Iγ3 promoters, upon LPS stimulation. Different scenarios are possible. For instance, the 3’ RR could activate one promoter per chromosome (e.g. Iγ3 on allele 1 and Iγ2b on allele 2), or one promoter on one allele and both promoters on the other allele (e.g. Iγ3 on allele 1 and both promoters on allele 2), or both promoters on the two alleles, etc. In the majority of cases, the 3’RR co-activates Iγ3 and Iγ2b on the same chromosome.

 

Reference

Two modes of cis-activation of switch transcription by the IgH super-enhancer.
Santos JM, Braikia FZ, Oudinet C, Dauba A, and Khamlichi AA. 
Proc Natl Acad Sci USA. July 16, 2019 116 (29) 14708-14713; first published July 2, 2019 https://doi.org/10.1073/pnas.1902250116

 

Contacts

Researcher : Ahmed Amine Khamlichi | T 05 61 17 55 22 | Ahmed.Khamlichi@ipbs.fr
Press : Françoise Viala | T 06 01 26 52 59 | communication@ipbs.fr