Stories about: antibody diversity

Getting a grip on genetic loops

Chromatin is housed inside the nucleus. A new discovery about its physical arrangement could pave the way for new therapeutics.
Artist’s rendering of chromatin, which is housed inside the nuclei of mammalian cells. A new discovery about its physical arrangement could pave the way for new therapeutics.

A new discovery about the spatial orientation and physical interactions of our genes provides a promising step forward in our ability to design custom antibodies. This, in turn, could revolutionize the fields of vaccine development and infection control.

“We are beginning to understand the full biological impact that the physical structure and movement of our genes play in regulating health and development,” says Frederick Alt, PhD, director of the Boston Children’s Hospital Program in Cellular and Molecular Medicine (PCMM) and the senior author of the new study, published in the latest issue of Cell.

Recent years of research by Alt and others in the field of molecular biology have revealed that it’s not just our genes themselves that determine health and disease states. It’s also the three-dimensional arrangement of our genes that plays a role in keeping genetic harmony. Failure of these structures may trigger genetic mutations or genome rearrangements leading to catastrophe.

The importance of genetic loops

Crammed inside the nucleus, chromatin, the chains of DNA and proteins that make up our chromosomes, is arranged in extensive loop arrangements. These loop configurations physically confine segments of genes that ought to work together in a close proximity to one another, increasingly their ability to work in tandem.

“All the genes contained inside one loop have a greater than random chance of coming together,” says Suvi Jain, PhD, a postdoctoral researcher in Alt’s lab and a co-first author on the study.

Meanwhile, genes that ought to stay apart remain blocked from reaching each other, held physically apart inside our chromosomes by the loop structures of our chromatin.

But while many chromatin loops are hardwired into certain formations throughout all our cells, it turns out that some types of cells, such as certain immune cells, are more prone to re-arrangement of these loops.

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Finding the long-sought master switch for antibody diversity

The different gene segments your immune system needs to build a diverse selection of antibodies are spread out across huge genomic distances. Frederick Alt may have found the genetic switch that helps manage all of the far flung pieces. (Jeremy Vandel/Flickr)

Imagine for a moment, that you are your immune system. On any given day, you’re faced with host of threats: a virus here, a bacterium there, a new fungus. And don’t forget those wayward cells lurking around the corner, the ones that might become a tumor.

Now, you have to respond to these challenges, but how you do it? Each looks different, meaning that you have to produce a new T or B cell (your two main tools) that can find, mark and guide the attack against each new threat.

Luckily, your T and B cells can turn to three sets of gene segments that, together, contain the genetic raw material for the variety you need. Called the variable (V), diversity (D) and joining (J) segments, they are constantly cut up, shuffled and rejoined by the genome to make new genes – a process called V(D)J recombination – for new receptors (on T cells) or antibodies (from B cells), giving your immune system the most diverse arsenal possible.

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