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Next Gen Sequencing Reveals Transposable Elements Can Re-wire Gene Regulatory Networks

Content sponsored by Sigma-Aldrich® Advanced Genomics

In 1983, Barbara McClintock won a Nobel Prize for discovering transposable elements (TEs)– the first woman to solely win the Prize. These genetic parasites can copy themselves and jump around the genome, and, as McClintock showed, when they insert themselves into the right place, they can dramatically change the appearance of their host.

Jumping genes

These ‘jumping genes’ explain how one kernel in an ear of maize can look so different from another. In addition, a TE which lands in the wrong region can throw a wrench in the normal functioning of the genome, resulting in diseases such as hemophilia, porphyria, and cancer. Due to their knack for reproducing, TEs represent a good chunk of the so-called ‘junk’ DNA which constitutes the majority of our genome. And because of their propensity for causing problems, they have developed a pretty bad rap.

A tangled mess

As NGS projects have ramped up, consequently a mountain of data on TEs has piled up. Unfortunately, these data are usually thrown out before genomic analyses begin in earnest. It’s not that scientists don’t find TEs interesting; these selfish bits of DNA are an endless source of fascination. The problem is that it’s hard to analyze TE sequences, which appear as a tangled mess of repeats scattered around the genome.

Don’t turn your back on important findings

For this reason, when researchers sit down to analyze their NextGen data, they often start by masking repeat sequences in hopes this will allow them to focus on the good stuff: coding regions. Is it possible that by throwing out all of these data on TEs we are turning our back on important findings? Recent findings suggest that the answer is yes.

Transposable elements and pregnancy

How do complex, novel traits arise? This question has engrossed evolutionary biologists since the field began. Recently, a group of researchers at Yale decided to investigate this problem by studying endometrial cells in mammals. Though endometrial cells may not sound particularly exciting, in truth they open a window onto the process by which mysterious new traits appear.

Giving birth to the placenta

The evolution of these cells laid the groundwork for the development of the placenta, one of the defining characteristics of most mammals. The hormone progesterone causes endometrial stromal cells, or ESCs, to form the maternal component of the placenta, allowing pregnancy as we know it to proceed.

ESC evolution

So how did ESCs evolve? Günter Wagner and colleagues nudged ESCs on the path toward becoming placenta by administering progesterone and cyclic AMP- an important biological messenger. They then used RNAseq to characterize the transcriptome of ESCs in humans and compared the results to endometrial cell transcriptomes from armadillos and opossums.

What’s the difference between a human and an armadillo?!

Why did they choose these animals? Armadillos, like humans, have a placenta, though the two species diverged 105 MYA. The opossum, in contrast, diverged an additional 150 MYA and has no placenta. The researchers hypothesized that if they could identify transcripts that were expressed in both humans and armadillos (but not opossums) they might gain insight into the gene regulatory network responsible for ESCs.

A surprising finding

A surprising finding soon emerged. Many of the differentially expressed genes in humans lay adjacent to a mammal-specific TE: MER20. And these nearby transposon sequences bound transcription factors essential for pregnancy. It appears that the spread of MER20 throughout the mammalian genome sprinkled enhancers, insulators, and repressors next to important genes, creating a pattern of expression that was unique to ESCs. By inserting itself into the genome so many times, it rewired the regulatory network of genes in mammalian endometrial cells, resulting in a complex new cell type that arose over a relatively short period of evolutionary time.

If TEs laid the framework for the placenta…what else have they done?

It has now been established that TEs played an important role in the evolution of mammalian pregnancy by creating a coordinately regulated network of genes in ESCs. If they could rewire an extensive regulatory gene network associated with the placenta, it’s tempting to believe that they may have shaped additional networks responsible for important biological processes.

Don’t throw out the baby with the bathwater!

So what is a researcher to do? Perhaps the next time we get NGS results, we should not be so swift to throw out the repeat data. The color of maize kernels, diseases such as hemophilia, and now pregnancy. What else are TEs responsible for?

Reference:

Lynch et al., (2011). Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals. Nature Genetics 43: 1154-1159.

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