Exploring Inheritance Beyond DNA

For much of his career Songtao Jia, a professor of biological sciences who joined Columbia in 2006, has been focused on epigenetic inheritance—traits that are not carried on DNA, but nevertheless are passed down from one generation to the next. A recent paper by Jia’s lab in the journal Genes & Development offered new insights on how that process works.

Columbia News sat down with Jia to discuss that paper, how understanding epigenetics could offer keys to treating disease, and what he works on when he isn’t at the lab.

What makes epigenetic inheritance interesting?

We generally know a fair amount about genetic inheritance, which is when genetic information is passed down through DNA.

But there are certain things that can be passed down from generation to generation independent of what’s in DNA. Even in two people with identical DNA, such as identical twins, genes can be turned on and off differently, so they do not have exactly the same expression pattern.

This kind of non-DNA inheritance is often determined by a class of proteins called histones, which regulate gene expression through the many modifications they carry. What we have found is that changes to histone modifications change how they fold DNA and how DNA is accessed by regulators, which changes how genes get expressed. And changes to histone modifications can be passed down from one generation to the next even when DNA stays the same.

My lab looks at a single-celled fungus called fission yeast. Looking at this yeast allows us to really simplify what we see and to distinguish genetic from epigenetic factors. Since every fission yeast has the same DNA, we can distinguish when something looks different from one generation to the next for epigenetic reasons. Fission yeast is the first documented, definitive example where people showed that epigenetic inheritance was at work, something we first saw about 30 years ago.

What’s a powerful example of epigenetic inheritance?

One good example is metabolism. There are indications that if people go through famine during pregnancy, their children and grandchildren tend to be more obese. The mechanistic basis is hard to study, because it can be hard to tease apart all the different influences, but it does seem to be the case based on studies done in mice, that metabolism-induced gene expression changes can be passed down through generations even when DNA remains the same.

What did your latest paper in Genes and Development look at?

This paper looks at two histone “chaperones,” which help the distribution of parental histones to newly synthesized DNA as it replicates. They’re called Mcm2 and Dpb3/4. It offers a lot of new detail on how they work and, importantly, definitively demonstrates the importance of parental histone distribution in epigenetic inheritance.  

During DNA replication, all the DNA doubles using the parental strands as template and splits into two daughter strands. Similarly, histones also double, and are evenly distributed between daughter strands to serve as a template to duplicate histone modifications. What we found is that Mcm2 and Dpb3/4 are essential for the even distribution of parental histones to daughter strands. Moreover, mutations in these histone chaperones disrupt this process, resulting in defective epigenetic inheritance. Now that we know how epigenetic inheritance is regulated and the critical players involved, we can find new ways to alter inheritance without modifying the DNA sequence. This approach can address many ethical challenges associated with genome editing as epigenetics can also be easily reversed.

What big questions does epigenetic inheritance pose for you that makes it so interesting?

Our research has big implications for many areas of biology relevant to human health, especially cancer treatment because cancer cells are essentially our own cells that have gone rogue and started to change both genetically and epigenetically. Understanding that epigenetic component is really important.

It also shows promise in cancer immunotherapy, basically boosting the immune system to recognize cancer cells. Essentially, scientists are trying to pioneer ways to modulate the epigenetic environments to help the immune system to more effectively recognize cancer cells in order to target them and kill them.

What do you like to do when you aren’t doing research?

I like to fish. I live just north of campus. There’s a pier at 125th street where I do a lot of fishing. I also fish in Central Park in the Harlem Meer. I get a lot of things. Bass, perch, eels, crabs. My goal is to get a striped bass.

Can you eat them?

It’s mostly catch and release. There’s a limit to how many fish you can keep. It’s about one fish per week or so. The water here is not that great, but I enjoy fishing for its own sake.