image: Plants like Arabidopsis, seen here, have two options to ensure accurate chromosome division—a molecule called DDM1 and a process known as RNAi. If Arabidopsis loses one of these, it’s fine. But if it loses both, it’s in trouble.
Credit: Martienssen lab/Cold Spring Harbor Laboratory
Tending a garden is hard work. Imagine it from the plants’ perspective. Each relies on fine-tuned genetic processes to pass down accurate copies of chromosomes to future generations. These processes sometimes involve billions of moving parts. Even the tiniest disruption can have a cascading effect. So, for plants like Arabidopsis thaliana, it’s good to have a backup plan.
“Chromosomes have to be accurately partitioned every time a cell divides,” explains Cold Spring Harbor Laboratory (CSHL) Professor and HHMI Investigator Rob Martienssen. “For that to happen, each chromosome has a centromere. In plants, centromeres control chromosome partitioning with the help of a molecule called DDM1.”
Martienssen discovered DDM1 in 1993 with a team that included Tetsuji Kakutani, then a postdoc with CSHL Fellow Eric Richards. Kakutani and Martienssen recently reunited to investigate a question 30 years in the making. When humans lose their version of DDM1, centromeres can’t divide evenly. This causes a severe genetic condition called ICF syndrome. But if the molecule is so important, why isn’t Arabidopsis affected when DDM1 is lost?
“We wondered why it would be so different. About 10 years later, we found that in yeast, centromere function is controlled by small RNAs. That process is called RNAi. Plants actually have both DDM1 and RNAi. So, we thought, ‘Let’s isolate these two in Arabidopsis to see what happens.’ We did that, and sure enough, the plants looked really horrible," explains Martienssen.
When the team looked closer, they found that a single transposon inside chromosome 5 was responsible for the defects. Transposons move around the genome, switching genes on and off. In Arabidopsis, they trigger DDM1 or RNAi to help centromeres divide. But when DDM1 and RNAi are missing, the process is disrupted.
“We found very few copies of this transposon anywhere else in the genome,” Martienssen says. “But the centromere of chromosome 5 was infested with these things. We thought, ‘Wow, OK, this really might be it.’ Then we started working on how to restore healthy function.”
Martienssen and the study’s lead author, Atsushi Shimada, developed molecules called short hairpin RNAs that target the transposons.
“Those small RNAs make up for the loss of DDM1. They recognized every copy of the transposon in the centromere and, amazingly, restored centromere function. So now the plants were fertile again. They make seeds. They look much better, " explains Martienssen.
Of course, it’s not all about plants. In humans, uneven centromere division has been linked to conditions like ICF and early cancer progression. Martienssen hopes his team’s work may one day point to better treatments for these and other diseases.