Cells have all kinds of intricate machinery to control genes, switching them on and off at the right times and under the right conditions. Components of this machinery include chromatin-modifying complexes, groups of proteins that manage how tightly DNA is packaged in the nucleus, controlling how accessible it is for transcription.
One of these complexes, MLL1, guides the activity of important growth and development genes, including the HOX gene family which is involved with limb and body plan patterning. Mutations in the genes that compose the MLL1 complex can lead to acute myeloid leukemia (AML), especially in young children, so scientists have long wanted to understand how it works and what goes wrong in the case of cancer.
New research from UChicago on a protein that holds the MLL1 complex together finds a surprising process for how the complex is recruited to different genes to control their activity. This process creates a feedback loop, where a key component of the MLL1 complex interacts with many different RNAs rather than recognizing specific sequences, and then uses RNA to dismantle itself when the job is done.
A negative feedback loop
The MLL gene was first connected to cancer by pioneering UChicago cancer geneticist Janet Rowley, who discovered that patients with AML and chronic myelogenous leukemia (CML) had pieces of chromosomes broken off and swapped with other chromosomes. These “translocations” were one of the first big discoveries showing that cancer is often driven by genetic abnormalities. MLL is located at the breakpoint where many of these translocations occur.
For years, scientists thought that long noncoding RNAs (which don’t make proteins) helped recruit MLL1 and WDR5, a protein that helps hold the complex together, to specific genes. But they believed that the matching was specific, meaning that WDR5 was looking for a particular genetic sequence, not just interacting randomly with any RNAs.
In the new study, published in Molecular Cell, Alex Ruthenburg, PhD, Associate Professor of Molecular Genetics and Cell Biology, and postdoctoral scholar Amoldeep Kainth, PhD, devised a method to identify which RNAs interact with WDR5. The answer: a lot of them. WDR5 binds with many different RNAs, mostly determined by how abundant and how long an RNA molecule is, not matching specific sequences (the scientific description for this behavior is “binding promiscuously”).
“I think before this work, everyone thought that this complex just binds to a small number of specific RNAs through WDR5, and that’s not what we see,” Ruthenburg said. “We see the complex binding all sorts of RNAs, so it expands the repertoire of what RNA can do by interacting and modulating complex activity.”
The team also discovered an unexpected consequence of this “promiscuous” activity. Once enough RNA bound to WDR5, it started to compete with other proteins needed to hold the MLL1 complex together. As a result, it fell apart and stopped promoting genetic activity.
“The working model we have now is that some amount of RNA helps in recruiting the MLL1 complex. It leads to gene activation that creates a lot of RNA in the neighboring environment, and eventually that high amount of RNA turns off the complex that activated the gene. So, it’s negative feedback,” Kainth said.
The researchers need to learn more to understand how mutations in MLL1 lead to cancer, but they have some ideas. Cancer is a disease of runaway genetic activity; if the MLL1 complex is broken or not able to shut down after it produces enough RNA, things could get out of hand.
