A recent study from Rockefeller University, published in Molecular Cell on July 13, reveals unexpected functions of the epigenetic modifier MLL4 that may shed light on its role in cancer. The research team, led by Robert Roeder at the Laboratory of Biochemistry and Molecular Biology, used biochemistry, genetics, and structural biology to explore how MLL4 interacts with other proteins to regulate gene activity.
MLL4 is part of a family of six mixed-lineage leukemia (MLL) histone lysine methyltransferases. While it promotes disease progression in certain leukemias by protecting cells from oxidative and genotoxic stress and maintaining stem cell properties, it acts as a tumor suppressor in solid tumors through cooperation with p53—a transcription factor known for activating genes involved in DNA damage response.
Roeder said, "This research demonstrates that MLL4 has functions in transcription that were entirely unknown before. And because MLL4 is a key regulator of gene activity, it's important to understand how it works—especially in cancer cells."
First author Jianfeng Sun explained that understanding the structure of MLL4 could clarify its dual roles. Sun said there are four subunits shared among the family but five unique ones found only in MLL4. Using cryo-EM imaging along with genetic techniques and an established transcription system, Sun's team created the first complete model showing all nine subunits—five unique—in multiple conformations. The findings revealed that while some parts anchor firmly to nucleosomes, a flexible arm searches for histones to tag with methylation markers—a signal for gene activation.
"We also found that the N-terminal region folds back onto the C-terminal region to form a unique structural architecture that is essential for the transcriptional coactivation function of MLL4 as well as for p53-dependent transcription in cells," Sun said.
Knocking out MLL4 genetically resulted in fewer genes targeted by p53 being activated—suggesting that without MLL4, p53’s ability as a genome guardian was compromised. Roeder described this as surprising: "MLL4's primary function in gene transcription is through histone 3 methylation, and yet here we're seeing that it's also essential for p53 target gene transcription as a direct p53 co-activator. That's a second—and entirely new—function," Roeder said. The researchers plan further studies into how MLL4 supports different cancer-related processes depending on cellular context.
