Benjamin Nacev: Excited to share our new story on cancer-associated histone mutations
Benjamin Nacev, Assistant Professor at the University of Pittsburgh School of Medicine, shared on LinkedIn: .
“I’m excited to share our new story on cancer-associated histone mutations! A few years ago, while early in my postdoc in Dave Allis’ lab, we published an expanded landscape of onco-histone mutations. Knowing what we do about histone and nucleosome structure and function, we generated a number of hypotheses about the role of these onco-histones in cancer, but this of course requires functional validation.
In our new paper, we dive deep into the consequences of a subset of cancer-associated mutations that occur at arginines in the H3 N-terminal tail. We used diverse techniques including histone methyltransferase assays, CUT and RUN, and scRNA-seq applied to stochastic differentiation models to understand the consequences of these H3 arginine mutants.
We showed that histone PTMs nearby the mutated arginines are disrupted in the presence of the mutants and focused on H3R2 and R26 mutants, which impair PRC2 activity (the latter also in vitro).
Because PRC2 is a critical regular of gene expression, is recurrently disrupted in cancer, and is critical for normal development, we studied the effects of H3R26 mutants in mesenchymal progenitors and in murine embryonic stem cells and showed that they disrupted normal differentiation.
Using scRNA-seq to study the aberrantly differentiated mesenchymal progenitors, we found that chromatin disruption by an H3R26 mutant is associated with an aberrant trajectory distinct from WT counterparts.
Notably, the perturbation of histone PTMs appeared to affect the mutant histone tail and not the global pool (i.e., they act in cis), akin to the H3G34 class of onco-histone mutants. However, we showed that H3K27me3 is recurrently depleted at the scale of specific domains, which are associated with E-box binding TFs and with transcriptional de-repression.
The functional characterization of the H3R26 mutant provides an example of a cis-acting counterpart to the classical H3K27M mutation, both of which affect PRC2 activity. Overall, these findings provide new insights into the functional consequences of a subset of onco-histone mutations and raise intriguing hypotheses about their role in cancer.
The data for this story was mostly generated in Dave Allis’ lab when I was postdoc. While Dave’s untimely passing meant that he couldn’t see this fully come to fruition, his mentorship and influence and insights into this project were invaluable.
I am grateful for having trained with him and hope that he would be proud of how this story turned out. Of course, I also have to thank Dave for establishing the many invaluable collaborations that were part of this work including with Tom Muir’s lab, with Benjamin Garcia’s group, and with the fantastic bioinformatic team at The Rockefeller University among others.”
Source: Benjamin Nacev/LinkedIn
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