Amazing stuff! Cancer is history (soon)!
"A family of mutations seen in about 20% of human cancers drives malignancy by changing the accessibility of genes to a particular regulatory protein, according to a study by Weill Cornell Medicine investigators. The findings suggest new therapeutic strategies for a variety of cancer types.
The study ... focused on a protein complex called the BAF complex, which regulates gene activity in the nucleus. Mutations in genes that encode subunits of this complex are found in tumors as different as lymphoma, breast cancer, ovarian cancer and liver cancer, but the common mechanism underlying this broad connection to cancers has been elusive.
In the study, the scientists showed that these BAF mutations effectively allow the three-dimensional architecture of DNA to be reshaped extensively by a protein called CTCF. This shifts gene activity in a direction that promotes malignancy, but deleting CTCF in an animal model reverses the effect. ...
When the BAF complex is lost, CTCF binding increases at thousands of sites across the genome and leads to a widespread reshaping of the three-dimensional loops and folds of DNA. These changes disrupt the normal contacts between genes and elements that regulate them and alter gene activity in a way that leads to faster cell division. ...
In mouse models and human patient data, the team found confirmatory evidence of CTCF’s role in BAF-mutant cancers, including evidence that disruptions of CTCF are associated with better patient outcomes. ..."
From the abstract:
"The BAF (also known as mammalian SWI/SNF) chromatin remodelling complexes are essential regulators of nucleosome positioning and transcription factor binding.
Loss-of-function (LOF) mutations in genes encoding components of the BAF complexes are among the most frequent across cancer types.
However, a unifying mechanism that explains their widespread disruption remains unclear.
Here we disrupted BAF function through pharmacological inhibition and ARID1A deletion across various mammalian cell types and tissues and observed a conserved chromatin response: increased accessibility at CTCF-binding sites. ARID1A LOF alone was sufficient to drive these changes, which demonstrates that canonical BAF (cBAF) disruption is the key driver of CTCF gain.
Genomic profiling showed increased CTCF and SMC3 occupancy, which reveals an antagonistic relationship between cBAF and CTCF–cohesin complexes. Furthermore, cBAF loss restructured 3D genome organization, which led to a strengthening of topologically associating domain boundaries and subdivision of large domains into smaller insulated structures. Long-range enhancer–promoter loops were replaced by shorter, promoter-proximal loops anchored at CTCF-enriched sites. To determine how CTCF function is enabled following cBAF loss, we profiled CTCF-interacting cofactors and found that CTCF binds directly to fully assembled PBAF. After cBAF depletion, PBAF was recruited to sites of increased CTCF occupancy, which demonstrates that there is an antagonistic switch between SWI/SNF subcomplexes.
In vivo, conditional Arid1a deletion in primary mouse cells resulted in the expansion of a highly proliferative population marked by elevated accessibility at CTCF sites.
This phenotype was fully reversed by either Ctcf or Pbrm1 deletion, which establishes that cBAF and the activity of CTCF and PBAF have contrasting roles."
Fig. 1: BAF LOF preferentially opens chromatin at CTCF sites across diverse cell types.
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