Our Science

The groundbreaking science behind our therapies continues to yield vital insights into diseases that have confounded physicians and researchers. Our core scientific approach is centered on the chromatin regulatory system, which opens and closes the right sections of DNA at the right time. Breakdowns in the chromatin regulatory system lead to a wide range of diseases, including cancer, impacting millions of people.

What is the chromatin regulatory system?

Chromatin is the 3-dimensional structure of DNA, which is tightly packed inside each cell.

Amazingly, in every human cell, DNA is compressed thousands of times so it can fit into the nucleus. How is this possible? It’s because the DNA is wound up, like a spool of thread, around a scaffold of proteins called histones, creating a structure called chromatin.

When the information stored in DNA is not in use, chromatin is wound up and tightly packed. But sometimes the cell needs to access the information, which means it has to unpack chromatin.

The chromatin regulatory system opens and closes the right sections of chromatin at the right time. This is essential for the cell to properly function and access the information stored in genes.

What is Gene Expression?

The chromatin regulatory system enables and orchestrates the first step of gene expression, accessing DNA by unpacking chromatin.

Gene expression requires a series of steps, in which DNA codes the production of a protein. The chromatin regulatory system orchestrates gene expression by controlling the first step of this process: the opening and closing of chromatin.

By orchestrating gene expression, the chromatin regulatory system determines the timing, amount, and location of the proteins made by the cell. The activity of the resulting proteins establishes the cell’s structure, function, and stage of development.

What are chromatin remodeling complexes?

Chromatin remodeling complexes and their partners, called transcription factors, are two key components of the chromatin regulatory system.

These two components work in concert to access and unpack chromatin. Transcription factors help direct chromatin remodeling complexes to the right locations on chromatin. Chromatin remodeling complexes open up the regions of chromatin to initiate gene expression.

There are numerous chromatin remodeling complexes and hundreds of transcription factor partners. The diversity and complexity of this system allows for fine-tuned orchestration of chromatin access at the right place and time across many cell types and stages of development.

Why is the chromatin regulatory system important in disease?

Addressing breakdowns in the chromatin regulatory system could represent a new class of therapies for over 2.5 million people with cancer.

In cancer and other diseases, mutations affect the function of the chromatin regulatory system. Sometimes these mutations result in genetically determined dependencies, which cancer cells rely on for survival.

Genetic dependencies make cancer cells more vulnerable to therapeutic intervention, providing the potential to selectively target diseased cells while minimizing impact to healthy cells.

In cancer, mutations can occur within subunits of the chromatin remodeling complex, in partner transcription factors, or lead to dysregulation of the system as a whole.

What is the BAF complex? Why is it important?

The BAF complex is the most mutated amongst a family of chromatin remodeling complexes.

One chromatin remodeling complex that is highly implicated in disease is the BAF complex. The BAF complex is made up of 12 to 15 subunits, out of 28 possible options. The exact subunit composition confers an amazing amount of specificity in terms of lineage type and transcription factor involvement. For example, cardiac cells use different subunits than brain cells and the BAF complex interacts with more than 100 transcription factor partners.

Mutations in the BAF complex or its partners lead to abnormal gene expression, which can result in diseases, such as cancer.

Publications

Centore et al. “Discovery of novel BAF inhibitors for the treatment of transcription factor-driven cancers” AACR, April 2021

Centore, Sandoval, Mendes Soares, Kadoch and Chan. “Mammalian SWI/SNF Chromatin Remodeling Complexes: Emerging Mechanisms and Therapeutic Strategies” TIGS 1709 August 29, 2020

Michel et al. “A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation” Nat. Cell Biol. 2018 Dec; 20(12): 1410–1420

Kadoch & Crabtree. “Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics” Science Advances 12 Jun 2015: Vol. 1, no. 5, e1500447

Hodges, Kirkland, and Crabtree. “The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer” Advance July 13, 2016

Valencia and Kadoch. “Chromatin regulatory mechanisms and therapeutic opportunities in cancer” Nat Cell Biol. 2019 Feb; 21(2): 152–161

Sandoval et al. “Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis” 2018, Molecular Cell 71, 554–566, August 16, 2018

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Our insights into the biology of the chromatin regulatory system are the foundation for our proprietary platform.