The Barisic Lab studies how chromatin remodelers control access to the genome. We focus on the SWI/SNF, CHD and ISWI complexes, which are frequently mutated in human cancers, especially in lymphomas, yet whose mechanisms of action remain poorly defined. We work across three scales. At individual nucleosomes, we ask how remodelers position nucleosomes to permit or block transcription factor binding, work that established a sequential hierarchy in which remodeling first lets pioneering transcription factors bind and then unmasks nearby sites for other factors, directing cell-fate. In interphase, we ask how local remodeling shapes chromatin domains and enhancer-promoter contacts, and we find that remodeler loss rewires three-dimensional chromatin interactions. In mitosis, we ask what remodeling means on maximally condensed chromatin. Our aim throughout is causal rather than correlative understanding, so we pair targeted protein degradation and CRISPR with single-cell and three-dimensional genomics, mouse models and machine learning.
Role of chromatin remodelers in transcription factor binding
Every cell in the body carries the same DNA, yet DNA is not read the same way in every cell. Most of DNA is wound tightly around proteins into a dense package called chromatin. Proteins that switch genes on cannot reach DNA that is packed away, so cells rely on molecular machines called chromatin remodelers to slide and rearrange that packaging. It was long assumed these machines were largely interchangeable, each simply opening chromatin so that anything could bind. We found the opposite. Different families of remodelers serve different clients, and the factors that depend on one are almost entirely separate from those that depend on another. Access to the genome is not a single door but a set of doors with different keys, and this discovery reframed how the field thinks about the control of gene activity (Nature, 2019).
Role of chromatin remodelers in cell-fate decisions and malignant transformation
When you are vaccinated or fight an infection, B cells enter a structure in the lymph node where they compete, mutate their antibodies and choose between becoming the cells that produce antibodies now and the memory cells that protect you for years. That choice depends on chromatin. We showed that a remodeler subunit called ARID1A sets the sequence in which two key regulatory proteins engage the genome, with the first clearing the way for the second. When ARID1A is lost, and it is among the most frequently mutated genes in human cancer, the sequence breaks and B cells drift toward an immature memory-like state that keeps re-entering the reaction instead of resolving it. In mice this accelerates follicular lymphoma, and in patients the same signature marks tumors at higher risk of turning aggressive. The same defect also creates a vulnerability, since these cells become exquisitely sensitive to drugs that block the remodeler's motor, pointing to a precision therapy for patients whose tumors carry the mutation (Cancer Cell, 2024).
Chromatin remodeling and the architecture of the genome
Two meters of DNA fit inside a nucleus a fraction of the width of a human hair, folded into loops and neighborhoods that place genes near the switches that control them, and then compacted again into chromosomes each time a cell divides. That folding is not incidental. It determines which genes talk to which switches, and whether a dividing cell distributes its chromosomes correctly or produces daughters with the wrong amount of DNA, a hallmark of cancer. We are asking what chromatin remodelers contribute to this architecture, working across many tissues and cell types and through every stage of the cell cycle.
