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Our genome is a long DNA polymer that must be folded to fit inside the nucleus. This folding is not a passive packing process, rather, it is actively regulated by multiple protein factors that create specific physical contacts between distant genomic regions. Growing evidence shows that these regulated DNA-DNA interactions are required for key cellular functions, including transcription, replication, and genome maintenance. Our lab aims to uncover the fundamental principles that govern how the genome folds in 3D, and to understand how this 3D organization influences genome function in health and disease. Specifically we focus on:
Our genome is a long DNA polymer that must be folded to fit inside the nucleus. This folding is not a passive packing process, rather, it is actively regulated by multiple protein factors that create specific physical contacts between distant genomic regions. Growing evidence shows that these regulated DNA-DNA interactions are required for key cellular functions, including transcription, replication, and genome maintenance. Our lab aims to uncover the fundamental principles that govern how the genome folds in 3D, and to understand how this 3D organization influences genome function in health and disease. Specifically we focus on:
1. How is the genome folded within the nucleus?
1. How is the genome folded within the nucleus?
A central player in genome folding is the cohesin complex, which functions as a molecular motor that extrude loops of DNA. Cohesin is loaded onto chromatin by loading factors and begins to reel in DNA, forming progressively growing loops. As the loop extend, cohesin may encounter CTCF, a DNA-binding protein. Upon encountering CTCF, cohesin extrusion is stalled, anchoring the loop at that position and preventing further extension beyond CTCF-binding sites. Unloading factors remove cohesin from chromatin, leading to loss of loop. Through this regulated process, chromatin loops are stabilized between defined genomic sites, shaping the genome’s 3D architecture.
A central player in genome folding is the cohesin complex, which functions as a molecular motor that extrude loops of DNA. Cohesin is loaded onto chromatin by loading factors and begins to reel in DNA, forming progressively growing loops. As the loop extend, cohesin may encounter CTCF, a DNA-binding protein. Upon encountering CTCF, cohesin extrusion is stalled, anchoring the loop at that position and preventing further extension beyond CTCF-binding sites. Unloading factors remove cohesin from chromatin, leading to loss of loop. Through this regulated process, chromatin loops are stabilized between defined genomic sites, shaping the genome’s 3D architecture.
To investigate how cohesin, its regulatory factors, and CTCF control genome folding, we combine genomic and imaging approaches. We use Hi-C, a genome-wide chromosome conformation capture technique, to measure the frequency of interactions between genomic loci. We also use DNA FISH (fluorescence in situ hybridization) to directly visualize spatial distances between specific genomic regions in individual cells.
2. What nuclear factors impact genome folding?
The nucleus is a highly complex and dynamic environment. It contains numerous molecular machines for transcription, DNA replication, and RNA processing. Moreover, chromatin is segregated into distinct structural and functional domains, including euchromatin, heterochromatin, and nuclear bodies. However, how this diverse nuclear landscape influences cohesin-mediated loop formation is still poorly understood. To address this, we perform genetic screens to discover novel nuclear factors that influence genome folding. We then investigate the mechanisms by which these factors function, using a combination of Hi-C, ChIP-seq, DNA FISH, and biochemical assays.
3. How does genome folding influence genome function?
Cohesin-mediated genome folding plays a key role in regulating how the genome functions. By bringing distant genomic elements into close proximity, chromatin loops can influence gene transcription, DNA replication, and DNA damage response. We investigate how disruption of genome folding affects transcriptional programs, replication dynamics, and genome stability. These studies aim to define how the spatial organization of the genome contributes to maintaining cellular health.
4. How does dysregulated genome folding contribute to disease?
Disruption of genome folding can have profound consequences on development and disease. One example is Cornelia de Lange Syndrome (CdLS), a severe developmental disorder characterized by craniofacial defects, limb defects, and intellectual disability. Approximately 65% of individuals with CdLS harbor mutations in genes encoding cohesin subunits or its associated factors, implicating genome folding defects in the etiology of the disease. We study how such mutations alter chromatin architecture and gene regulation during development, aiming to connect molecular changes with clinical features.
Genome folding defects are also emerging as a factor in cancer. The cohesin subunits are frequently mutated in several cancers, including leukemias, bladder cancer, and glioblastoma. We investigate how the loss or dysfunction of cohesin disrupts normal 3D genome organization in cancer and whether these changes promote cancer through mis-regulated gene expression, impaired DNA repair, and/or genome integrity.
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