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Jill Dowen
Jill Dowen, PhD

It is known that the three-dimensional organization of the genome within the nucleus is important for proper gene expression and ultimately development. The mechanisms behind this organization, however, are not yet fully understood. Recently, the lab of Jill Dowen, PhD, published a study in Epigenetics & Chromatin solving a piece of this complex puzzle.

Cohesin is a protein complex involved in sister chromatid cohesion during DNA replication and DNA repair, but its role in forming DNA loops that regulate gene activity during interphase is not well understood. Cohesin brings together two distant sites in the genome by forming a DNA loop structure. While some DNA loops bring active enhancers to target gene promoters and other DNA loops prevent such enhancer-promoter interactions, it is unclear how cohesin molecules can promote these distinct effects.

Nicole Arruda
Nicole Arruda, graduate student

Work led by graduate student Nicole Arruda investigated the roles of cohesin accessory proteins STAG1 and STAG2 in cohesin localization in the genome and gene expression. Working in mouse embryonic stem cells, they demonstrate that STAG1 and STAG2 display both overlapping and distinct functions. Utilizing CRISPR/Cas9 genome editing, they generated stable single-knockout lines in order to study the individual contributions of the two STAG proteins to cohesin function. They found that cohesin-STAG1 and cohesin-STAG2 complexes co-occupy the genome and are not re-distributed upon loss of either STAG protein. Despite this, they found that STAG1 and STAG2 have somewhat distinct roles in gene expression and maintenance of stem cell identity. Loss of both STAG1 and STAG2 lead to major defects in cohesin stability on the genome, gene expression, and cell proliferation. Overall, it was critical for cells to retain at least one STAG protein for proper function. They conclude that while STAG1 and STAG2 are not specificity factors for where cohesin molecules localize on the genome, they do differentially impact the function of cohesin molecules in gene regulation at specific sites.

Understanding the roles of cohesin and its interacting proteins is a major contribution to solving the puzzle of how the 3D genome is formed and functions. Studies like these provide knowledge of basic cell processes in development and insights into how these processes fail in human disease.

Check out their work here:

Arruda, N.L., Carico, Z.M., Justice, M., Liu, Y.F., Zhou, J., Stefan., H.C., Dowen, J.M., Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells. Epigenetics & Chromatin 13, 32 (2020). https://doi.org/10.1186/s13072-020-00353-9