
Researcher Profiles

Aaron D. Viny, M.D.
Memorial Sloan Kettering Cancer Center
2018 Funding recipient
Cohesin complex mutations decouple chromatin structure and transcriptional output in myelodysplastic syndrome
EvansMDS Young Investigator Award
PROJECT SUMMARY
Genetic defects in the cohesin complex, a key component requires for normal chromatin architecture, have been identified in several solid tumors and myeloid malignancies. Cohesin facilitates tissue-specific gene expression through DNA looping, and its loss leads to impaired transcriptional output and impaired cell identity. Our work has identified a non-hierarchical cooperative interplay between key lineage defining transcription factors and DNA architecture. Using mouse models, we have illustrated that Stag2, the most commonly mutated cohesin component in human cancer, impairs bone marrow stem cells from maturing in a normal fashion, resulting in low numbers of platelets, red blood cells, and in B-lymphocytes. I have used novel methods to reconstruct cellular DNA structure and found that loop structures are lost at regions of the genome that are essential for stem cell transition to a fate-committed hematopoietic lineage. This corresponds to loss of genomic accessibility and loss of gene expression. Under microscopy the impaired stem cell differentiation resembles myelodysplasia with histologic features seen in human myelodysplastic syndrome.