WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation.

Ning Qing Liu, Michela Maresca, Teun van den Brand, Luca Braccioli, Marijne M G A Schijns, Hans Teunissen, Benoit G Bruneau, Elphѐge P Nora, Elzo de Wit

Nature genetics 2021 Jan

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The cohesin complex has an essential role in maintaining genome organization. However, its role in gene regulation remains largely unresolved. Here we report that the cohesin release factor WAPL creates a pool of free cohesin, in a process known as cohesin turnover, which reloads it to cell-type-specific binding sites. Paradoxically, stabilization of cohesin binding, following WAPL ablation, results in depletion of cohesin from these cell-type-specific regions, loss of gene expression and differentiation. Chromosome conformation capture experiments show that cohesin turnover is important for maintaining promoter-enhancer loops. Binding of cohesin to cell-type-specific sites is dependent on the pioneer transcription factors OCT4 (POU5F1) and SOX2, but not NANOG. We show the importance of cohesin turnover in controlling transcription and propose that a cycle of cohesin loading and off-loading, instead of static cohesin binding, mediates promoter and enhancer interactions critical for gene regulation.

Citation

Ning Qing Liu, Michela Maresca, Teun van den Brand, Luca Braccioli, Marijne M G A Schijns, Hans Teunissen, Benoit G Bruneau, Elphѐge P Nora, Elzo de Wit. WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation. Nature genetics. 2021 Jan;53(1):100-109