Cohesin positions the epigenetic reader Phf2 within the genome.
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| Title: | Cohesin positions the epigenetic reader Phf2 within the genome. |
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| Authors: | Tang, Wen, Costantino, Lorenzo, Stocsits, Roman, Wutz, Gordana, Ladurner, Rene, Hudecz, Otto, Mechtler, Karl, Peters, Jan-Michael |
| Source: | EMBO Journal; Feb2025, Vol. 44 Issue 3, p736-766, 31p |
| Subject Terms: | CHROMOSOMAL proteins, COHESINS, HISTONE demethylases, CARRIER proteins, CYTOLOGY |
| Abstract: | Genomic DNA is assembled into chromatin by histones, and extruded into loops by cohesin. These mechanisms control important genomic functions, but whether histones and cohesin cooperate in genome regulation is poorly understood. Here we identify Phf2, a member of the Jumonji-C family of histone demethylases, as a cohesin-interacting protein. Phf2 binds to H3K4me3 nucleosomes at active transcription start sites (TSSs), but also co-localizes with cohesin. Cohesin depletion reduces Phf2 binding at sites lacking H3K4me3, and depletion of Wapl and CTCF re-positions Phf2 together with cohesin in the genome, resulting in the accumulation of both proteins in chromosomal regions called vermicelli and cohesin islands. Conversely, Phf2 depletion reduces cohesin binding at TSSs lacking CTCF and decreases the number of short cohesin loops, while increasing the length of heterochromatic B compartments. These results suggest that Phf2 is an 'epigenetic reader', which is translocated through the genome by cohesin-mediated DNA loop extrusion, and which recruits cohesin to active TSSs and limits the size of B compartments. These findings reveal an unexpected degree of cooperativity between epigenetic and architectural mechanisms of eukaryotic genome regulation. Synopsis: Genomic DNA is extruded into loops by cohesin and regulated by histone-modification binding proteins, but how these architectural and epigenetic regulatory mechanisms cooperate is poorly understood. This study describes and functionally characterizes interactions between cohesin and the epigenetic reader protein Phf2. The PHD-finger and JmjC-domain protein Phf2 binds a conserved essential sequence (CES) on cohesin. Phf2 co-localizes with H3K4me3-nucleosomes and cohesin in the genome. Cohesin contributes to genomic positioning of Phf2, possibly via loop extrusion. Phf2 limits the size of heterochromatic B compartments and contributes to the formation of short cohesin loops. Phf2 recruits cohesin to active transcription start sites. Phf2 interacts directly with cohesin, promotes cohesin binding at transcription start sites, and limits the size of chromosomal B compartments. [ABSTRACT FROM AUTHOR] |
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| Database: | Complementary Index |
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