TY - JOUR
T1 - Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins
AU - Wutz, Gordana
AU - Várnai, Csilla
AU - Nagasaka, Kota
AU - Cisneros, David A
AU - Stocsits, Roman R
AU - Tang, Wen
AU - Schoenfelder, Stefan
AU - Jessberger, Gregor
AU - Muhar, Matthias
AU - Hossain, M Julius
AU - Walther, Nike
AU - Koch, Birgit
AU - Kueblbeck, Moritz
AU - Ellenberg, Jan
AU - Zuber, Johannes
AU - Fraser, Peter
AU - Peters, Jan‐Michael
PY - 2017/12/7
Y1 - 2017/12/7
N2 - Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome‐wide function in mediating long‐range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
AB - Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome‐wide function in mediating long‐range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
KW - chromatin condensation
KW - chromatin structure
KW - genome organization
KW - loop extrusion
KW - vermicelli
UR - https://doi.org/10.15252/embj.201798004
U2 - 10.15252/embj.201798004
DO - 10.15252/embj.201798004
M3 - Article
SN - 0261-4189
VL - 36
SP - 3573
EP - 3599
JO - The EMBO journal
JF - The EMBO journal
IS - 24
ER -