The ZBTB transcription factors Mod (mdg4) and Cp190 are known to play critical roles in the regulation of insulator activities in Drosophila ( 52–56). Therefore, the comprehensive identification of cohesin-interacting partners will provide a valuable resource for the identification of candidate regulators of 3D genome organization and will support the idea that the redundancy between cohesin and various transcription factors modulates local chromatin interactions or specific interactions under different conditions.
We hypothesized that there are additional transcription factors involved in cohesin-mediated chromatin interactions. These factors, including CTCF, YY1, ZNF143, ADNP, MAZ, WIZ and BHLHE40 ( 41–51), usually occupy insulators or gene promoters, and their perturbation modulates the global 3D chromatin organization or affects a subset of chromatin interactions. Previous studies have identified multiple transcription factors involved in 3D genome organization that interact directly or indirectly with cohesin. These direct regulators of cohesin have been shown to regulate global 3D genome organization ( 37–40). Cohesin is loaded by NIPBL and MAU2, stabilized by CTCF at insulators, and removed by WAPL ( 34–36). Previous genomic distribution mapping efforts suggested that cohesin occupies promoters, enhancers and insulators ( 31–33). Structural maintenance of the chromosome (SMC) complexes (cohesin, condensin and SMC5/SMC6) are crucial for the organization of interphase chromatin structures ( 28–30). The dissection of these molecular mechanisms is crucial to understanding the regulation of the 3D genome during development and disease. Many different chromatin structural regulators have been depleted in different studies, resulting in different effects on 3D genome organization ( 23–27). To describe these mechanisms, the looping model, tracking model and phase separation-based compartmentalization model have been introduced ( 19–22). Although enhancer- and promoter-mediated local chromatin architectures have been studied for several decades ( 13–18), the molecular basis of their establishment, maintenance and disruption remains unclear. We propose that multiple ZBTB transcription factors orchestrate the chromatin binding of cohesin to regulate chromatin interactions, and we provide a catalog of many additional proteins associated with cohesin that warrant further investigation.Ĭhromatin structures are partitioned into hierarchical units, including chromosome territories, A/B compartments, topologically associating domains (TADs), enhancer–promoter loops, nucleosome clutches, globular chromatin domains and nucleosomes ( 1–12).
Strikingly, multiomic analyses revealed that the other four ZBTB factors interacted with cohesin, and double degradation of ZBTB21 and ZBTB7B led to a further decrease in cohesin chromatin occupancy. Acute protein degradation followed by time-series genomic binding quantitation and BAT Hi-C analysis were conducted, and the results showed that the transcription factor ZBTB21 contributes to cohesin chromatin binding, 3D chromatin interactions and transcriptional repression. Here, we performed proteomic profiling of the cohesin in chromatin and identified transcription factors, RNA-binding proteins and chromatin regulators associated with cohesin. Cohesin is essential for 3D chromatin organization, and its interacting partners are candidate regulators. One bottleneck in understanding the principles of 3D chromatin structures is caused by the paucity of known regulators.
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