BAZ2A safeguards genome architecture of ground‐state pluripotent stem cells. (14th October 2020)

• Record Type: Journal Article
• Authors: Dalcher, Damian; Tan, Jennifer Yihong; Bersaglieri, Cristiana; Peña‐Hernández, Rodrigo; Vollenweider, Eva; Zeyen, Stefan; Schmid, Marc W; Bianchi, Valerio; Butz, Stefan; Roganowicz, Marcin; Kuzyakiv, Rostyslav; Baubec, Tuncay; Marques, Ana Claudia; Santoro, Raffaella
• Is Part Of: EMBO journal. Volume 39:Number 23(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-10-14
• Subjects: BAZ2A -- genome organization -- ground‐state embryonic stem cells -- H3K27me3 -- Topoisomerase 2A; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020105606
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Chromosomes have an intrinsic tendency to segregate into compartments, forming long‐distance contacts between loci of similar chromatin states. How genome compartmentalization is regulated remains elusive. Here, comparison of mouse ground‐state embryonic stem cells (ESCs) characterized by open and active chromatin, and advanced serum ESCs with a more closed and repressed genome, reveals distinct regulation of their genome organization due to differential dependency on BAZ2A/TIP5, a component of the chromatin remodeling complex NoRC. On ESC chromatin, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. BAZ2A associates with chromatin sub‐domains within the active A compartment, which intersect through long‐range contacts. We found that ground‐state chromatin selectively requires BAZ2A to limit the invasion of active domains into repressive compartments. BAZ2A depletion increases chromatin accessibility at B compartments. Furthermore, BAZ2A regulates H3K27me3 genome occupancy in a TOP2A‐dependent manner. Finally, ground‐state ESCs require BAZ2A for growth, differentiation, and correct expression of developmental genes. Our results uncover the propensity of open chromatin domains to invade repressive domains, which is counteracted by chromatin remodeling to establish genome partitioning and preserve cell identity. Synopsis: How genome organization is regulated in embryonic stem cells (ESC) according to cell state and chromatin structure remains elusive. Here, comparison of basic, ground‐state to developmentally advanced mouse ESCs reveals nucleolar remodeling complex (NoRC) component BAZ2A/TIP5 as a critical regulator of genome partitioning and cell identity. BAZ2A binds at active and open genome and supports growth of ground‐state but not advanced ESCs. BAZ2A interacts with SNF2H, TOP2A and cohesin on ESC chromatin. BAZ2A associates with chromatin sub‐domains within the active A‐compartment that intersect through long‐range contacts. BAZ2A deletion perturbs gene expression and histone H3K27 trimethylation in ground‐state ESCs. BAZ2A limits invasion of ESC active chromatin into inactive domains. Abstract : The NoRC chromatin remodeller subunit BAZ2A restricts active chromatin compartments and secures developmental gene expression in ESCs.