Targeting CEBPA to restore cellular identity and tissue homeostasis in pulmonary fibrosis.
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ABSTRACT:
PROVIDER: PRJNA1103685 | ENA |
REPOSITORIES: ENA
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Project description:Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape three-dimensional (3D) genome organization remain incompletely understood. Here we present evidence that the lineage-instructive TF CEBPA drives extensive chromatin compartment switching and promotes the formation of long-range chromatin hubs during induced B cell to macrophage transdifferentiation. A large intrinsically disordered region (IDR) enables CEBPA to undergo in vitro phase separation and to co-condense with transcriptional partners, which is at least partially mediated by aromatic residues. Furthermore, CEBPA forms visible nuclear condensates in transdifferentiating B cells that co-localize with co-activator condensates and recover rapidly upon photobleaching. Finally, native CEBPA-expressing cell types such as primary granulocyte-macrophage progenitors (GMPs), liver cells and trophectoderm cells also reveal nuclear CEBPA condensates and long-range 3D chromatin hubs at CEBPA-bound regions. These findings support a model in which CEBPA acts as a 3D genome structural organizer and suggest that this effect is mediated at least in part by its phase-separation capacity.
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Project description:Weaker CEBPA binding in the human than in the mouse genome is a general trait of the human genome across multiple biological conditions. Alu repeats carry strong CEBPA binding motifs, which compete with regulatory regions for CEBPA binding. To directly test this hypothesis, we attempted to overcome Alu competition by using, first, a CRISPR-dCas9 system in BLaER1 cells (Rapino et al. 2013). By promoting the recruitment of the inactive Cas9 to Alu regions with specific gRNAs targeting Alu repeats containing strong CEBPA motifs we protected them, hampering CEBPA binding to these regions. We tested the effect of two different paired gRNA constructs in two replicates and one control paired gRNA in two replicates. Second, we also further overexpressed CEBPA in human BLaER1 cells to overcome Alu competition. We tested two doses of CEBPA overexpression in two replicates and one control experiment in two replicates.
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Project description:To investigate the mechanisms by which C/EBPa drives basophil differentiation and maintains basophil identity, we examined whether or not C/EBPa promotes basophil molecular programming and simultaneously represses mast cell molecular programming. We performed genome-wide gene expression profiling on basophils and mast cells and found that 6798 genes were shared by mast cells and basophils; 2033 genes were expressed 2-10 (log2 1-3.3)-fold higher in basophils (differentially expressed in basophils); and 413 genes were expressed greater than 10 (log2 3.3)-fold in basophils (highly expressed in basophils). On the other hand, we found 569 genes were expressed 2-10 (log2 -1 to -3.3) fold higher in mast cells and 171 genes were highly expressed in mast cells [greater than 10 fold (log2 -3.3)]. We treated purified basophils prepared from Cebpaf/f RosaYFP/creER mice and Cebpa+/+ RosaYFP/creER control mice with or without 4HT treatment for five days. Gene expression in the treated basophils was analyzed using microarray analysis. Overall, deletion of C/EBPa in basophils resulted in a reduction of mRNA expression for 248 genes and led to an increase in mRNA expression for 255 genes. The majority of the C/EBPa-regulated genes were either differentially or highly expressed in basophils or mast cells. In this study, we compared gene expression in basophils and mast cell and identified genes which specifically expressed in basophils and mast cells. By using Cebpa conditional knock out mice, we identified Cebpa regulated genes in basophils.
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