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Reduction of ZFX levels decreases histone H4 acetylation and increases Pol2 pausing at target promoters [GRO-seq]

ABSTRACT: The ZFX transcriptional activator binds to CpG island promoters, with a major peak at ~200-250bp downstream from transcription start sites. Because ZFX binds within the transcribed region, we investigated whether it regulates transcriptional elongation. We used GRO-seq to show that loss or reduction of ZFX increased the pause ratio at ZFX-regulated promoters. To further investigate the mechanisms by which ZFX regulates transcription, we determined regions of the protein needed for transactivation and for recruitment to the chromatin. Interestingly, although ZFX has 13 grouped zinc fingers, deletion of the first 11 fingers produces a protein that can still bind to chromatin and activate transcription. We next used TurboID-MS to detect ZFX-interacting proteins, identifying ZNF593, proteins that interact with the N-terminal transactivation domain (e.g. histone modifying proteins), and proteins that interact with ZFX when it is bound to the chromatin (e.g. TAFs and other histone modifying proteins). Our studies support a model in which ZFX enhances elongation at target promoters by recruiting H4 acetylation complexes and reducing pausing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241281 | GEO | 2024/04/23

REPOSITORIES: GEO

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Reduction of ZFX levels decreases histone H4 acetylation and increases the pause ratio at target promoters

Project description:The ZFX transcriptional activator binds to CpG island promoters, with a major peak at ~200-250bp downstream from transcription start sites. Because ZFX binds within the transcribed region, we investigated whether it regulates transcriptional elongation. We used GRO-seq to show that loss or reduction of ZFX increased the pause ratio at ZFX-regulated promoters. To further investigate the mechanisms by which ZFX regulates transcription, we determined regions of the protein needed for transactivation and for recruitment to the chromatin. Interestingly, although ZFX has 13 grouped zinc fingers, deletion of the first 11 fingers produces a protein that can still bind to chromatin and activate transcription. We next used TurboID-MS to detect ZFX-interacting proteins, identifying ZNF593, proteins that interact with the N-terminal transactivation domain (e.g. histone modifying proteins), and proteins that interact with ZFX when it is bound to the chromatin (e.g. TAFs and other histone modifying proteins). Our studies support a model in which ZFX enhances elongation at target promoters by recruiting H4 acetylation complexes and reducing pausing.

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Reduction of ZFX levels decreases histone H4 acetylation and increases Pol2 pausing at target promoters [RNA-Seq]

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Characterization of the ZFX family of transcription factors that bind downstream of the start site of CpG island promoters [EPIC array]

Project description:Our study focuses on a family of ubiquitously expressed human C2H2 zinc finger proteins comprised of ZFX, ZFY, and ZNF711. Although their protein structure suggests that ZFX, ZFY, and ZNF711 are transcriptional regulators, the mechanisms by which they influence transcription have not yet been elucidated. We used CRISPR-mediated deletion to create bi-allelic knockouts of ZFX and/or ZNF711 in female HEK293T cells (which naturally lack ZFY). We found that loss of either ZFX or ZNF711 reduced cell growth and that the double knockout cells have major defects in proliferation. RNA-seq analysis revealed that thousands of genes showed altered expression in the double knockout clones, suggesting that these TFs are critical regulators of the transcriptome. To gain insight into how these TFs regulate transcription, we created mutant ZFX proteins and analyzed them for DNA binding and transactivation capability. We found that zinc fingers 11-13 are necessary and sufficient for DNA binding and, in combination with the N terminal region, constitute a functional transactivator. Our functional analyses of the ZFX family provides important new insights into transcriptional regulation in human cells by members of the large, but under-studied family of C2H2 zinc finger proteins.

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Characterization of the ZFX family of transcription factors that bind downstream of the start site of CpG island promoters

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Role of Cofilin 1 pathway and actin dynamics in nuclear retinoid receptor function

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2011-08-25 | E-GEOD-31665 | biostudies-arrayexpress

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Sub1 and RPA associate with RNA Polymerase II at different stages of transcription

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