Intrinsically Disordered Regions Steer the Function Coordination of the Traveling Chromatin Modifier During Pol II Elongation
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae Schizosaccharomyces pombe
PROVIDER: GSE254580 | GEO | 2024/11/13
REPOSITORIES: GEO
Similar Datasets
Project description:The Rpd3S histone deacetylase complex suppresses cryptic initiation and maintains genomic integrity by deacetylating transcribed nucleosomes subsequent to RNA Pol II passage. Recent cryo-EM structure analysis of Rpd3S emphasized the significance of two asymmetrical Rco1/Eaf3 dimers in nucleosome binding. However, the mechanism by which Rpd3S interacts with nucleosomal substrates while traveling with elongating Pol II remains elusive. In this study, we elucidate the crucial role of the Rco1 N-terminal Intrinsically Disordered Region (IDR) in regulating Pol II association. Mutations within the K/R cluster of Rco1 IDR significantly impede Rpd3S binding to CTD, while leaving the overall complex integrity and nucleosome recognition unaffected. Moreover, we identify the Rco1-PHD1 and Eaf3-CHD domains as the minimal module responsible for specific interaction with Ser5-phosphorylated CTD. The Rco1 IDR functions by relieving autoinhibition from its C-terminal regions, enabling the binding of PHD-CHD to CTD. Additionally, we uncover an evolutionarily conserved mechanism governing the distinct roles of the asymmetrical Rco1/Eaf3 dimers, which coordinate nucleosome engagement and Pol II binding. These findings offer valuable new perspectives on the functional dynamics of mobile epigenetic modifying complexes that accompany processive machinery.
2024-11-13 | GSE254579 | GEO
Project description:The Rpd3S histone deacetylase complex suppresses cryptic initiation and maintains genomic integrity by deacetylating transcribed nucleosomes subsequent to RNA Pol II passage. Recent cryo-EM structure analysis of Rpd3S emphasized the significance of two asymmetrical Rco1/Eaf3 dimers in nucleosome binding. However, the mechanism by which Rpd3S interacts with nucleosomal substrates while traveling with elongating Pol II remains elusive. In this study, we elucidate the crucial role of the Rco1 N-terminal Intrinsically Disordered Region (IDR) in regulating Pol II association. Mutations within the K/R cluster of Rco1 IDR significantly impede Rpd3S binding to CTD, while leaving the overall complex integrity and nucleosome recognition unaffected. Moreover, we identify the Rco1-PHD1 and Eaf3-CHD domains as the minimal module responsible for specific interaction with Ser5-phosphorylated CTD. The Rco1 IDR functions by relieving autoinhibition from its C-terminal regions, enabling the binding of PHD-CHD to CTD. Additionally, we uncover an evolutionarily conserved mechanism governing the distinct roles of the asymmetrical Rco1/Eaf3 dimers, which coordinate nucleosome engagement and Pol II binding. These findings offer valuable new perspectives on the functional dynamics of mobile epigenetic modifying complexes that accompany processive machinery.
2024-11-13 | GSE254578 | GEO
Project description:Intrinsically Disordered Regions Steer the Function Coordination of the Traveling Chromatin Modifier During Pol II Elongation
| PRJNA1071079 | ENA
Project description:Intrinsically Disordered Regions Steer the Function Coordination of the Traveling Chromatin Modifier During Pol II Elongation (RNA-Seq)
| PRJNA1071289 | ENA
Project description:Intrinsically Disordered Regions Steer the Function Coordination of the Traveling Chromatin Modifier During Pol II Elongation (ChIP-Seq)
| PRJNA1071290 | ENA
Project description:Transcription elongation factor Spt6 associates with RNA polymerase II (Pol II) and acts as a histone chaperone, which promotes the reassembly of nucleosomes following the passage of Pol II. The precise mechanism of nucleosome reassembly mediated by Spt6 remains unclear. In this study, we used a hybrid approach combining cryo-electron microscopy and small-angle X-ray scattering to visualize the architecture of Spt6 from Saccharomyces cerevisiae. The reconstructed overall architecture of Spt6 reveals not only the core of Spt6, but also its flexible N- and C-termini, which are critical for Spt6's function. We found that the acidic N-terminal region of Spt6 prevents the binding of Spt6 not only to the Pol II CTD and Pol II CTD-linker, but also to pre-formed intact nucleosomes and nucleosomal DNA. The N-terminal region of Spt6 self-associates with the tSH2 domain and the core of Spt6 and thus controls binding to Pol II and nucleosomes. Furthermore, we found that Spt6 promotes the assembly of nucleosomes in vitro. These data indicate that the cooperation between the intrinsically disordered and structured regions of Spt6 regulates nucleosome and Pol II CTD binding, and also nucleosome assembly.
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Project description:Intrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as 'evolutionary signatures' of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue function in vivo, and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.
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Project description:Autophagy is an essential eukaryotic pathway required for cellular homeostasis. Numerous key autophagy effectors and regulators have been identified, but the mechanism by which they carry out their function in autophagy is not fully understood. Our rigorous bioinformatic analysis shows that the majority of key human autophagy proteins include intrinsically disordered regions (IDRs), which are sequences lacking stable secondary and tertiary structure; suggesting that IDRs play an important, yet hitherto uninvestigated, role in autophagy. Available crystal structures corroborate the absence of structure in some of these predicted IDRs. Regions of orthologs equivalent to the IDRs predicted in the human autophagy proteins are poorly conserved, indicating that these regions may have diverse functions in different homologs. We also show that IDRs predicted in human proteins contain several regions predicted to facilitate protein-protein interactions, and delineate the network of proteins that interact with each predicted IDR-containing autophagy protein, suggesting that many of these interactions may involve IDRs. Lastly, we experimentally show that a BCL2 homology 3 domain (BH3D), within the key autophagy effector BECN1 is an IDR. This BH3D undergoes a dramatic conformational change from coil to ?-helix upon binding to BCL2s, with the C-terminal half of this BH3D constituting a binding motif, which serves to anchor the interaction of the BH3D to BCL2s. The information presented here will help inform future in-depth investigations of the biological role and mechanism of IDRs in autophagy proteins.
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