Browsing by Subject "telomeres"
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Item The histone methyltransferases Set5 and Set1 have overlapping functions in gene silencing and telomere maintenance(Taylor & Francis, 2016-12-02) Jezek, Meagan; Gast, Alison; Choi, Grace; Kulkarni, Rushmie; Quijote, Jeremiah; Graham-Yooll, Andrew; Park, DoHwan; Green, ErinGenes adjacent to telomeres are subject to transcriptional repression mediated by an integrated set of chromatin modifying and remodeling factors. The telomeres of Saccharomyces cerevisiae have served as a model for dissecting the function of diverse chromatin proteins in gene silencing, and their study has revealed overlapping roles for many chromatin proteins in either promoting or antagonizing gene repression. The H3K4 methyltransferase Set1, which is commonly linked to transcriptional activation, has been implicated in telomere silencing. Set5 is an H4 K5, K8, and K12 methyltransferase that functions with Set1 to promote repression at telomeres. Here, we analyzed the combined role for Set1 and Set5 in gene expression control at native yeast telomeres. Our data reveal that Set1 and Set5 promote a Sir protein-independent mechanism of repression that may primarily rely on regulation of H4K5ac and H4K8ac at telomeric regions. Furthermore, cells lacking both Set1 and Set5 have highly correlated transcriptomes to mutants in telomere maintenance pathways and display defects in telomere stability, linking their roles in silencing to protection of telomeres. Our data therefore provide insight into and clarify potential mechanisms by which Set1 contributes to telomere silencing and shed light on the function of Set5 at telomeres.Item Histone Modifications and the Maintenance of Telomere Integrity(MDPI, 2019-02-25) Jezek, Meagan; Green, Erin M.Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. The integrity of telomeres is maintained by a coordinated network of proteins and RNAs, such as the telomerase holoenzyme and protective proteins that prevent the recognition of the telomere ends as a DNA double-strand breaks. The structure of chromatin at telomeres and within adjacent subtelomeres has been implicated in telomere maintenance pathways in model systems and humans. Specific post-translational modifications of histones, including methylation, acetylation, and ubiquitination, have been shown to be necessary for maintaining a chromatin environment that promotes telomere integrity. Here we review the current knowledge regarding the role of histone modifications in maintaining telomeric and subtelomeric chromatin, discuss the implications of histone modification marks as they relate to human disease, and highlight key areas for future research.Item Investigating the regulation of the chromatin landscape by Set4 in Saccharomyces cerevisiae(2020-01-20) Jethmalani, Yogita; Green, Erin M; Biological Sciences; Biological SciencesThe regulation of chromatin is important for transcription, DNA replication and DNA damage repair. In the presence of environmental stress, the cell mounts stress response pathways that involve changes in chromatin structure to promote cell survival. Set4 belongs to the Set3 subfamily of SET domain-containing proteins in yeast. Other members of this subfamily are budding yeast Set3, Drosophila melanogaster UpSET and the mammalian proteins MLL5 and SETD5. The defining features of this subfamily are the presence of a divergent SET domain and the presence of a PHD finger, with the exception of SETD5. Set4'sparalog, Set3 has been shown to work in a complex and catalyze histone deacetylation leading to gene repression through binding H3K4 methylation via its PHD finger. Set4 shares sequence similarity to fly UpSET and human MLL5, however, little is known about the biochemical or biological roles of Set4. We have shown a role for Set4 in promoting cell survival during oxidative stress by contributing to stress response gene expression programs. We also determined that Set4 regulates genes enriched near telomeres under normal and stress conditions. We also found that deleting Set4 disrupts the histone deacetylase complex occupancy at telomeres, thereby leading to changes in the chromatin landscape. Similar to other members of the Set3 subfamily, Set4 does not possess methyltransferase activity due to the inactive SET domain, therefore we hypothesize that it functions through directing other chromatin regulators, including histone deacetylases, to chromatin. Set4 has a PHD finger as well and we found that although other PHD fingers generally bind to methylated lysines on histone tails, Set4'sPHD finger does not bind to histones. However, we did find that Set4'sPHD finger is important for its chromatin localization and binds to nucleic acids in vitro. This suggests that Set4 may regulate gene expression through a mechanism independent of histone methylation. This work has defined a role for Set4 as a regulator of the telomeric chromatin landscape by working in conjunction with histone deacetylases and as a calibrator of stress defense pathways. The study of Set4 has expanded our understanding of the Set3 subfamily of SET domain-containing proteins in gene expression control during environmental stress response.Item Investigation of the mechanism of Set1-mediated telomere silencing and maintenance in Saccharomyces cerevisiae(2021-01-01) Jezek, Meagan; Green, Erin M; Biological Sciences; Biological SciencesMaintenance of telomeres, the transcriptionally silent nucleoprotein structures found at the ends of linear chromosomes, is necessary for genomic integrity. Altered telomere dynamics are associated with genomic instability and implicated in cellular aging and many types of cancer. Dysregulation of the chromatin structure at or adjacent to these protective caps can lead to dysfunctional telomeres. A number of proteins are involved in chromatin formation and maintenance. The enzyme Set1 is a lysine methyltransferase known to regulate chromatin dynamics through its modification of histone H3. Loss of Set1 is associated with defects in telomere silencing and maintenance, although the mechanism by which Set1 regulates telomeres is still unclear. The goal of this project was to further characterize the role Set1 plays at telomeres and elucidate the mechanisms underlying its functions in telomere silencing and maintenance. This has been done by assessing the catalytic and non-catalytic functions of Set1 at telomeres, and investigating its interactions with known telomere maintenance pathways. We have found that telomere maintenance by Set1 has H3K4 methylation dependent and independent components. We have also found that Set1-dependent telomere regulation is independent of the Sir complex, and instead likely dependent on regulation of CST (Cdc13-Stn1-Ten1) and telomerase by Set1. This information contributes to a more complete and comprehensive understanding of regulation of telomere integrity, which could play a vital role in the research into cellular aging and disease associated with abnormal gene regulation.Item Set5 and Set1 cooperate to repress gene expression at telomeres and retrotransposons(Taylor & Francis, 2014-01-17) Martín, Glòria Mas; King, Devin A; Green, Erin; Garcia-Nieto, Pablo E; Alexander, Richard; Collins, Sean R; Krogan, Nevan J; Gozani, Or P; Morrison, Ashby JA complex interplay between multiple chromatin modifiers is critical for cells to regulate chromatin structure and accessibility during essential DNA-templated processes such as transcription. However, the coordinated activities of these chromatin modifiers in the regulation of gene expression are not fully understood. We previously determined that the budding yeast histone H4 methyltransferase Set5 functions together with Set1, the H3K4 methyltransferase, in specific cellular contexts. Here, we sought to understand the relationship between these evolutionarily conserved enzymes in the regulation of gene expression. We generated a comprehensive genetic interaction map of the functionally uncharacterized Set5 methyltransferase and expanded the existing genetic interactome of the global chromatin modifier Set1, revealing functional overlap of the two enzymes in chromatin-related networks, such as transcription. Furthermore, gene expression profiling via RNA-Seq revealed an unexpected synergistic role of Set1 and Set5 in repressing transcription of Ty transposable elements and genes located in subtelomeric regions. This study uncovers novel pathways in which the methyltransferase Set5 participates and, more importantly, reveals a partnership between Set1 and Set5 in transcriptional repression near repetitive DNA elements in budding yeast. Together, our results define a new functional relationship between histone H3 and H4 methyltransferases, whose combined activity may be implicated in preserving genomic integrity.