Transcriptional Activation of Pericentromeric Satellite Repeats and Disruption of Centromeric Clustering upon Proteasome Inhibition

Natisvili, Theona; Yandım, Cihangir; Silva, Raquel S.; Emanuelli, Giulia; Krueger, Felix; Nageshwaran, Sathiji; Festenstein, Richard

doi:10.1371/journal.pone.0165873

Cited by 7 publications

(5 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Satellites are mostly associated with heterochromatin [80, 81] and it is known that the heterochromatic histone mark H3K9 methylation gets passively diluted during the first two cell divisions after fertilisation as mentioned above [8, 13]. This could be one of the possible reasons behind the obvious global increase in satellite expression at the 4-cell stage.…”

Section: Discussionmentioning

confidence: 99%

Expression dynamics of repetitive DNA in early human embryonic development

Yandım

Karakülah

2019

BMC Genomics

View full text Add to dashboard Cite

Background The last decade witnessed a number of genome-wide studies on human pre-implantation, which mostly focused on genes and provided only limited information on repeats, excluding the satellites. Considering the fact that repeats constitute a large portion of our genome with reported links to human physiology and disease, a thorough understanding of their spatiotemporal regulation during human embryogenesis will give invaluable clues on chromatin dynamics across time and space. Therefore, we performed a detailed expression analysis of all repetitive DNA elements including the satellites across stages of human pre-implantation and embryonic stem cells. Results We uncovered stage-specific expressions of more than a thousand repeat elements whose expressions fluctuated with a mild global decrease at the blastocyst stage. Most satellites were highly expressed at the 4-cell level and expressions of ACRO1 and D20S16 specifically peaked at this point. Whereas all members of the SVA elements were highly upregulated at 8-cell and morula stages, other transposons and small RNA repeats exhibited a high level of variation among their specific subtypes. Our repeat enrichment analysis in gene promoters coupled with expression correlations highlighted potential links between repeat expressions and nearby genes, emphasising mostly 8-cell and morula specific genes together with SVA_D, LTR5_Hs and LTR70 transposons. The DNA methylation analysis further complemented the understanding on the mechanistic aspects of the repeatome’s regulation per se and revealed critical stages where DNA methylation levels are negatively correlating with repeat expression. Conclusions Taken together, our study shows that specific expression patterns are not exclusive to genes and long non-coding RNAs but the repeatome also exhibits an intriguingly dynamic pattern at the global scale. Repeats identified in this study; particularly satellites, which were historically associated with heterochromatin, and those with potential links to nearby gene expression provide valuable insights into the understanding of key events in genomic regulation and warrant further research in epigenetics, genomics and developmental biology. Electronic supplementary material The online version of this article (10.1186/s12864-019-5803-1) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression dynamics of repetitive DNA in early human embryonic development

Yandım

Karakülah

2019

BMC Genomics

View full text Add to dashboard Cite

show abstract

“…In addition, developmentally regulated genes in Drosophila can be transcribed in the absence of H3K4me3 and H3K36me3 (Perez-Lluch et al, 2015) while essentially normal transcriptional regulation in that organism can occur in the complete absence of H3K4 methylation (Hodl and Basler, 2012). In mouse, major satellite repeat genes are transcriptionally induced in response to proteasome inhibition in the absence of changes in either repressing or activating marks (Natisvili et al, 2016). Activation of heterochromatic transcription, at least in certain cases, can be attributed to the co-occupancy of gene-specific transcription factors and pioneer factors with repressive chromatin (Sekinger and Gross, 1999; Sekinger and Gross, 2001; Chen and Widom, 2005; Perez-Lluch et al, 2015; Bondra and Rine, 2023).…”

Section: Introductionmentioning

confidence: 99%

A critical role for Pol II CTD phosphorylation in heterochromatic gene activation

Kainth,

Zhang,

Gross

2024

Preprint

View full text Add to dashboard Cite

How gene activation works in heterochromatin, and how the mechanism might differ from the one used in euchromatin, has been largely unexplored. Previous work has shown that in SIR-regulated heterochromatin of Saccharomyces cerevisiae, gene activation occurs in the absence of covalent histone modifications and other alterations of chromatin commonly associated with transcription. Here we demonstrate that such activation occurs in a substantial fraction of cells, and this raises the possibility that an alternative activation pathway might be used. We address one such possibility, Pol II CTD phosphorylation, and explore this idea using a natural telomere-linked gene, YFR057w, as a model. Unlike covalent histone modifications, CTD phosphorylation at Ser2, Ser5 and Ser7 is abundant at the drug-induced heterochromatic gene. Particularly enriched relative to the euchromatic state is Ser2 phosphorylation. Consistent with a functional role for Ser2P, YFR057w is negligibly activated in cells deficient in the Ser2 CTD kinases Ctk1 and Bur1 even though the gene is strongly stimulated in ctk1Δ bur1 cells when it is placed in a euchromatic context. Collectively, our results are consistent with a critical role for Ser2 CTD phosphorylation in driving Pol II recruitment and transcription of a natural heterochromatic gene - an activity that may help supplant the need for histone epigenetic modifications.

show abstract

“…Outside of genes, the proteasome has also been shown to occupy specialized chromosomal domains like centromeric regions [ 7 ]. In most eukaryotic species studied to date, centromeric DNA consists of large arrays of repetitive elements, termed satellite repeats, which provide a platform for the assembly of the kinetochore, the protein complex involved in the attachment of chromosomes to the mitotic spindle [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…This includes centromeric and pericentromeric satellites in cancer cells [ 18 ], pericentromeric Sat III in stress conditions [ 19 ], and mouse minor satellites upon DNA damage [ 20 ]. Accumulation of pericentromeric satellite repeats has also been observed upon inhibition of the proteasome [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibition alters mitotic progression through the upregulation of centromeric α‐Satellite RNAs

et al. 2021

View full text Add to dashboard Cite

Cell cycle progression requires control of the abundance of several proteins and RNAs over space and time to properly transit from one phase to the next and to ensure faithful genomic inheritance in daughter cells. The proteasome, the main protein degradation system of the cell, facilitates the establishment of a proteome specific to each phase of the cell cycle. Its activity also strongly influences transcription. Here, we detected the upregulation of repetitive RNAs upon proteasome inhibition in human cancer cells using RNA‐seq. The effect of proteasome inhibition on centromeres was remarkable, especially on α‐Satellite RNAs. We showed that α‐Satellite RNAs fluctuate along the cell cycle and interact with members of the cohesin ring, suggesting that these transcripts may take part in the regulation of mitotic progression. Next, we forced exogenous overexpression and used gapmer oligonucleotide targeting to demonstrate that α‐Sat RNAs have regulatory roles in mitosis. Finally, we explored the transcriptional regulation of α‐Satellite DNA. Through in silico analyses, we detected the presence of CCAAT transcription factor‐binding motifs within α‐Satellite centromeric arrays. Using high‐resolution three‐dimensional immuno‐FISH and ChIP‐qPCR, we showed an association between the α‐Satellite upregulation and the recruitment of the transcription factor NFY‐A to the centromere upon MG132‐induced proteasome inhibition. Together, our results show that the proteasome controls α‐Satellite RNAs associated with the regulation of mitosis.

show abstract

Transcriptional Activation of Pericentromeric Satellite Repeats and Disruption of Centromeric Clustering upon Proteasome Inhibition

Cited by 7 publications

References 79 publications

Expression dynamics of repetitive DNA in early human embryonic development

Expression dynamics of repetitive DNA in early human embryonic development

A critical role for Pol II CTD phosphorylation in heterochromatic gene activation

Proteasome inhibition alters mitotic progression through the upregulation of centromeric α‐Satellite RNAs

Contact Info

Product

Resources

About