scholarly journals Epigenetic engineering shows that a human centromere resists silencing mediated by H3K27me3/K9me3

2016 ◽  
Vol 27 (1) ◽  
pp. 177-196 ◽  
Author(s):  
Nuno M. C. Martins ◽  
Jan H. Bergmann ◽  
Nobuaki Shono ◽  
Hiroshi Kimura ◽  
Vladimir Larionov ◽  
...  

Centromeres are characterized by the centromere-specific H3 variant CENP-A, which is embedded in chromatin with a pattern characteristic of active transcription that is required for centromere identity. It is unclear how centromeres remain transcriptionally active despite being flanked by repressive pericentric heterochromatin. To further understand centrochromatin’s response to repressive signals, we nucleated a Polycomb-like chromatin state within the centromere of a human artificial chromosome (HAC) by tethering the methyltransferase EZH2. This led to deposition of the H3K27me3 mark and PRC1 repressor binding. Surprisingly, this state did not abolish HAC centromere function or transcription, and this apparent resistance was not observed on a noncentromeric locus, where transcription was silenced. Directly tethering the reader/repressor PRC1 bypassed this resistance, inactivating the centromere. We observed analogous responses when tethering the heterochromatin Editor Suv39h1-methyltransferase domain (centromere resistance) or reader HP1α (centromere inactivation), respectively. Our results reveal that the HAC centromere can resist repressive pathways driven by H3K9me3/H3K27me3 and may help to explain how centromeres are able to resist inactivation by flanking heterochromatin.

Chromosoma ◽  
1998 ◽  
Vol 107 (6-7) ◽  
pp. 406-416 ◽  
Author(s):  
Hiroshi Masumoto ◽  
Masashi Ikeno ◽  
Megumi Nakano ◽  
Tuneko Okazaki ◽  
Brenda Grimes ◽  
...  

2020 ◽  
Vol 133 (14) ◽  
pp. jcs242610 ◽  
Author(s):  
Nuno M. C. Martins ◽  
Fernanda Cisneros-Soberanis ◽  
Elisa Pesenti ◽  
Natalia Y. Kochanova ◽  
Wei-Hao Shang ◽  
...  

ABSTRACTMost eukaryotic centromeres are located within heterochromatic regions. Paradoxically, heterochromatin can also antagonize de novo centromere formation, and some centromeres lack it altogether. In order to investigate the importance of heterochromatin at centromeres, we used epigenetic engineering of a synthetic alphoidtetO human artificial chromosome (HAC), to which chimeric proteins can be targeted. By tethering the JMJD2D demethylase (also known as KDM4D), we removed heterochromatin mark H3K9me3 (histone 3 lysine 9 trimethylation) specifically from the HAC centromere. This caused no short-term defects, but long-term tethering reduced HAC centromere protein levels and triggered HAC mis-segregation. However, centromeric CENP-A was maintained at a reduced level. Furthermore, HAC centromere function was compatible with an alternative low-H3K9me3, high-H3K27me3 chromatin signature, as long as residual levels of H3K9me3 remained. When JMJD2D was released from the HAC, H3K9me3 levels recovered over several days back to initial levels along with CENP-A and CENP-C centromere levels, and mitotic segregation fidelity. Our results suggest that a minimal level of heterochromatin is required to stabilize mitotic centromere function but not for maintaining centromere epigenetic memory, and that a homeostatic pathway maintains heterochromatin at centromeres.This article has an associated First Person interview with the first authors of the paper.


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