EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent

Ai, Shanshan; Peng, Yong; Li, Chen; Gu, Fei; Yu, Xianhong; Yue, Yanzhu; Ma, Qing; Chen, Jinghai; Lin, Zhiqiang; Zhou, Pingzhu; Xie, Huafeng; Prendiville, Terence; Zheng, Wen; Liu, Yuli; Orkin, Stuart H.; Wang, Dazhi; Yu, Jia; Pu, William T.; He, Aibin

doi:10.7554/elife.24570

Cited by 43 publications

(41 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, our results highlight a noncanonical, enzymatically independent mode of action of both PRC1 and PRC2 during HCMV infection. These noncatalytic functions have been reported previously in the field of oncology, especially for EZH2 but also for EED, RING1B, and BMI1 (49)(50)(51)(52)(53)(54)(55).…”

Section: Discussionsupporting

confidence: 81%

A Noncanonical Function of Polycomb Repressive Complexes Promotes Human Cytomegalovirus Lytic DNA Replication and Serves as a Novel Cellular Target for Antiviral Intervention

Svrlanska

Reichel²,

Schilling³

et al. 2019

J Virol

View full text Add to dashboard Cite

Chromatin-based modifications of herpesviral genomes play a crucial role in dictating the outcome of infection. Consistent with this, host cell multiprotein complexes, such as polycomb repressive complexes (PRCs), were proposed to act as epigenetic regulators of herpesviral latency. In particular, PRC2 has recently been shown to contribute to the silencing of human cytomegalovirus (HCMV) genomes. Here, we identify a novel proviral role of PRC1 and PRC2, the two main polycomb repressive complexes, during productive HCMV infection. Western blot analyses revealed strong HCMV-mediated upregulation of RING finger protein 1B (RING1B) and B lymphoma Moloney murine leukemia virus insertion region 1 homolog (BMI1) as well as of enhancer of zeste homolog 2 (EZH2), suppressor of zeste 12 (SUZ12), and embryonic ectoderm development (EED), which constitute the core components of PRC1 and PRC2, respectively. Furthermore, we observed a relocalization of PRC components to viral replication compartments, whereas histone modifications conferred by the respective PRCs were specifically excluded from these sites. Depletion of individual PRC1/PRC2 proteins by RNA interference resulted in a significant reduction of newly synthesized viral genomes and, in consequence, a decreased release of viral particles. Furthermore, accelerated native isolation of protein on nascent DNA (aniPOND) revealed a physical association of EZH2 and BMI1 with nascent HCMV DNA, suggesting a direct contribution of PRC proteins to viral DNA replication. Strikingly, substances solely inhibiting the enzymatic activity of PRC1/2 did not exert antiviral effects, while drugs affecting the abundance of PRC core components strongly compromised HCMV genome synthesis and particle release. Taken together, our data reveal an enzymatically independent, noncanonical function of both PRC1 and PRC2 during HCMV DNA replication, which may serve as a novel cellular target for antiviral therapy. IMPORTANCE Polycomb group (PcG) proteins are primarily known as transcriptional repressors that modify chromatin and contribute to the establishment and maintenance of cell fates. Furthermore, emerging evidence indicates that overexpression of PcG proteins in various types of cancers contributes to the dysregulation of cellular proliferation. Consequently, several inhibitors targeting PcG proteins are presently undergoing preclinical and clinical evaluation. Here, we show that infection with human cytomegalovirus also induces a strong upregulation of several PcG proteins. Our data suggest that viral DNA replication depends on a noncanonical function of polycomb repressor complexes which is independent of the so-far-described enzymatic activities of individual PcG factors. Importantly, we observe that a subclass of inhibitory drugs that affect the abundance of PcG proteins strongly interferes with viral replication. This principle may serve as a novel promising target for antiviral treatment. Citation Svrlanska A, Reichel A, Schilling E-M, Scherer M, Stamminger T, Reuter N. 2019. A noncano...

show abstract

Section: Discussionsupporting

confidence: 81%

A Noncanonical Function of Polycomb Repressive Complexes Promotes Human Cytomegalovirus Lytic DNA Replication and Serves as a Novel Cellular Target for Antiviral Intervention

Svrlanska

Reichel²,

Schilling³

et al. 2019

J Virol

View full text Add to dashboard Cite

show abstract

“…The Bio- Hoxb5 pro-pre-B cells were cultured in vitro for three days prior to collection for streptavidin-mediated chromatin precipitation using a protocol described previously 53 , 54 . Briefly, eight million sorted GFP + Bio- Hoxb5 pro-pre-B cells were fixed with 1% formaldehyde in culture medium for 12 min at room temperature followed by quenching with 0.125M glycine for 5min.…”

Section: Methodsmentioning

confidence: 99%

Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes

Zhang

Dong

et al. 2018

Nat Immunol

Self Cite

View full text Add to dashboard Cite

Deletion of B cell master regulators reprogrammed B cells into T cells that were either functional defects or tumorigenic potential. Here we show that Hoxb5, which is expressed in uncommitted hematopoietic progenitors but absent in committed B and T lineages, could reprogram pro-pre-B cells into functional early T cell progenitors. The reprogramming started in bone marrow and completed in thymus, giving rise to T lymphocytes with transcriptomes, hierarchical differentiation, tissue distribution and immune functions closely resembling their natural counterparts. Hoxb5 repressed B cell master genes, activated T cell regulators and regulated crucial chromatin modifiers in pro-pre-B cells, ultimately driving B to T cell fate conversion. Our results provide a de novo paradigm for generating normal and functional T cells through reprogramming in vivo.

show abstract

“…These proteins have been shown to be involved in gene silencing independent of H3K27me3. For example, Eed interacts with histone deacetylases and enhances their catalytic activity (Ai et al ., ). Thus, the full effects of miR‐101a‐3p overexpression may be mediated by repression of multiple functions of the PRC2.…”

Section: Discussionmentioning

confidence: 97%

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

Cohen

Jackson

Ballestas

et al. 2017

Eur J of Neuroscience

View full text Add to dashboard Cite

A greater understanding of neural mechanisms that contribute to anxiety is needed in order to develop better therapeutic interventions. The current study interrogates a novel molecular mechanism that shapes anxiety-like behavior, demonstrating that the microRNA miR-101a-3p and its target, enhancer of zeste homolog 2 (Ezh2) in the amygdala, contribute to rodent anxiety-like behavior. We utilized rats that were selectively-bred for differences in emotionality and stress reactivity, showing that high novelty responding (HR) rats, which display low trait anxiety, have lower miR-101a-3p levels in the amygdala compared to low novelty responding (LR) rats that characteristically display high trait anxiety. To determine if there is a causal relationship between amygdalar miR-101a-3p and anxiety behavior, we used a viral approach to over-express miR-101a-3p in the amygdala of HR rats and test whether it would increase their typically low levels of anxiety-like behavior. We found that increasing miR-101a-3p in the amygdala increased HRs’ anxiety-like behavior in the open field test and elevated plus maze. Viral-mediated miR-101a-3p over-expression also reduced expression of the histone methyltransferase Ezh2, which mediates gene silencing via tri-methylation of histone 3 at lysine 27 (H3K27me3). Knockdown of Ezh2 with short-interfering RNA (siRNA) also increased HRs’ anxiety-like behavior, but to a lesser degree than miR-101a-3p over-expression. Overall our data demonstrate that increasing miR-101a-3p expression in the amygdala increases anxiety-like behavior and that this effect is at least partially mediated via repression of Ezh2. This work adds to the growing body of evidence implicating miRNAs and epigenetic regulation as molecular mediators of anxiety behavior.

show abstract

EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent

Cited by 43 publications

References 61 publications

A Noncanonical Function of Polycomb Repressive Complexes Promotes Human Cytomegalovirus Lytic DNA Replication and Serves as a Novel Cellular Target for Antiviral Intervention

A Noncanonical Function of Polycomb Repressive Complexes Promotes Human Cytomegalovirus Lytic DNA Replication and Serves as a Novel Cellular Target for Antiviral Intervention

Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

Contact Info

Product

Resources

About