Structural Basis for EPC1-Mediated Recruitment of MBTD1 into the NuA4/TIP60 Acetyltransferase Complex

Devoucoux, Maëva; Song, Xiaosheng; Li, Li; Ayaz, Gamze; Cheng, Harry; Tempel, W.; Cheng, Dong; Loppnau, P.; Côté, Jacques; Min, Jinrong

doi:10.1016/j.celrep.2020.03.003

Cited by 18 publications

(16 citation statements)

References 35 publications

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“…The PHF1 fraction contained the core subunits EZH2, EED and SUZ12 of the PRC2 complex, as well as RBBP4 and the PRC2.1 specific PALI1. The EPC1(1-581) fraction contained all the subunits of NuA4/TIP60 complex except MBDT1, which was expected since it associates through an interaction with EPC1 C-terminus (aa644-672) (Jacquet et al 2016; Zhang et al 2020). Strikingly, the EPC1-PHF1 fraction contained subunits of both the TIP60 and PRC2.1 complexes.…”

Section: Resultsmentioning

confidence: 88%

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Sudarshan

Avvakumov

Lalonde

et al. 2021

Preprint

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Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with Endometrial Stromal Sarcomas (ESS) and Ossifying FibroMyxoid Tumors (OFMT) leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a co-activator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a mega-complex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome. These are linked to aberrant gene expression, in particular over an entire topologically-associated domain including part of the HOXD cluster. Furthermore, we show that JAZF1, implicated with PRC2 components in the most frequent translocations in ESS, is a potent transcription activator that physically associates with NuA4/TIP60. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas employ the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes leading to mislocalization of histone marks and aberrant polycomb target gene expression.

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Section: Resultsmentioning

confidence: 88%

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Sudarshan

Avvakumov

Lalonde

et al. 2021

Preprint

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“…The enhancer of polycomb homolog 1 ( EPC1 ) gene codes for a protein member of the polycomb group (PcG) family and is gene target of miR-381 ( Kozomara, Birgaoanu & Griffiths-Jones, 2019 ). The coded product of EPC1 is a part of the NuA4 (Nucleosome Acetyltransferase of H)/TIP60 (Tat Interacting Protein 60) acetyltransferase complex, which participates in several processes to repair DNA double strand breaks (DBSs) and apoptosis ( Zhang et al, 2020 ). Also, it has been reported that EPC1 acts as an oncogene in some types of cancer, such as acute myeloid leukemia (AML), since its suppression triggered apoptosis in cell lines ( Huang et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of miR-381-3p and miR-23b-3p in skeletal muscle could be a possible estimator of early post-mortem interval in rats

Martínez-Rivera

Cárdenas-Monroy

Millan-Catalan

et al. 2021

PeerJ

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Background The post-mortem interval (PMI) is the time elapsed since the dead of an individual until the body is found, which is relevant for forensic purposes. The miRNAs regulate the expression of some genes; and due to their small size, they can better support degradation, which makes them suitable for forensic analysis. In the present work, we evaluated the gene expression of miR-381-3p, miR-23b-3p, and miR-144-3p in skeletal muscle in a murine model at the early PMI. Methods We designed a rat model to evaluate the early PMI under controlled conditions. This model consisted in 25 rats divided into five groups of rats, that correspond to the 0, 3, 6, 12 and 24 hours of PMI. The 0 h-PMI was considered as the control group. Muscle samples were taken from each rat to analyze the expression of miR-381-3p, miR-23b-3p, and miR-144-3p by quantitative RT-PCR. The gene expression of each miRNA was expressed as Fold Change (FC) and compared among groups. To find the targets of these miRNAs and the pathways where they participate, we performed an in-silico analysis. From the gene targets of miR-381-3p identified in the silico analysis, the EPC1 gene was selected for gene expression analysis by quantitative RT-PCR in these samples. Also, to evaluate if miR-381-3p could predict the early PMI, a mixed effects model was calculated using its gene expression. Results An upregulation of miR-381-3p was found at 24 h-PMI compared with the control group of 0 h-PMI and (FC = 1.02 vs. FC = 1.96; p = 0.0079). This was the opposite for miR-23b-3p, which had a down-regulation at 24 h-PMI compared to 0 h-PMI (FC = 1.22 vs. FC = 0.13; p = 0.0079). Moreover, the gene expression of miR-381-3p increased throughout the first 24 h of PMI, contrary to miR-23b-3p. The targets of these two miRNAs, participate in biological pathways related to hypoxia, apoptosis, and RNA metabolism. The gene expression of EPC1 was found downregulated at 3 and 12 h of PMI, whereas it remained unchanged at 6 h and 24 h of PMI. Using a multivariate analysis, it was possible to predict the FC of miR-381-3p of all but 6 h-PMI analyzed PMIs. Discussion The present results suggest that miR-23b-3p and miR-381-3p participate at the early PMI, probably regulating the expression of some genes related to the autolysis process as EPC1 gene. Although the miR-381-3p gene expression is a potential estimator of PMI, further studies will be required to obtain better estimates.

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“…The enhancer of polycomb homolog 1 (EPC1) gene codes for a protein member of the polycomb group (PcG) family and is gene target of miR-381 (Kozomara, Birgaoanu & Griffiths-Jones, 2019). The coded product of EPC1 is a part of the NuA4 (Nucleosome Acetyltransferase of H)/TIP60 (Tat Interacting Protein 60) acetyltransferase complex, which participate in several processes to repair DNA double strand breaks (DBSs) and apoptosis (Zhang et al, 2020). Also, it has been reported that EPC1 acts as an oncogene in some types of cancer, such as acute myeloid leukemia (AML), since its suppression triggered PeerJ reviewing PDF | (2020:08:51757:1:1:NEW 10 Feb 2021)…”

Section: Manuscript To Be Reviewedmentioning

confidence: 99%

Peer Review #2 of "Dysregulation of miR-381-3p and miR-23b-3p in skeletal muscle could be a possible estimator of early post-mortem interval in rats (v0.1)"

2021

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Structural Basis for EPC1-Mediated Recruitment of MBTD1 into the NuA4/TIP60 Acetyltransferase Complex

Abstract: Highlights d The crystal structure of EPC1 bound to MBTD1 is determined d MBTD1 employs two distinct regions to recognize H4K20me and EPC1 d Mutations at the MBTD1-EPC1 interface affect gene expression and DNA repair

Cited by 18 publications

References 35 publications

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Dysregulation of miR-381-3p and miR-23b-3p in skeletal muscle could be a possible estimator of early post-mortem interval in rats

Peer Review #2 of "Dysregulation of miR-381-3p and miR-23b-3p in skeletal muscle could be a possible estimator of early post-mortem interval in rats (v0.1)"

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