Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

Zhao, Bo; Zhang, Weidao; Duan, Yongchao; Lu, Yujie; Cun, Yixian; Li, Chaohui; Guo, Kun; Nie, Wei; Li, Lei; Zhang, Rugang; Zheng, Ping

doi:10.1016/j.stem.2015.03.017

Cited by 50 publications

(77 citation statements)

References 65 publications

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“…For example, the maternal effect gene Khdc3 (also known as FILIA) (Zheng and Dean, 2009) is among the top downregulated genes upon combined loss of Kdm4a/c in mESCs . Khdc3 is known to regulate genomic stability in mESCs (Zhao et al, 2015) and similar de-regulation in the oocyte could contribute to the developmental arrest we observe following Kdm4a deletion. Moreover, Csf2ra is expressed on the surface of early preimplantation embryos, where it promotes glucose transport and blastomere viability by binding to Csf2 secreted from the uterus (Robertson et al, 2001).…”

Section: Discussionmentioning

confidence: 80%

Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development

et al. 2017

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Regulation of chromatin composition through post-translational modifications of histones contributes to transcriptional regulation and is essential for many cellular processes, including differentiation and development. KDM4A (JMJD2A) is a lysine demethylase with specificity towards di- and tri-methylated lysine 9 and lysine 36 of histone H3 (H3K9me2/me3 and H3K36me2/me3). Here, we report that as a maternal factor plays a key role in embryo survival and is vital for female fertility. female mice ovulate normally with comparable fertilization but poor implantation rates, and cannot support healthy transplanted embryos to term. This is due to a role for Kdm4a in uterine function, where its loss causes reduced expression of key genes involved in ion transport, nutrient supply and cytokine signalling, which impact embryo survival. In addition, a significant proportion of Kdm4a-deficient oocytes displays a poor intrinsic ability to develop into blastocysts. These embryos cannot compete with healthy embryos for implantation , highlighting as a maternal effect gene. Thus, our study dissects an important dual role for maternal Kdm4a in determining faithful early embryonic development and the implantation process.

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Section: Discussionmentioning

confidence: 80%

Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development

et al. 2017

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“…To understand the molecular basis underlying the observed superior replication stress response in ESCs, we performed iPOND (isolate proteins on nascent DNA) [27] combined with an unbiased mass spectrometry analysis in three replicates to identify proteins that bind to replication forks in mESCs (Figure 2A). In one replicate we were able to detect an ESC-specific protein Filia, a protein that we had shown in a previous study to play critical roles in maintaining genome stability of mESCs by regulating DDR [11] (Supplementary information, Figure S2A). In addition, Filia interacts with Floped [28], which is also ESC specific (Supplementary information, Figure S2B).…”

Section: Identification Of Filia-floped As a Novel Esc-specific Replimentioning

confidence: 85%

“…To determine whether this newly discovered ESC-specific replication fork protein complex is implicated in the HU-induced DNA replication stress response, we investigated the influence of Filia or Floped deficiency on nascent DNA degradation, replication fork restart and new replication origin firing by DNA fiber analysis. Filia −/− ESCs, Filia −/− ESCs expressing FiliaS349A, a mutant that does not undergo nuclear import of Filia, and Filia −/− ESCs complemented with wild-type (WT) Filia have been previously established [11]. Floped −/− ESCs were generated from Floped mutant mice [28,29], and were complemented with Myc-Floped or Flag-Floped by stable transformation to establish Floped-rescued ESCs (Supplementary information, Figure S3A).…”

Section: Filia and Floped Function Synergistically To Promote Efficiementioning

confidence: 99%

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Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex

et al. 2017

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Pluripotent stem cells (PSCs) harbor constitutive DNA replication stress during their rapid proliferation and the consequent genome instability hampers their applications in regenerative medicine. It is therefore important to understand the regulatory mechanisms of replication stress response in PSCs. Here, we report that mouse embryonic stem cells (ESCs) are superior to differentiated cells in resolving replication stress. Specifically, ESCs utilize a unique Filia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks, therefore maintaining genomic stability. The ESC-specific Filia-Floped complex resides on replication forks under normal conditions. Replication stress stimulates their recruitment to stalling forks and the serine 151 residue of Filia is phosphorylated in an ATR-dependent manner. This modification enables the Filia-Floped complex to act as a functional scaffold, which then promotes the stalling fork restart through a dual mechanism: both enhancing recruitment of the replication fork restart protein, Blm, and stimulating ATR kinase activation. In the Blm pathway, the scaffolds recruit the E3 ubiquitin ligase, Trim25, to the stalled replication forks, and in turn Trim25 tethers and concentrates Blm at stalled replication forks through ubiquitination. In differentiated cells, the recruitment of the Trim25-Blm complex to replication forks and the activation of ATR signaling are much less robust due to lack of the ESC-specific Filia-Floped scaffold. Thus, our study reveals that ESCs utilize an additional and unique regulatory layer to efficiently promote the stalled fork restart and maintain genomic stability.

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“…Therefore, at least in human pluripotent stem cells, the CRISPR system can be regarded as a precise recognition machinery. Further study is required to shed light on whether immortalized cell lines have abnormal DNA repair pathways similar to cancer, or whether pluripotent stem cells equip a particular DNA repair mechanism to maintain genomic integrity, such as Zscan4 [76] or Filia genes [77]. …”

Section: Introductionmentioning

confidence: 99%

Genome Editing Gene Therapy for Duchenne Muscular Dystrophy

Hotta

2015

JND

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Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by loss of function of the dystrophin gene on the X chromosome. Gene augmentation of dystrophin is challenging due to the large size of the dystrophin cDNA. Emerging genome editing technologies, such as TALEN and CRISPR-Cas9 systems, open a new erain the restoration of functional dystrophin and are a hallmark of bona fide gene therapy. In this review, we summarize current genome editing approaches, properties of target cell types for ex vivo gene therapy, and perspectives of in vivo gene therapy including genome editing in human zygotes. Although technical challenges, such as efficacy, accuracy, and delivery of the genome editing components, remain to be further improved, yet genome editing technologies offer a new avenue for the gene therapy of DMD.

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Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

Cited by 50 publications

References 65 publications

Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development

Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development

Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex

Genome Editing Gene Therapy for Duchenne Muscular Dystrophy

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