Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Tahmasebi, Soroush; Jafarnejad, Seyed Mehdi; Tam, Ingrid S; Gonatopoulos-Pournatzis, Thomas; Matta‐Camacho, Edna; Tsukumo, Yoshinori; Yanagiya, Akiko; Li, Wencheng; Atlasi, Yaser; Caron, Maxime; Braunschweig, Ulrich; Pearl, Dana; Khoutorsky, Arkady; Gkogkas, Christos G.; Nadon, Robert; Bourque, Guillaume; Yang, Xiang-Jiao; Tian, Bin; Stunnenberg, Hendrik G.; Yamanaka, Yojiro; Blencowe, Benjamin J.; Giguère, Vincent; Sonenberg, Nahum

doi:10.1073/pnas.1615540113

Cited by 57 publications

(84 citation statements)

References 72 publications

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“…The appearance of YY2 may be due to the fact that the C-terminal binding domains of YY1 and YY2 are highly conserved. Indeed, ChIP-seq derived binding peaks of YY2 contained the YY1 motif at peak centers, indicating that YY2 binds similar regions and that there is an overlap of genes regulated by both TFs [45,46].…”

Section: Results On the Extended Feature Spacementioning

confidence: 99%

Integrative prediction of gene expression with chromatin accessibility and conformation data

Schmidt

Kern

Schulz

2019

Preprint

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Background: Enhancers play a fundamental role in orchestrating cell state and development. Although several methods have been developed to identify enhancers, linking them to their target genes is still an open problem. Several theories have been proposed on the functional mechanisms of enhancers, which triggered the development of various methods to infer promoter enhancer interactions (PEIs). The advancement of high-throughput techniques describing the three-dimensional organisation of the chromatin, paved the way to pinpoint long-range PEIs. Here we investigated whether including PEIs in computational models for the prediction of gene expression improves performance and interpretability. Results: We have extended our Tepic framework to include DNA contacts deduced from chromatin conformation capture experiments and compared various methods to determine PEIs using predictive modelling of gene expression from chromatin accessibility data and predicted transcription factor (TF) motif data. We found that including long-range PEIs deduced from both HiC and HiChIP data indeed improves model performance. We designed a novel machine learning approach that allows to prioritize TFs in distal loop and promoter regions with respect to their importance for gene expression regulation. Our analysis revealed a set of core TFs that are part of enhancer-promoter loops involving YY1 in different cell lines. Conclusion: We show that the integration of chromatin conformation data improves gene expression prediction, underlining the importance of enhancer looping for gene expression regulation. Our general approach can be used to prioritize TFs that are involved in distal and promoter-proximal regulation using accessibility, conformation and expression data.

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Section: Results On the Extended Feature Spacementioning

confidence: 99%

Integrative prediction of gene expression with chromatin accessibility and conformation data

Schmidt

Kern

Schulz

2019

Preprint

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“…It harbors 5 miRNAs: Has-miR-550a-3p, Has-miR-335-3p, Has-miR-571, Has-miR-377-3p, Has-miR-105-5p. Interestingly, a huge literature argues that several mRNA targets work in important phases of embryo development: SOCS and FOX targets are spatio-temporally regulated in the endometrium, reflecting the acquisition of receptivity, maternal recognition of pregnancy and implantation [288,289]; YY2 is one of the major regulators of mouse embryonic stem cell self-renewal and lineage commitment [290] as well as the RNA methyltransferases NSUN4 is enriched in mouse tissues during embryo development [291]. Interestingly, NANOS1 has an essential role in the central nervous system development [292].…”

Section: Spz-dependent Cernet Involved In Germ Cell Progression and Ementioning

confidence: 99%

Histone Post-Translational Modifications and CircRNAs in Mouse and Human Spermatozoa: Potential Epigenetic Marks to Assess Human Sperm Quality

Chioccarelli

Pierantoni

Manfrevola

et al. 2020

JCM

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Spermatozoa (SPZ) are motile cells, characterized by a cargo of epigenetic information including histone post-translational modifications (histone PTMs) and non-coding RNAs. Specific histone PTMs are present in developing germ cells, with a key role in spermatogenic events such as self-renewal and commitment of spermatogonia (SPG), meiotic recombination, nuclear condensation in spermatids (SPT). Nuclear condensation is related to chromatin remodeling events and requires a massive histone-to-protamine exchange. After this event a small percentage of chromatin is condensed by histones and SPZ contain nucleoprotamines and a small fraction of nucleohistone chromatin carrying a landascape of histone PTMs. Circular RNAs (circRNAs), a new class of non-coding RNAs, characterized by a nonlinear back-spliced junction, able to play as microRNA (miRNA) sponges, protein scaffolds and translation templates, have been recently characterized in both human and mouse SPZ. Since their abundance in eukaryote tissues, it is challenging to deepen their biological function, especially in the field of reproduction. Here we review the critical role of histone PTMs in male germ cells and the profile of circRNAs in mouse and human SPZ. Furthermore, we discuss their suggested role as novel epigenetic biomarkers to assess sperm quality and improve artificial insemination procedure.

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“…Although the role of YY1 in cardiomyocyte differentiation, cardiac development, and cardiomyopathy has been previously explored (Sucharov et al, 2003;Morikawa et al, 2013;Beketaev et al, 2015), studies of the involvement of YY2 in cardiovascular development and diseases have been limited, albeit that YY2 expression was detected in mouse hearts during both embryogenesis and postnatal stages (Drews et al, 2009). In a more recent study, it was revealed that the expression of YY2 induced by doxycycline promoted the differentiation of mouse embryonic stem cells into cardiovascular lineages (Tahmasebi et al, 2016), indicating an important role for YY2 in cardiac lineage commitment. In the present study, we found that the expression of YY2 induced by a-MHC-Cre, which was activated at ∼E9.0, caused partial prenatal lethality (i.e., after E16.5).…”

Section: Yy2 and Cardiomyopathymentioning

confidence: 99%

“…Our microarray analysis further confirmed that cell cycle genes were dysregulated in E14.5 dTg mouse hearts, as evidenced by the decreased pH3 staining in dTg hearts compared with control hearts. Given that YY2 depletion mediated by CRISPR/Cas9 caused peri-implantation lethality (Tahmasebi et al, 2016), we believe that YY2 plays a critical role in cell death and proliferation and that the level of YY2 should be tightly controlled during embryogenesis. Intriguingly, we did not observe any discernible cell cycle progression defect or increased apoptosis in CRISPR/Cas9-mediated YY2 knockout Hela cells.…”

Section: Yy2 and Cardiomyopathymentioning

confidence: 99%

“…Interestingly, YY2 has been shown to be constitutively expressed in the embryonic and adult hearts of mice (Drews et al, 2009). Furthermore, the overexpression of YY2 in mouse embryonic stem cells has been shown to drive the expression of cardiovascular genes (Tahmasebi et al, 2016). However, whether YY2 has a role in cardiac disease is not known.…”

Section: Introductionmentioning

confidence: 99%

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Contribution of Increased Expression of Yin Yang 2 to Development of Cardiomyopathy

Zhang

Beketaev²,

Segura³

et al. 2020

Front. Mol. Biosci.

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Yin Yang 2 (YY2) is a member of the Yin Yang family of transcription factors. Although the bioactivity of YY2 has been previously studied, its role in cardiovascular diseases is not known. We observed the increased expression of YY2 in failing human hearts compared with control hearts, raising the question of whether YY2 is involved in the pathogenesis of cardiomyopathy. To investigate the potential contribution of YY2 to the development of cardiomyopathy, we crossed two independent transgenic (Tg) mouse lines, pCAG-YY2-Tg+and alpha-myosin heavy chain-cre (α-MHC-Cre), to generate two independent double transgenic (dTg) mouse lines in which the conditional cardiomyocyte-specific expression of YY2 driven by the α-MHC promoter was mediated by Cre recombinase, starting at embryonic day 9.0. In dTg mice, we observed partial embryonic lethality and hearts with defective cardiomyocyte proliferation. Surviving dTg mice from both lines developed cardiomyopathy and heart failure that occurred with aging, showing different degrees of severity that were associated with the level of transgene expression. The development of cardiomyopathy was accompanied by increased levels of cardiac disease markers, apoptosis, and cardiac fibrosis. Our studies further revealed that the Cre-mediated cardiomyocyte-specific increase in YY2 expression led to increased levels of Beclin 1 and LC3II, indicating that YY2 is involved in mediating autophagic activity in mouse hearts in vivo. Also, compared with control hearts, dTg mouse hearts showed increased JNK activity. Because autophagy and JNK activity are important for maintaining cardiac homeostasis, the dysregulation of these signaling pathways may contribute to YY2-induced cardiomyopathy and heart failure in vivo.

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Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Cited by 57 publications

References 72 publications

Integrative prediction of gene expression with chromatin accessibility and conformation data

Integrative prediction of gene expression with chromatin accessibility and conformation data

Histone Post-Translational Modifications and CircRNAs in Mouse and Human Spermatozoa: Potential Epigenetic Marks to Assess Human Sperm Quality

Contribution of Increased Expression of Yin Yang 2 to Development of Cardiomyopathy

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