scholarly journals DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency

2019 ◽  
Author(s):  
Katy A McLaughlin ◽  
Ilya M Flyamer ◽  
John P Thomson ◽  
Heidi K Mjoseng ◽  
Ruchi Shukla ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Gene Regulation ◽  
Ground State ◽  
Embryonic Stem ◽  
Genome Organisation ◽  
Dna Hypomethylation ◽  
3D Genome ◽  
And Function

The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in 2i conditions results in redistribution of polycomb (H3K27me3) away from its target loci. Here we demonstrate that 3D genome organisation is also altered in 2i. We found chromatin decompaction at polycomb target loci as well as loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground-state, we are able to restore the H3K27me3 distribution, and polycomb-mediated 3D genome organisation that is characteristic of primed ESCs grown in serum, to ESCs in 2i. However, these cells retain the functional characteristics of 2i ground state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organisation but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.

scholarly journals The Role of RNA Methylation in Regulating Stem Cell Fate and Function-Focus on m6A

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Weiwei Sun ◽  
Bin Zhang ◽  
Qingli Bie ◽  
Na Ma ◽  
Na Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Adult Stem Cells ◽  
Embryonic Stem ◽  
Biological Role ◽  
Rna Methylation ◽  
Induced Pluripotent ◽  
And Function

The biological role of RNA methylation in stem cells has attracted increasing attention. Recent studies have demonstrated that RNA methylation plays a crucial role in self-renewal, differentiation, and tumorigenicity of stem cells. In this review, we focus on the biological role of RNA methylation modifications including N6-methyladenosine, 5-methylcytosine, and uridylation in embryonic stem cells, adult stem cells, induced pluripotent stem cells, and cancer stem cells, so as to provide new insights into the potential innovative treatments of cancer or other complex diseases.

scholarly journals Relaxed 3D genome conformation facilitates the pluripotent to totipotent state transition in embryonic stem cells

2020 ◽  
Author(s):  
Jiali Yu ◽  
Yezhang Zhu ◽  
Jiahui Gu ◽  
Chaoran Xue ◽  
Long Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Genome Organization ◽  
Critical Role ◽  
Embryonic Stem ◽  
List Type ◽  
Down Regulation ◽  
Chromatin Loops ◽  
3D Genome

SUMMARYThe 3D genome organization is crucial for gene regulation. Although recent studies have revealed a uniquely relaxed genome conformation in totipotent early blastmeres of both fertilized and cloned embryos, how weakened higher-order chromatin structure is functionally linked to totipotency acquisition remains elusive. Using low-input Hi-C, ATAC-seq, and ChIP-seq, we systematically examined the dynamics of 3D genome and epigenome during pluripotency-to-totipotency transition in mouse embryonic stem cells (ESCs). The totipotent 2-cell-embro-like cells (2CLCs) exhibit more relaxed chromatin architecture compared to ESCs, including global weakening of both enhancer-promoter interactions and TAD insulation. While the former leads to inactivation of ESC enhancers and down-regulation of pluripotent genes, the latter may facilitate contacts between the new enhancers arising in 2CLCs and neighboring 2C genes. Importantly, disruption of chromatin loops by depleting CTCF or cohesin promotes ESC to 2CLC transition. Our results thus establish a critical role of 3D genome organization in totipotency acquisition.HIGHLIGHTSGlobal weakening of the 3D genome conformation during ESC to 2CLC transitionLoss of enhancer-promoter loops and down-regulation of pluripotent genes in 2CLCsInactivation of ESC enhancers and formation of new enhancers in 2CLCsDisruption of chromatin loops by depleting CTCF or cohesin promotes 2CLC emergence

scholarly journals DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

2020 ◽  
Author(s):  
Qian Du ◽  
Grady C. Smith ◽  
Phuc Loi Luu ◽  
James M. Ferguson ◽  
Nicola J. Armstrong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Replication ◽  
Replication Timing ◽  
Genome Architecture ◽  
Genome Organisation ◽  
Dna Hypomethylation ◽  
3D Genome ◽  
Timing Precision ◽  
The Impact ◽  
Dna Replication Timing

AbstractDNA replication timing and three-dimensional (3D) genome organisation occur across large domains associated with distinct epigenome patterns to functionally compartmentalise genome regulation. However, it is still unclear if alternations in the epigenome, in particular cancer-related DNA hypomethylation, can directly result in alterations to cancer higher order genome architecture. Here, we use Hi-C and single cell Repli-Seq, in the colorectal cancer DNMT1 and DNMT3B DNA methyltransferases double knockout model, to determine the impact of DNA hypomethylation on replication timing and 3D genome organisation. First, we find that the hypomethylated cells show a striking loss of replication timing precision with gain of cell-to-cell replication timing heterogeneity and loss of 3D genome compartmentalisation. Second, hypomethylated regions that undergo a large change in replication timing also show loss of allelic replication timing, including at cancer-related genes. Finally, we observe the formation of broad ectopic H3K4me3-H3K9me3 domains across hypomethylated regions where late replication is maintained, that potentially prevent aberrant transcription and loss of genome organisation after DNA demethylation. Together, our results highlight a previously underappreciated role for DNA methylation in maintenance of 3D genome architecture.

scholarly journals Impact of DNA methylation on 3D genome structure

2020 ◽  
Author(s):  
Diana Buitrago ◽  
Mireia Labrador ◽  
Juan Pablo Arcon ◽  
Rafael Lema ◽  
Oscar Flores ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Chromatin Structure ◽  
Chromatin Condensation ◽  
Genome Structure ◽  
Model System ◽  
Structure And Function ◽  
3D Genome ◽  
And Function

Abstract The extreme complexity of epigenetic regulation in higher organisms makes the determination of the intrinsic effect of DNA methylation in chromatin structure and function challenging. We investigated the role of DNA methylation in a simpler model system, budding yeast (Saccharomyces cerevisiae), an organism in which methylation-related machinery is normally absent thus making it a perfect model system to study the intrinsic role of methylation in chromatin structure and function. With this aim, we expressed the murine DNA Methyl Transferases in S. cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. We showed that despite the lack of machinery for positioning and reading of methylation marks, the methylation pattern follows a conserved pattern, the level of DNA methylation being very low at the 5’ end of the gene, and then increasing gradually toward the 3’ end, mimicking mammalian behavior. DNA methylation and gene expression correlate as DNA methylation is lower at the TSS and higher at the TTS in highly expressed genes compared to lowly expressed ones, mimicking again mammalian behavior. We found that methylated DNA is unlikely to be wrapped around nucleosomes, but is concentrated in linkers and nucleosome free regions. DNA methylation increases chromatin condensation in the peri-centromeric region, decreases overall DNA flexibility and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.

scholarly journals SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells

2017 ◽  
Author(s):  
Özgen Deniz ◽  
Lorenzo de la Rica ◽  
Kevin C. L. Cheng ◽  
Dominik Spensberger ◽  
Miguel R. Branco
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Endogenous Retroviruses ◽  
Preimplantation Embryos ◽  
Dependent Manner ◽  
Epigenetic Mechanisms

BackgroundEndogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET- dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos.ResultsWe used naïve ESCs to investigate the role of SETDB1 in ERV regulation and, in particular, its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We found that, in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, however, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these transposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming.ConclusionsOur results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation.

scholarly journals The role of nucleotide excision repair in protecting embryonic stem cells from genotoxic effects of UV-induced DNA damage

1999 ◽  
Vol 27 (16) ◽  
pp. 3276-3282 ◽  
Author(s):  
P. P. H. Van Sloun ◽  
J. G. Jansen ◽  
G. Weeda ◽  
L. H. F. Mullenders ◽  
A. A. van Zeeland ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Embryonic Stem ◽  
Genotoxic Effects ◽  
Nucleotide Excision

scholarly journals Modulation of Differentiation of Embryonic Stem Cells by Polypyrrole: The Impact on Neurogenesis

2021 ◽  
Vol 22 (2) ◽  
pp. 501
Author(s):  
Kateřina Skopalová ◽  
Katarzyna Anna Radaszkiewicz ◽  
Věra Kašpárková ◽  
Jaroslav Stejskal ◽  
Patrycja Bober ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Active Role ◽  
Low Molecular Weight ◽  
Conducting Materials ◽  
The Impact ◽  
Erk Kinase

The active role of biomaterials in the regeneration of tissues and their ability to modulate the behavior of stem cells in terms of their differentiation is highly advantageous. Here, polypyrrole, as a representantive of electro-conducting materials, is found to modulate the behavior of embryonic stem cells. Concretely, the aqueous extracts of polypyrrole induce neurogenesis within embryonic bodies formed from embryonic stem cells. This finding ledto an effort to determine the physiological cascade which is responsible for this effect. The polypyrrole modulates signaling pathways of Akt and ERK kinase through their phosphorylation. These effects are related to the presence of low-molecular-weight compounds present in aqueous polypyrrole extracts, determined by mass spectroscopy. The results show that consequences related to the modulation of stem cell differentiation must also be taken into account when polypyrrole is considered as a biomaterial.

scholarly journals Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cristian Carmeli ◽  
Zoltán Kutalik ◽  
Pashupati P. Mishra ◽  
Eleonora Porcu ◽  
Cyrille Delpierre ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Cohort Studies ◽  
Early Life ◽  
Life Experiences ◽  
Socioeconomic Disadvantage ◽  
Mediating Role ◽  
The Impact ◽  
The Relationship

AbstractIndividuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.

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