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KLF4 inhibits early neural differentiation of ESCs by coordinating specific 3D chromatin structure, a new mechanism of early neural differentiation

ABSTRACT: Circular RNA has been reported to be dynamically expressed during embryonic development and regulates human embryonic stem cells (hESCs), but the identification and regulation of functional circular RNA in mouse embryonic stem cells (mESC) remains unclear. Neural differentiation of embryonic stem cells (ESCs) requires precisely orchestrated gene regulation, a process governed in part by changes in 3D chromatin structure. How these changes regulate gene expression in this context remains unclear. In this study, we observed enrichment of the transcription factor KLF4 at some poised or closed enhancers at TSS-linked regions of genes associated with neural differentiation. Combination analysis of ChIP, HiChIP and RNA-seq data indicated that KLF4 loss in ESCs induced changes in 3D chromatin structure, including increased chromatin interaction loops between neural differentiation-associated genes and active enhancers, leading to upregulated expression of neural differentiation-associated genes and therefore early neural differentiation. This study suggests KLF4 inhibits early neural differentiation by regulation of 3D chromatin structure, which is a new mechanism of early neural differentiation. Conclusions: Our study suggests KLF4 inhibits early neural differentiation by regulation of 3D chromatin structure, which is a new mechanism of early neural differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE213418 | GEO | 2022/09/20

REPOSITORIES: GEO

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KLF4 inhibits early neural differentiation of ESCs by coordinating specific 3D chromatin structure

Project description:Neural differentiation of embryonic stem cells (ESCs) requires precisely orchestrated gene regulation, a process governed in part by changes in 3D chromatin structure. How these changes regulate gene expression in this context remains unclear. In this study, we observed enrichment of the transcription factor KLF4 at some poised or closed enhancers at TSS-linked regions of genes associated with neural differentiation, such as Pax6. Combination analysis employing ChIP, HiChIP and RNA-seq data indicated that KLF4 loss in ESCs induced changes in 3D chromatin structure, including increased chromatin interaction loops between neural differentiation-associated genes and active enhancers. And changes of chromatin structure upregulated expression of neural differentiation-associated genes and promoted early neural differentiation. This study reveals that KLF4 has a differentiation inhibitory effect in regulating 3D chromatin structure and suggests KLF4 inhibits early neural differentiation by regulation of 3D chromatin structure, which is a new mechanism of early neural differentiation.

2022-06-01 | GSE194068 | GEO

KLF4 inhibits early neural differentiation of ESCs by coordinating specific 3D chromatin structure

Project description:KLF4 inhibits early neural differentiation of ESCs by coordinating specific 3D chromatin structure

| PRJNA798967 | ENA

4C-seq: Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci

Project description:Hox genes are essential regulators of embryonic development. They are activated in a temporal sequence following their topological order within their genomic clusters. Subsequently, states of activity are fine-tuned and maintained to translate into domains of progressively overlapping gene products. While the mechanisms underlying such temporal and spatial progressions begin to be understood, many of their aspects remain unclear. We have systematically analyzed the 3D chromatin organization of Hox clusters in vivo, during their activation using high-resolution circular chromosome conformation capture (4C-seq). Initially, Hox clusters are organized as single 3D chromatin compartments decorated with bivalent chromatin marks. Their progressive transcriptional activation is associated with a dynamic bi-modal 3D organization, whereby the genes switch one after the other, from an inactive to an active 3D compartment. These local 3D dynamics occur within a larger constitutive framework of interactions within the surrounding Topological Associated Domains, which confirms previous results that regulation of this process in primarily cluster intrinsic. The local step-wise progression in time can be stopped and memorized at various body levels and hence it may accounts for the various chromatin architectures previously described at different anterior to posterior body levels for the same embryo at a later stage. Circular Chromosome Conformation Capture (4C-seq) samples from mouse ES cells and mouse embryonic samples at different stages of development. Data based on 41 biological samples.

2014-04-28 | E-GEOD-55342 | biostudies-arrayexpress

TCC in pluripotent and differentiated cells

Project description:Regulation of gene expression underlies the establishment and maintenance of cell identity. Chromatin structure and gene activity are linked. Recently CTCF anchored loops have been described as major features of chromatin organisation. However, the dynamics and role for these structures in differentiation is unknown. We used Tethered Chromatin Conformation Capture (TCC) to assess for the dynamics of CTCF-anchor loop formation upon differentiation of mouse embryonic stem cells (ESC) and neural stem cells (NSC).

2018-11-08 | E-MTAB-4870 | biostudies-arrayexpress

Dynamic alterations of 3D chromatin structure during differentiation

Project description:Regulation of gene expression underlies the establishment and maintenance of cell identity. Chromatin structure and gene activity are linked at long-range via positioning of loci to transcriptionally permissive (euchromatin) or repressive (heterochromatin) environments and at short-range by connecting cis regulatory elements such as promoters and enhancers. However, the dynamics of these processes during cell differentiation still remains unclear. We used Tethered Chromatin Conformation Capture (TCC) to compare the three dimensional chromatin structure of mouse embryonic stem cells (ESC) and neural stem cells (NSC) which we directly derived from the ESC.

2019-08-27 | E-MTAB-2063 | biostudies-arrayexpress

Dynamic alterations of 3D chromatin structure during differentiation RNA-seq

2019-08-27 | E-MTAB-2125 | biostudies-arrayexpress

Two enhancers synergistically regulate HoxB genes expressions and retinoic acid-induced early ESCs differentiation through 3D chromatin structure

Project description:Homeobox B cluster (HoxB) genes play important roles in RA-induced early ESCs differentiation. In this study, we identified two enhancers synergistically regulate HoxB genes expressions through 3D chromatin structure and thus regulate RA-induced early ESCs differentiation. 4C data showed interactions between HoxB genes and the two enhancers. CRISPR/Cas9-mediated individual or compound deletion of the two enhancers significantly inhibits HoxB genes expressions while transcriptome analysis revealed that RA induced early ESCs differentiation was blocked in the enhancer KO cells. Our study suggests new mechanism by which two enhancers regulate HoxB genes expressions and retinoic acid-induced early ESCs differentiation through 3D chromatin structure.

2021-03-01 | GSE165725 | GEO

Dynamic alterations of 3D chromatin structure during differentiation

Project description:Dynamic alterations of 3D chromatin structure during differentiation

| PRJEB4939 | ENA

Global Reorganization of Chromatin Architecture during Embronic Stem Cell Differentiation

Project description:The 3D organization of the genome is important for regulation of diverse nuclear processes ranging from transcription to DNA replication. Knowledge of the higher order chromatin structure is critical for understanding mechanisms of gene regulation by long-range control elements such as enhancers and insulators. We describe high resolution, genome-wide dynamic chromatin interaction maps in human embryonic stem cells (hESC) as they differentiate into four distinct embryonic cell lineages. Extensive reorganization of higher-order chromatin structure occurs during hESC differentiation. In this process, topological domains remain largely intact but inter-domain association patterns change dramatically, coincident with widespread changes in chromatin state and gene expression. Moreover, using proximity ligation sequencing to generate chromosome span haplotypes, widespread allele biased gene activities are detected. The allelic gene expression patterns can be correlated to epigenetic state at distal enhancers, supporting the role of these elements in regulating gene expression over a distance. Two biological replicates of Hi-C experiment and one replicate of CTCF ChIP-Seq experiment in embryonic stem cells and 4 other differentiated cell-types from H1 cell line. Re-analysis of data from GSE16256 in an allele specific manner is linked as supplementary data.

2015-02-18 | E-GEOD-52457 | biostudies-arrayexpress

RNA-seq: Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci

Project description:Hox genes are essential regulators of embryonic development. They are activated in a temporal sequence following their topological order within their genomic clusters. Subsequently, states of activity are fine-tuned and maintained to translate into domains of progressively overlapping gene products. While the mechanisms underlying such temporal and spatial progressions begin to be understood, many of their aspects remain unclear. We have systematically analyzed the 3D chromatin organization of Hox clusters in vivo, during their activation using high-resolution circular chromosome conformation capture (4C-seq). Initially, Hox clusters are organized as single 3D chromatin compartments decorated with bivalent chromatin marks. Their progressive transcriptional activation is associated with a dynamic bi-modal 3D organization, whereby the genes switch one after the other, from an inactive to an active 3D compartment. These local 3D dynamics occur within a larger constitutive framework of interactions within the surrounding Topological Associated Domains, which confirms previous results that regulation of this process in primarily cluster intrinsic. The local step-wise progression in time can be stopped and memorized at various body levels and hence it may accounts for the various chromatin architectures previously described at different anterior to posterior body levels for the same embryo at a later stage. RNA-seq from mouse ES cells and mouse embryonic stage E10.5 forebrain. Data based on 2 biological samples.

2014-04-28 | E-GEOD-54952 | biostudies-arrayexpress

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