KLF4 binding is involved in the organization and regulation of 3D enhancer networks during acquisition and maintenance of pluripotency [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129494 | GEO | 2019/09/06
REPOSITORIES: GEO
Similar Datasets
Project description:Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified by reprogramming somatic cells to pluripotent stem cells (PSCs) via expression of OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their target gene loci in a temporal manner remains incompletely understood. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and its association to 3D enhancer rewiring and transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts (MEFs) to PSCs. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in the connectivity of enhancers, while disruption of individual KLF4 binding sites from PSC-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying TF during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding.
2019-09-03 | PXD014631 | Pride
Project description:Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified in somatic cell reprogramming to pluripotent stem cells (PSCs) by OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their targets in a temporal manner remains largely elusive. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and the association to 3D enhancer rewiring and the transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts to (MEFs) to PSCs. Inducible depletion of KLF factors in PSC caused a genome-wide decrease in connectivity of enhancers and disruption of KLF4 binding site from PSC-specific enhancers was sufficient to reduce expression of genes within the enhancer hub partly by impairing long-range contacts. Our study provides an integrative view of the intricate activities of a master regulator during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding.
2019-09-06 | GSE129495 | GEO
Project description:Summary: Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified in somatic cell reprogramming to pluripotent stem cells (PSCs) by OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their targets in a temporal manner remains largely elusive. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and the association to 3D enhancer rewiring and the transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts to (MEFs) to PSCs. Inducible depletion of KLF factors in PSC caused a genome-wide decrease in connectivity of enhancers and disruption of KLF4 binding site from PSC-specific enhancers was sufficient to reduce expression of genes within the enhancer hub partly by impairing long-range contacts. Our study provides an integrative view of the intricate activities of a master regulator during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding. Purpose: We captured on a genome-wide scale the binding of KLF4 during iPSC formation and its effects on chromatin state, transcriptional activity and chromatin topology around its targets. Methods: We used a well-characterized reprogramming system to apply genome-wide assays that map KLF4 binding (ChIP-seq), chromatin accessibility (ATAC-seq), enhancer and gene activity (H3K27ac ChIP-seq and RNA-seq), enhancer connectivity (H3K27ac Hi-ChIP) as well as KLF4-centric chromatin looping (KLF4 Hi-ChIP) at different stages during acquisition of pluripotency. Results: Integrative analysis of our results generated a reference map of stage-specific chromatin changes around KLF4 bound loci and established strong links with enhancer. rewiring and concordant transcriptional changes. Genetic manipulation of KLF4 binding from a PSC enhancer further supported the ability of KLF4 to function both as a transcriptional regulator and a chromatin organizer. Conclusions: Our study offers novel insights into the intricate roles of a master regulator during cell fate transition.
2019-09-06 | GSE113339 | GEO
Project description:Summary: Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified in somatic cell reprogramming to pluripotent stem cells (PSCs) by OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their targets in a temporal manner remains largely elusive. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and the association to 3D enhancer rewiring and the transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts to (MEFs) to PSCs. Inducible depletion of KLF factors in PSC caused a genome-wide decrease in connectivity of enhancers and disruption of KLF4 binding site from PSC-specific enhancers was sufficient to reduce expression of genes within the enhancer hub partly by impairing long-range contacts. Our study provides an integrative view of the intricate activities of a master regulator during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding. Purpose: We captured on a genome-wide scale the binding of KLF4 during iPSC formation and its effects on chromatin state, transcriptional activity and chromatin topology around its targets. Methods: We used a well-characterized reprogramming system to apply genome-wide assays that map KLF4 binding (ChIP-seq), chromatin accessibility (ATAC-seq), enhancer and gene activity (H3K27ac ChIP-seq and RNA-seq), enhancer connectivity (H3K27ac Hi-ChIP) as well as KLF4-centric chromatin looping (KLF4 Hi-ChIP) at different stages during acquisition of pluripotency. Results: Integrative analysis of our results generated a reference map of stage-specific chromatin changes around KLF4 bound loci and established strong links with enhancer. rewiring and concordant transcriptional changes. Genetic manipulation of KLF4 binding from a PSC enhancer further supported the ability of KLF4 to function both as a transcriptional regulator and a chromatin organizer. Conclusions: Our study offers novel insights into the intricate roles of a master regulator during cell fate transition.
2019-09-06 | GSE113430 | GEO
Project description:Summary: Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified in somatic cell reprogramming to pluripotent stem cells (PSCs) by OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their targets in a temporal manner remains largely elusive. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and the association to 3D enhancer rewiring and the transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts to (MEFs) to PSCs. Inducible depletion of KLF factors in PSC caused a genome-wide decrease in connectivity of enhancers and disruption of KLF4 binding site from PSC-specific enhancers was sufficient to reduce expression of genes within the enhancer hub partly by impairing long-range contacts. Our study provides an integrative view of the intricate activities of a master regulator during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding. Purpose: We captured on a genome-wide scale the binding of KLF4 during iPSC formation and its effects on chromatin state, transcriptional activity and chromatin topology around its targets. Methods: We used a well-characterized reprogramming system to apply genome-wide assays that map KLF4 binding (ChIP-seq), chromatin accessibility (ATAC-seq), enhancer and gene activity (H3K27ac ChIP-seq and RNA-seq), enhancer connectivity (H3K27ac Hi-ChIP) as well as KLF4-centric chromatin looping (KLF4 Hi-ChIP) at different stages during acquisition of pluripotency. Results: Integrative analysis of our results generated a reference map of stage-specific chromatin changes around KLF4 bound loci and established strong links with enhancer. rewiring and concordant transcriptional changes. Genetic manipulation of KLF4 binding from a PSC enhancer further supported the ability of KLF4 to function both as a transcriptional regulator and a chromatin organizer. Conclusions: Our study offers novel insights into the intricate roles of a master regulator during cell fate transition.
2019-09-06 | GSE113429 | GEO
Project description:Summary: Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified in somatic cell reprogramming to pluripotent stem cells (PSCs) by OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their targets in a temporal manner remains largely elusive. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and the association to 3D enhancer rewiring and the transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts to (MEFs) to PSCs. Inducible depletion of KLF factors in PSC caused a genome-wide decrease in connectivity of enhancers and disruption of KLF4 binding site from PSC-specific enhancers was sufficient to reduce expression of genes within the enhancer hub partly by impairing long-range contacts. Our study provides an integrative view of the intricate activities of a master regulator during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding. Purpose: We captured on a genome-wide scale the binding of KLF4 during iPSC formation and its effects on chromatin state, transcriptional activity and chromatin topology around its targets. Methods: We used a well-characterized reprogramming system to apply genome-wide assays that map KLF4 binding (ChIP-seq), chromatin accessibility (ATAC-seq), enhancer and gene activity (H3K27ac ChIP-seq and RNA-seq), enhancer connectivity (H3K27ac Hi-ChIP) as well as KLF4-centric chromatin looping (KLF4 Hi-ChIP) at different stages during acquisition of pluripotency. Results: Integrative analysis of our results generated a reference map of stage-specific chromatin changes around KLF4 bound loci and established strong links with enhancer. rewiring and concordant transcriptional changes. Genetic manipulation of KLF4 binding from a PSC enhancer further supported the ability of KLF4 to function both as a transcriptional regulator and a chromatin organizer. Conclusions: Our study offers novel insights into the intricate roles of a master regulator during cell fate transition.
2019-09-06 | GSE113428 | GEO
Project description:Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression
2019-05-24 | MSV000083857 | MassIVE
Project description:Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription-factors (TFs), and chromatin-states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that early in reprogramming OSK extensively bind somatic-enhancers and initiate their decommissioning by recruiting Hdac1. Concurrently, OSK engage other sites, including specific pluripotency-enhancers, and induce the relocation of somatic TFs to these sites and away from somatic-enhancers, extending somatic-enhancer decommissioning genome-wide. Pluripotency-enhancer selection early in reprogramming occurs predominantly at sites with high OSK-motif densities and requires collaborative binding by OSK. Most pluripotency-enhancers are selected later and occupied by OS and stage-specific-TFs like Esrrb. Overexpression of stage-specific-TFs influences reprogramming efficiency by changing OSK-occupancy, somatic-enhancer decommissioning, and pluripotency-enhancer selection. We propose that collaborative interactions among OSK and with stage-specific-TFs direct both somatic-enhancer decommissioning and pluripotency-enhancer selection, which drives the enhancer reorganization underlying reprogramming
2017-01-19 | GSE90893 | GEO
Project description:Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription-factors (TFs), and chromatin-states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that early in reprogramming OSK extensively bind somatic-enhancers and initiate their decommissioning by recruiting Hdac1. Concurrently, OSK engage other sites, including specific pluripotency-enhancers, and induce the relocation of somatic TFs to these sites and away from somatic-enhancers, extending somatic-enhancer decommissioning genome-wide. Pluripotency-enhancer selection early in reprogramming occurs predominantly at sites with high OSK-motif densities and requires collaborative binding by OSK. Most pluripotency-enhancers are selected later and occupied by OS and stage-specific-TFs like Esrrb. Overexpression of stage-specific-TFs influences reprogramming efficiency by changing OSK-occupancy, somatic-enhancer decommissioning, and pluripotency-enhancer selection. We propose that collaborative interactions among OSK and with stage-specific-TFs direct both somatic-enhancer decommissioning and pluripotency-enhancer selection, which drives the enhancer reorganization underlying reprogramming
2017-01-19 | GSE90892 | GEO
Project description:Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription-factors (TFs), and chromatin-states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that early in reprogramming OSK extensively bind somatic-enhancers and initiate their decommissioning by recruiting Hdac1. Concurrently, OSK engage other sites, including specific pluripotency-enhancers, and induce the relocation of somatic TFs to these sites and away from somatic-enhancers, extending somatic-enhancer decommissioning genome-wide. Pluripotency-enhancer selection early in reprogramming occurs predominantly at sites with high OSK-motif densities and requires collaborative binding by OSK. Most pluripotency-enhancers are selected later and occupied by OS and stage-specific-TFs like Esrrb. Overexpression of stage-specific-TFs influences reprogramming efficiency by changing OSK-occupancy, somatic-enhancer decommissioning, and pluripotency-enhancer selection. We propose that collaborative interactions among OSK and with stage-specific-TFs direct both somatic-enhancer decommissioning and pluripotency-enhancer selection, which drives the enhancer reorganization underlying reprogramming
2017-01-19 | GSE90894 | GEO