KLF4 is involved in the organization and regulation of pluripotency-associated three-dimensional enhancer networks

Giammartino, Dafne Campigli Di; Kloetgen, Andreas; Polyzos, Alexander; Liu, Yiyuan; Kim, Daleum; Murphy, Dylan; Abuhashem, Abderhman; Cavaliere, Paola; Aronson, Boaz E.; Shah, Veevek; Dephoure, Noah; Stadtfeld, Matthias; Tsirigos, Aristotelis; Apostolou, Effie

doi:10.1038/s41556-019-0390-6

Cited by 142 publications

(157 citation statements)

References 78 publications

(91 reference statements)

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“…Our results identify a functional overlap between two members of the same family of orphan nuclear receptors, Esrrb and Nr5a2, in supporting pluripotency in ESCs. Similar redundant functions have been described for another family of auxiliary pluripotency TFs, KLFs (Di Giammartino et al, 2019;Yamane et al, 2018). The individual deletion of Klf4, Klf2 and Klf5 is compatible with self-renewal in ESCs, but not the concomitant loss of all three TFs.…”

Section: Discussionsupporting

confidence: 60%

The combined action of Esrrb and Nr5a2 is essential for naïve pluripotency

Festuccia

Owens

Chervova

et al. 2020

Preprint

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The maintenance of pluripotency in mouse embryonic stem cells (ESCs) is governed by the action of an interconnected network of transcription factors. Among them, only Oct4 and Sox2 have been shown to be strictly required for the self-renewal of ESCs and pluripotency, particularly in culture conditions where differentiation cues are chemically inhibited. Here, we report that the conjunct activity of two orphan nuclear receptors, Esrrb and Nr5a2, parallels the importance of that of Oct4 and Sox2 in naïve ESCs. By occupying a large common set of regulatory elements, these two factors control the binding of Oct4, Sox2 and Nanog to DNA. Consequently, in their absence the pluripotency network collapses and the transcriptome is substantially deregulated, leading to the differentiation of ESCs. Altogether, this work identifies orphan nuclear receptors, previously thought to be performing supportive functions, as a new set of core regulators of naïve pluripotency.

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Section: Discussionsupporting

confidence: 60%

The combined action of Esrrb and Nr5a2 is essential for naïve pluripotency

Festuccia

Owens

Chervova

et al. 2020

Preprint

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“…While the global transcriptional resetting patterns and the respective GO terms of both eTREs and genes were highly concordant, this does not allow drawing firm conclusions on the relative reactivation of enhancers and their target genes. To address this, we assigned eTREs to their most proximal gene based on linear distance (<20kb) ( Figure 3E), and to one or more distal target genes (>20kb) ( Figure 3F) based on long-range chromatin contacts detected by H3K27ac HiChIP analysis in asynchronous PSCs (Di Giammartino et al, 2019). Both approaches showed coordinated activation of eTREs and their target genes at frequencies significantly higher than expected by chance ( Figures 3E and 3F).…”

Section: Enhancer Reactivation Patterns Mirror the Kinetics Of Proximmentioning

confidence: 97%

“…Not significant (q>0.001) terms are shown in gray. enriches for structural over regulatory loops (Bonev et al, 2017;Di Giammartino et al, 2019;Mumbach et al, 2016), and does not cover a large fraction (~50%) of expressed genes and eTREs. Therefore, we decided to revisit this question by performing high-resolution 4C-seq around the promoters of 11 example genes with distinct reactivation patterns and biological relevance (Table S5).…”

Section: Different Patterns Of Chromatin Loops Characterize Early or mentioning

confidence: 99%

“…Mouse embryonic fibroblasts (MEFs) were isolated from E13.5 embryos from R26Fucci2aR (Mort et al, 2014) mice in a mixed C57BL/6, DBA/2, and CD1 background (gift from Hadjantonakis lab (MSKCC)). Male MEFs were co-infected with a FUGW-rtTA (Maherali et al, 2008) and TRE-OKSM (STEMCCA) cassette (Sommer et al, 2009) according to standard protocols (Di Giammartino et al, 2019) and were then reprogrammed in the presence of 1μg/ml of doxycycline and 50μg/ml of ascorbic acid for 12 days prior to dox withdrawal for establishment of transgene-free induced PSCs (iPSCs). Individual iPSC clones were picked and screened for successful reprogramming based on expression of multiple pluripotency markers.…”

Section: Cell Line Generationmentioning

confidence: 99%

“…We used filtered Hi-C read pairs as described above and in (Di Giammartino et al, 2019) before binning and normalizing each replicate. We extracted read pairs from the 10kb bin that the read mate maps around the virtual viewpoint.…”

Section: Virtual 4cmentioning

confidence: 99%

See 2 more Smart Citations

Mitotic retention of H3K27 acetylation promotes rapid topological and transcriptional resetting of stem cell-related genes and enhancers upon G1 entry

Pelham-Webb

Polyzos

Wojenski

et al. 2020

Preprint

Self Cite

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The identity of dividing cells is challenged during mitosis, as transcription is halted and chromatin architecture drastically altered. How cell type-specific gene expression and genomic organization are faithfully reset upon G1 entry in daughter cells remains elusive. To address this issue, we characterized at a genome-wide scale the dynamic transcriptional and architectural resetting of mouse pluripotent stem cells (PSCs) upon mitotic exit. This revealed distinct patterns of transcriptional reactivation with rapid induction of stem cell genes and their enhancers, a more gradual recovery of metabolic and cell cycle genes, and a weak and transient activation of lineage-specific genes only during G1. Topological reorganization also occurred in an asynchronous manner and associated with the levels and kinetics of transcriptional reactivation. Chromatin interactions around active promoters and enhancers, and particularly super enhancers, reformed at a faster rate than CTCF/Cohesin-bound structural loops. Interestingly, regions with mitotic retention of the active histone mark H3K27ac and/or specific DNA binding factors showed faster transcriptional and architectural resetting, and chemical inhibition of H3K27 acetylation specifically during mitosis abrogated rapid reactivation of H3K27ac-bookmarked genes. Finally, we observed a contact between the promoter of an endoderm master regulator, Gata6, and a novel enhancer which was preestablished in PSCs and preserved during mitosis. Our study provides an integrative map of the topological and transcriptional changes that lead to the resetting of pluripotent stem cell identity during mitotic exit, and reveals distinct patterns and features that balance the dual requirements for self-renewal and differentiation.

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A Lightweight Framework For Chromatin Loop Detection at the Single‐Cell Level

Wang,

Alinejad‐Rokny,

Lin

et al. 2023

Advanced Science

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Single‐cell Hi‐C (scHi‐C) has made it possible to analyze chromatin organization at the single‐cell level. However, scHi‐C experiments generate inherently sparse data, which poses a challenge for loop calling methods. The existing approach performs significance tests across the imputed dense contact maps, leading to substantial computational overhead and loss of information at the single‐cell level. To overcome this limitation, a lightweight framework called scGSLoop is proposed, which sets a new paradigm for scHi‐C loop calling by adapting the training and inferencing strategies of graph‐based deep learning to leverage the sequence features and 1D positional information of genomic loci. With this framework, sparsity is no longer a challenge, but rather an advantage that the model leverages to achieve unprecedented computational efficiency. Compared to existing methods, scGSLoop makes more accurate predictions and is able to identify more loops that have the potential to play regulatory roles in genome functioning. Moreover, scGSLoop preserves single‐cell information by identifying a distinct group of loops for each individual cell, which not only enables an understanding of the variability of chromatin looping states between cells, but also allows scGSLoop to be extended for the investigation of multi‐connected hubs and their underlying mechanisms.

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KLF4 is involved in the organization and regulation of pluripotency-associated three-dimensional enhancer networks

Cited by 142 publications

References 78 publications

The combined action of Esrrb and Nr5a2 is essential for naïve pluripotency

The combined action of Esrrb and Nr5a2 is essential for naïve pluripotency

Mitotic retention of H3K27 acetylation promotes rapid topological and transcriptional resetting of stem cell-related genes and enhancers upon G1 entry

A Lightweight Framework For Chromatin Loop Detection at the Single‐Cell Level

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