Establishment and function of chromatin modification at enhancers

Tafessu, Amanuel; Banaszynski, Laura A.

doi:10.1098/rsob.200255

Cited by 14 publications

(13 citation statements)

References 223 publications

(304 reference statements)

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“…In addition, we used ATAC-seq to generate a map of chromatin accessibility in DTC1 and SU-CCS-1 cells. The majority of EWSR1-ATF1 distal binding sites were found to be associated with active enhancer elements, marked by the presence of H3K4me1, H3K27ac, and ATAC signals 23 , 24 (Fig. 1c ).…”

Section: Resultsmentioning

confidence: 99%

“…The transition from a closed to a fully active chromatin state requires the interplay between cooperative TFs and chromatin remodeling complexes and co-activators 24 . Based on the role of wt ATF1 as an activator in other cellular models 13 , 30 , we reasoned that maintenance of its expression in CCS, coupled with enrichment in the ATF1 motif at EWSR1-ATF1 binding sites, may argue in favor of a cooperation between EWSR1-ATF1 and wt ATF1 in chromatin activation.…”

Section: Resultsmentioning

confidence: 99%

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EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

et al. 2022

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Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

et al. 2022

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“…Histone acetylation, and particularly H3K27ac, broadly defines transcriptionally active regions of the genome. This modification is put in place by histone acetyltransferases that are recruited to target sites through the sequence-specific binding of transcription factors (TFs) to short motifs found at regulatory elements (12)(13)(14). The ability of TFs to bind target sites in part depends on chromatin accessibility, and methods such as assay for transposase-accessible chromatin using sequencing (ATAC-seq) are frequently used as a proxy for determining sites of TF binding within the genome (15).…”

Section: Main Textmentioning

confidence: 99%

Loss of heterochromatin at endogenous retroviruses creates competition for transcription factor binding

O’Hara

Banaszynski

2022

Preprint

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The mammalian genome is partitioned into active and inactive regions, broadly termed euchromatin and heterochromatin, respectively. The majority of heterochromatin consists of repetitive elements, including endogenous retroviruses (ERVs). ERVs are enriched in regulatory elements containing transcription factor (TF) binding sites with individual families containing hundreds to thousands of distinct copies scattered throughout the genome. We hypothesized that epigenetic derepression of ERVs (such as that observed during early development) may alter the stoichiometry between TFs and their euchromatic target sites, with ERVs effectively competing for these factors. To test this, we modeled acute heterochromatin loss using inducible deletion of the co-repressor KAP1 in mouse embryonic stem cells (ESCs). Upon KAP1 deletion, we observe clear reductions in chromatin accessibility, histone acetylation, and TF binding at euchromatic regions. To directly test the concept of global binding site competition, we designed exogenous binding site arrays (EBSAs) to introduce upwards of 1500 copies of the OCT4 TF binding motif into ESCs. OCT4 EBSAs specifically reduce chromatin accessibility at POU family motifs and result in reduced transcription of the pluripotency machinery with subsequent differentiation. Overall, these data support a model in which heterochromatin at ERVs promotes euchromatic TF binding and transcriptional homoeostasis. We propose that regulated ERV derepression during pre-implantation may serve as a developmental siphon to weaken the robustness of ongoing transcription programs in favor of the plasticity required for cell fate specification.

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“…Depending on the MBS position, it can activate transcription of noncoding RNA molecules, thus leading to post-transcriptional repression [48] . Additional regulatory molecules may be essential to facilitate access of the p300 active site [60] or other interacting partners may be involved [61] . Overall, the effect of p300 recruitment to the gene regulatory elements appears to be context-dependent [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%