ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

Teng, Yu-Ching; Sundaresan, Aishwarya; O’Hara, Ryan; Gant, Vincent U.; Li, Minhua; Matarazzo, Sara; Warshaw, Jane N.; Basu, Amrita; Banaszynski, Laura A.

doi:10.1101/2021.05.07.443199

Cited by 8 publications

(17 citation statements)

References 77 publications

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“…A merged peak file was generated for KAP1 and SETDB1 (GSE151053) ( 55 ) containing all WT and KO peaks in the respective condition. H3K9me3 regions were generated by intersecting merged ATAC peaks (either KAP1 or SETDB1) with H3K9me3 Cut and Tag peaks (in WT ESCs).…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

“…Datasets are deposited in the NCBI Gene Expression Omnibus using the following accession numbers: SuperSeries GSExx, ATAC-seq GSExxx, CUT&Tag GSExxx. Other datasets used for this study are available under GSE41903 ( 4 ), GSE151053 ( 44 ) and GSE114548 ( 45 ).…”

Section: Data Availabilitymentioning

confidence: 99%

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

O’Hara

Banaszynski

2022

Preprint

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“…ATAC-seq analysis ATAC-seq datasets for H3.3 KO, HIRA KO, ATRX KO, DAXX KO and corresponding WT cells were obtained from GEO (GSE151013) [80]. FastQ reads were trimmed and adapters removed using Trimgalore and Cutadapt.…”

Section: Atac-seqmentioning

confidence: 99%

“…Datasets are deposited in the NCBI Gene Expression Omnibus using the following accession numbers: SuperSeries GSExxx, ATAC-seq GSExxx, ChIP-seq GSExxx, and GRO-seq GSExxx. Other datasets used for this study are available under GSE114551 [25] and GSE151058 [80].…”

Section: Declarations Ethics Approval and Consent To Participatementioning

confidence: 99%

H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements

Tafessu

O’Hara

Matarazzo

et al. 2022

Preprint

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Background: The histone variant H3.3 is enriched at active regulatory elements such as promoters and enhancers in mammalian genomes. These regions are highly accessible, creating an environment that is permissive to transcription factor binding and the recruitment of transcriptional coactivators that establish a unique chromatin post-translational landscape. How H3.3 contributes to the establishment and function of chromatin states at these regions is poorly understood. Results: We performed genomic analyses of features associated with active promoter chromatin in mouse embryonic stem cells (ESCs) and found evidence of subtle yet widespread promoter dysregulation in the absence of H3.3. Loss of H3.3 deposition at promoters reduces chromatin accessibility and transcription factor (TF) footprinting for nearly all TFs expressed in ESCs. H3.3 deletion leads to reduced promoter enrichment of the transcriptional coactivator and histone acetyltransferase, p300. Subsequently, histone H3 acetylation at lysine 27 (H3K27ac) is reduced at promoters in the absence of H3.3, along with reduced enrichment of the bromodomain-containing protein BRD4, an acetyl lysine reader. Despite the observed chromatin dysregulation, H3.3 KO ESCs maintain transcription from ESC-specific genes. However, upon undirected differentiation, H3.3 KO cells retain footprinting of ESC-specific TFs motifs and fail to generate footprints of lineage-specific TF motifs, in line with their diminished capacity to differentiate. Conclusions: H3.3 facilitates DNA accessibility, TF binding, and histone post-translational modification at active promoters. While H3.3 is not required for maintaining transcription in ESCs, it is required for TF binding at new promoters during differentiation.

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“…ATRX is an X-linked chromatin remodeler that functions in genome stabilization and heterochromatin formation (Dyer, et al 2017; Teng, et al 2021), regulating transcription in both activation and repression manners (Levy, et al 2015; Voon, et al 2015). We noted that ATRX mutation was associated with lower XAR-PIX in tumor samples ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Comprehensively characterizing evolutionarily conserved differential dosage compensations of the X chromosome during development and in diseases

Guo

Fang

Chen

et al. 2022

Preprint

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The active X chromosome in mammals is upregulated to balance its dosage to autosomes during evolution. However, it is elusive why the currently known dosage compensation machinery showed uneven and small influence on X genes, necessitating systemic investigation of X dosage in different angles and identification of new dosage regulators. Here, based on >20,000 transcriptomes, we identified two gene groups (ploidy-sensitive chrX [PSX] and ploidy-insensitive chrX [PIX] genes) on chromosome X, with distinct sensitivity to genome ploidy and showing distinct but evolutionarily-conserved (across tissues in both primates and mouse) dosage compensations (X-over-Autosome dosage Ratio, or XAR). We also demonstrated that the trends of XAR-PIX and XAR-PSX in cancers were divergent, with XAR-PIX down-regulated and XAR-PSX up-regulated, compared to corresponding normal tissues, which was supported at both the RNA and protein level across tissue types. We further explored potential XAR regulators systematically and identified and experimentally validated two new independent regulators, mild TP53 (verified in human) and potent ATRX (verified in both human and mouse), expanding the current dosage compensation machinery with only the MOF complex in mammals. Lastly, we presented interesting findings of XAR-PIX and XAR-PSX dynamics during stem cell differentiation and embryo preimplantation, as well as in female-predominant lupus patients. For example, we showed the opposite trends of XARs during stem cell differentiation and in cancer. Collectively, we provided insights to further unravel the mystery of X dosage compensation during evolution.

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ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

Cited by 8 publications

References 77 publications

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

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

H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements

Comprehensively characterizing evolutionarily conserved differential dosage compensations of the X chromosome during development and in diseases

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