Runx1 Shapes the Chromatin Landscape Via a Cascade of Direct and Indirect Targets

Hass, Matthew R.; Brisette, Daniel; Parameswaran, Sreeja; Pujato, Mario; Donmez, Omer; Kottyan, Leah C.; Weirauch, Matthew T.; Kopan, Raphael

doi:10.1101/2020.09.25.313767

Cited by 3 publications

(3 citation statements)

References 58 publications

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“…Nevertheless, the inhibition of binding via DNA methylation detected in vitro is not always observed in vivo or can be restricted to some genomic regions [63][64][65]. Supporting evidence for pioneer function has been reported for FLI1 [36,66,67], RUNX1 and RUNX3 [68,69]. How these factors can engage with closed chromatin would require further investigations.…”

Section: Discussionmentioning

confidence: 98%

Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers

Lemma

Fleischer

Martinsen

et al. 2021

Preprint

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Methylation of cytosines on DNA is a prominent modification associated with gene expression regulation. Aberrant DNA methylation patterns have recurrently been linked to dysregulation of the regulatory program in cancer cells. To shed light on the underlying molecular mechanism driving this process, we hypothesized that aberrant methylation patterns could be controlled by the binding of specific transcription factors (TFs) across cancer types. By combining DNA methylation arrays and gene expression data with TF binding sites (TFBSs), we explored the interplay between TF binding and DNA methylation in 19 cancer cohorts. We performed emQTL (expression-methylation quantitative trait loci) analyses in each cohort and identified 13 TFs whose expression levels are correlated with local DNA methylation patterns around their binding site in at least 2 cancer types. The 13 TFs are mainly associated with local demethylation and are enriched for pioneer function, suggesting a specific role for these TFs in modulating chromatin structure and transcription in cancer patients. Furthermore, we confirmed that de novo methylation is precluded across cancers at CpGs lying in genomic regions enriched for TF-binding signatures associated with SP1, CTCF, NRF1, GABPA, KLF9, and/or YY1. The modulation of DNA methylation associated with TF binding was observed at cis-regulatory regions controlling immune- and cancer-associated pathways, corroborating that the emQTL signals were derived from both cancer and tumour-infiltrating cells. As a case example, we experimentally confirmed that FOXA1 knock-down is associated with higher methylation in regions bound by FOXA1 in breast cancer MCF-7 cells. Finally, we reported physical interactions between FOXA1 with TET1 and TET2 at physiological levels in MCF-7 cells, adding further support for FOXA1 attracting TET1 and TET2 to induce local demethylation in cancer.

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Section: Discussionmentioning

confidence: 98%

Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers

Lemma

Fleischer

Martinsen

et al. 2021

Preprint

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“…The most strongly enriched sequence mapping directly to the human genome arises from a site at the 3’ end of the coding region of the INHBB growth factor (table 1). INHBB is a Polycomb target (30) and the identified site is adjacent to an ATAC-seq accessible peak that binds the Runx2 pioneer transcription factor in mouse (31). A sequence from intron 4 of the PSD2 gene was also notably enriched only in E. cuniculi , where it was represented at a similar order of magnitude to 601, ANK1-POU6F2 and INHBB .…”

Section: Resultsmentioning

confidence: 99%

Histone sequence variation in divergent eukaryotes facilitates diversity in chromatin packaging

Patwal

Hien

Golden

et al. 2021

Preprint

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The histone proteins defining nucleosome structure are highly conserved in common model organisms and are frequently portrayed as uniform chromatin building blocks. We surveyed over 1700 complete eukaryotic genomes and confirm that almost all encode recognisable canonical core histones. Nevertheless, divergent eukaryotes show unrecognised diversity in histone sequences and offer an opportunity to observe the potential for nucleosome variation. Recombinant histones for Plasmodium falciparum, Giardia lamblia, Encephalitozoon cuniculi and Leishmania major were prepared alongside those for human, Xenopus laevis and Saccharomyces cerevisiae. All could be assembled into nucleosomes in vitro on sequences known to direct positioning with metazoan histones. P. falciparum histones refolded into very stable nucleosomes consistent with a highly regulated transcriptional programme. In contrast, G. lamblia and E. cuniculi histones formed less stable nucleosomes and were prone to aggregation as H3-H4 tetramers. Inspection of the histone fold dimer interface residues suggested a potential to form tetrasomal arrays consistent with polymerisation. DNA binding preferences observed using systematic evolution of ligands by exponential enrichment (SELEX) for human, P. falciparum and E. cuniculi histone octamers were highly similar and reflect a shared capability to package diverse genomic sequences. This demonstrates that nucleosomal organisation is retained across eukaryotes and can accommodate genome variation, but histone protein sequences vary more than commonly recognised to provide the potential for diversity of chromatin features.

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“…Regulatory Element Locus Intersection (RELI): The RELI algorithm estimated the enrichment of specific genomic features within next generation sequencing datasets, as reported previously [21,56,57]. In addition to comparing pairs of datasets (e.g., two ChIPseq peak sets), RELI systematically estimated the significance of intersections of the genomic coordinates of genetic variants and ChIP-seq peaks, as described previously [21].…”

Section: Methodsmentioning

confidence: 99%

Epigenetic and Transcriptional Dysregulation in CD4+ T cells of Patients with Atopic Dermatitis

Eapen

Parameswaran

Forney

et al. 2021

Preprint

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Atopic dermatitis (AD) is one of the most common skin disorders in children. Disease etiology involves genetic and environmental factors, with the 29 independent AD risk loci enriched for risk allele-dependent gene expression in the skin and CD4+ T cell compartments. We investigated epigenetic mechanisms that may account for genetic susceptibility in CD4+ T cells. To understand gene regulatory activity differences in peripheral blood T cells in AD, we measured chromatin accessibility (ATAC-seq), NFKB1 binding (ChIP-seq), and gene expression (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD and age-matched, non-allergic controls. Open chromatin regions in stimulated CD4+ T cells were highly enriched for AD genetic risk variants, with almost half of AD risk loci overlapping with AD-dependent ATAC-seq peaks. AD-specific open chromatin regions were strongly enriched for NFκB DNA binding motifs. ChIP-seq identified hundreds of NFKB1-occupied genomic loci that were AD-specific or Control-specific. As expected, the AD-specific ChIP-seq peaks were strongly enriched for NFκB DNA binding motifs. Surprisingly, Control-specific NKFB1 ChIP-seq peaks were not enriched for NFKB1 motifs, instead containing motifs for other classes of human TFs, suggesting a mechanism involving altered indirect NFKB1 binding. Using DNA sequencing data, we identified 63 instances of genotype-dependent chromatin accessibility at 36 AD risk variants (30% of AD risk loci) that could lead to genotype-dependent expression at these loci. We propose that CD4+ T cells respond to stimulation in an AD-specific manner, resulting in disease and genotype-dependent chromatin accessibility involving NFKB binding.AUTHOR SUMMARYStimulated CD4+ T cells from patients with atopic dermatitis have disease-dependent regulation of how gene expression is regulated. This regulation is disease dependent and the way the DNA is accessible and the transcription factor NFKB1 binds is enriched for genetic risk variants. Clinically, the CD4+ T cells in the peripheral blood of patients with AD respond to stimulation in a disease and genotype-dependent manner.

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Runx1 Shapes the Chromatin Landscape Via a Cascade of Direct and Indirect Targets

Cited by 3 publications

References 58 publications

Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers

Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers

Histone sequence variation in divergent eukaryotes facilitates diversity in chromatin packaging

Epigenetic and Transcriptional Dysregulation in CD4+ T cells of Patients with Atopic Dermatitis

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