RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells

Suzuki, Tsuyoshi; Shimizu, Yuri; Furuhata, Erina; Maeda, Shiori; Kishima, Mami; Nishimura, Hajime; Enomoto, Saaya; Hayashizaki, Yoshihide; Suzuki, Harukazu

doi:10.1182/bloodadvances.2017005710

Cited by 69 publications

(95 citation statements)

References 64 publications

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“…We reasoned that, if the identified motifs are important for recruiting the enzymes, these motifs would be enriched around the binding sites of the recruited enzymes. To this end, we have collected all the available ChIP-seq experiments of TET and DNMT enzymes [45][46][47][48] . Indeed, at the center of TET1 ChIP-seq peaks in hESC H1 cells 46 , the UM sites occur 26.7 times of expected counts (see details in Methods), whereas MM motifs occur roughly same (1.4 times) as the expected counts ( Figure 2C, first panel from the left).…”

Section: Identified Motifs Are Significantly Enriched At Tets and Dnmmentioning

confidence: 99%

“…DNMTs and TETs ChIP-seq peaks were downloaded from the published studies 45,47,48 . The 5000bp neighbor regions around the ChIP-seq peaks were included as the background or edge.…”

Section: Normalized Motif Occurrence and Center-to-edge Enrichment Atmentioning

confidence: 99%

“…Each gene body was split into ten equal bins and the Beta values of all CpGs in the same bin were averaged over all genes. Lower panel shows the correlation between the motif occurrences and CpG methylation in ROADMAP (WGBS data from H1, mesoderm and liver) and TCGA (450K methylation of CpGs averaged in patients from PAAD, LUAD and BRCA) around TP53 (chr17:7,540,000 -7,650,000) C. Normalized motif occurrence of UM, MM and known TFs (excluding matched) from HOCOMOCO 29 at 5000 bp windows centering ChIP-seq peaks of TET1, DNMT3A and DNMT3B collected from various studies [45][46][47] . Lower panel shows the clustered heatmap of normalized z-score.…”

Section: Feedforward Loop Analysismentioning

confidence: 99%

“…Foreground (FG), mQTL at TET1-UM sites. Background (BG), mQTL at TET1 binding peaks[45][46][47] . To ensure the statistical significance, we only considered the cancers with >100 CpGs within 5000bp of TET1-UM sites (see details in Methods).…”

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confidence: 99%

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Identification of DNA motifs that regulate DNA methylation

Wang¹,

Zhang²,

Ngo³

et al. 2019

Preprint

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DNA methylation is an important epigenetic mark but how its locus-specificity is decided in relation to DNA sequence is not fully understood. Here, we have analyzed 34 diverse wholegenome bisulfite sequencing datasets in human and identified 313 motifs, including 92 and 221 associated with methylation (methylation motifs, MMs) and unmethylation (unmethylation motifs, UMs), respectively. The functionality of these motifs is supported by multiple lines of evidences. First, the methylation levels at the MM and UM motifs are respectively higher and lower than the genomic background. Second, these motifs are enriched at the binding sites of methylation modifying enzymes including DNMT3A and TET1, indicating their possible roles of recruiting these enzymes. Third, these motifs significantly overlap with SNPs associated with gene expression and those with DNA methylation. Fourth, disruption of these motifs by SNPs is associated with significantly altered methylation level of the CpGs in the neighbor regions. Furthermore, these motifs together with somatic SNPs are predictive of cancer subtypes and patient survival. We revealed some of these motifs were also associated with histone modifications, suggesting possible interplay between the two types of epigenetic modifications. We also found some motifs form feed forward loops to contribute to DNA methylation dynamics. Results Defining DNA methylation regions and de novo motif discoveryWe aimed to identify DNA motifs associated with DNA methylation and thus started with searching for methylation regions that have the strongest signals. We collected whole genome bisulfite sequencing (WGBS) data of 34 human methylomes generated by the NIH Roadmap Epigenomics Project 15,16 (Figure 1A). We took an approach similar to the Ziller et al. study 17 and defined 1.55 million methylation regions containing 11.5 million CpG sites in the 34 methylomes. Because the methylome data is noisy, we only considered regions containing 2 or more CpGs within 400 bp apart, which covers 29.2% of the human genome.

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Section: Identified Motifs Are Significantly Enriched At Tets and Dnmmentioning

confidence: 99%

“…DNMTs and TETs ChIP-seq peaks were downloaded from the published studies 45,47,48 . The 5000bp neighbor regions around the ChIP-seq peaks were included as the background or edge.…”

Section: Normalized Motif Occurrence and Center-to-edge Enrichment Atmentioning

confidence: 99%

Section: Feedforward Loop Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of DNA motifs that regulate DNA methylation

Wang¹,

Zhang²,

Ngo³

et al. 2019

Preprint

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“…Although this is better supported at the level of pioneer factors, it is feasible that other TFs involved in lineage commitment are also able to recruit TETs to specific genomic loci. While several TFs are involved in DNA demethylation by interacting with TET proteins (e.g., Nanog during establishment of pluripotency [101], the hematopoiesis-related RUNX1 [102] and EBF1 [103], PU.1 in osteoclast differentiation [104], and PPARγ in adipogenesis [105]), screening systems suggest that many others may share this property [106]. Alternatively, enhancer elements that distinguish cell types may be specifically targeted by TETs based on their chromatin conformation and histone mark profile.…”

Section: Perspectives and Concluding Remarksmentioning

confidence: 99%

5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell

2018

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Abstract:Recently described as the sixth base of the DNA macromolecule, the precise role of 5-hydroxymethylcytosine (5hmC) is the subject of debate. Early studies indicate that it is functionally distinct from cytosine DNA methylation (5mC), and there is evidence for 5hmC being a stable derivate of 5mC, rather than just an intermediate of demethylation. Moreover, 5hmC events correlate in time and space with key differentiation steps in mammalian cells. Such events span the three embryonic germ layers and multiple progenitor cell subtypes, suggesting a general mechanism. Because of the growing understanding of the role of progenitor cells in disease origin, we attempted to provide a detailed summary on the currently available literature supporting 5hmC as a key player in adult progenitor cell differentiation. This summary consolidates the emerging role for 5hmC in defining cellular fate.

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Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage–Myofibroblast Transition in Non‐Small‐Cell Lung Carcinoma

Tang,

Chan,

Chung

et al. 2023

Advanced Science

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Macrophage‐myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro‐tumoral cancer‐associated fibroblasts (CAFs) in non‐small cell lung carcinoma (NSCLC) in a TGF‐β1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor‐associated macrophage at single‐cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT‐specific TGF‐β1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT‐derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage‐specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage‐specific genetic deletion and systemic pharmacological inhibition of TGF‐β1/Smad3/Runx1 signaling effectively prevent MMT‐driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC.

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RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells

Abstract: Key Points• Ectopic expression of RUNX1 induces binding site-directed DNA demethylation, in which hematopoietic gene promoters are included.• RUNX1 binding sites are enriched in demethylated regions during hematopoietic development.

Cited by 69 publications

References 64 publications

Identification of DNA motifs that regulate DNA methylation

Identification of DNA motifs that regulate DNA methylation

5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage–Myofibroblast Transition in Non‐Small‐Cell Lung Carcinoma

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