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Pre-existing chromatin states regulate KLF4 binding to eliminate leukemic cells [mouse ChIP]

ABSTRACT: Transcription factors collaborate with chromatin's epigenetic states to regulate cell fate decisions. While recent work suggested that histone modifications could regulate the activity of pioneer transcription factors in vitro, it was unclear whether these findings applied in vivo, or if chromatin states could influence transcription factor binding to affect cell fate. In this work, we identified that H3K18ac, a potential caner-related histone mark, could regulate Klf4's genomic binding, thereby affecting divergent cellular destinies in leukemia cells and HSPCs. This unveils prospective opportunities for applying transcription factors combined with epigenetic markers in clinical applications. In summary, our results suggest that pre-existing chromatin states could regulate transcription factor binding in vivo, and therefore influence the cell fate decision.

ORGANISM(S): Mus musculus

PROVIDER: GSE261981 | GEO | 2026/08/15

REPOSITORIES: GEO

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Project description:<p>Non-coding elements in our genomes that play critical roles in complex disease are frequently marked by highly unstable RNA species. Sequencing nascent RNAs attached to an actively transcribing RNA polymerase complex can identify unstable RNAs, including those templated from gene-distal enhancers (eRNAs). However, nascent RNA sequencing techniques remain challenging to apply in some cell lines and especially to intact tissues, limiting broad applications in fields such as cancer genomics and personalized medicine. Here we report the development of chromatin run-on and sequencing (ChRO-seq), a novel run-on technology that maps the location of RNA polymerase using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in 23 human glioblastoma (GBM) brain tumors and patient derived xenografts. Remarkably, >90,000 distal enhancers discovered using the signature of eRNA biogenesis within primary GBMs closely resemble those found in the normal human brain, and diverge substantially from GBM cell models. Despite extensive overall similarity, 12% of enhancers in each GBM distinguish normal and malignant brain tissue. These enhancers drive regulatory programs similar to the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. These results demonstrate that GBMs largely retain the enhancer landscape associated with their tissue of origin, but selectively adopt regulatory programs that are responsible for driving stem-like cell properties. We also identified enhancers and their associated transcription factors that regulate genes characteristic of each known GBM subtype, and discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study uncovers new insights into the molecular etiology of GBM and introduces ChRO-seq which can now be used to map regulatory programs contributing to a variety of complex diseases.</p>

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Pre-existing chromatin states regulate KLF4 binding to eliminate leukemic cells [mouse ChIP]

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