Identification of mammalian transcription factors that bind to inaccessible chromatin

Abstract

Transcription factors (TFs) are proteins that affect gene expression by binding to regulatory regions of DNA in a sequence specific manner. The binding of TFs to DNA is controlled by many factors, including the DNA sequence, concentration of TF, chromatin accessibility and co-factors. Here, we systematically investigated the binding mechanism of hundreds of TFs by analysing ChIP-seq data with our explainable statistical model, ChIPanalyser. This tool uses as inputs the DNA sequence binding motif; the capacity to distinguish between strong and weak binding sites; the concentration of TF; and chromatin accessibility. We found that approximately one third of TFs are predicted to bind the genome in a DNA accessibility independent fashion, which includes TFs that can open the chromatin, their co-factors and TFs with similar motifs. Our model predicted this to be the case when the TF binds to its strongest binding regions in the genome, and only a small number of TFs have the capacity to bind dense chromatin at their weakest binding regions, such as CTCF, USF2 and CEBPB. Our study demonstrated that the binding of hundreds of human and mouse TFs is predicted by ChIPanalyser with high accuracy and showed that many TFs can bind dense chromatin.

Detection of new pioneer transcription factors as cell-type specific nucleosome binders

“…To validate the remaining 20 PTF predictions, we performed literature searches and found that RFX5 had the ability to displace nucleosomes 14 . In addition, many of the predicted PTFs such as ZKSCAN1, USF1,USF2 and SRF, were confirmed by a recent study 57 .…”

“…Among those with a high PCC > 0.5, were ZKSCAN1, ESR1, NFATC3, ZBTB7B, MAX, and TBX2. Half of them were also predicted to be pioneer by a recent study 57 . With the exception of a few cases, none of transcription factors was identified as being pioneer in all cell types because pioneer activity is often cell- type specific.…”

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

“…The increased frequency of binding motifs related to the central ISR transcriptional regulator ATF4, as well as ATF4 targets, is suggestive that retrograde signaling might have the potential to alter chromatin structure. Indeed, ATF4 is a pioneer factor capable of altering chromatin accessibility (113,114), which could be consistent with the transcriptional signatures observed in metabolic tissues with mitochondrial damage. However, it is unclear how the induction of ATF4 remodels sites of chromatin accessibility that are lost at key markers of β cell maturity, such as NeuroD1 (80).…”

Detection of new pioneer transcription factors as cell-type-specific nucleosome binders

“…To validate the remaining 20 PTF predictions, we performed literature searches and found that RFX5 had the ability to displace nucleosomes ( Zhu et al, 2018 ). In addition, many of the predicted PTFs, such as ZKSCAN1, USF1, USF2, and SRF, were confirmed by a recent study ( Pop et al, 2023 ).…”