Pioneer factors — key regulators of chromatin and gene expression

Bulyk, Martha L.; Drouin, Jacques; Harrison, Melissa M.; Taipale, Jussi; Zaret, Kenneth S.

doi:10.1038/s41576-023-00648-z

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…Indeed, the acute nature of chemical biology studies allowed us to investigate the pioneering capabilities of endogenous FOXA1 while avoiding the potential limitations, such as changes in cell growth or cell state, imposed by prolonged genetic manipulations of this essential lineage TF 42 . In considering how the chemical redirection of FOXA1 to compacted chromatin regions triggers remodeling to achieve an open chromatin state, we suspect, as others have suggested 23,56,65 , that FOXA1 binding likely paves a path for ATP-dependent chromatin remodelers to promote the stable formation of open chromatin. Consistent with this hypothesis, we found by co-IP experiments that FOXA1 associates with chromatin remodeling such as SWI-SNF and these interactions were unperturbed by WX-02-23 engagement.…”

Section: Discussionmentioning

confidence: 92%

“…Despite the clear importance of pioneer factors in normal development and tumorigenesis, the mechanisms of action of these key regulatory proteins remain difficult to study in living systems. Investigations of FOXA1 and other pioneer factors have largely relied on correlating in vitro biochemical activities with cellular phenotypes derived from genetic disruption or heterologous expression systems 23 . However, inferring the direct biochemical functions of TFs, especially those involved in the dynamic regulation of chromatin structure, from cell models of prolonged genetic perturbation or protein overexpression can be problematic 24,25 .…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, the lineage relationship between cancer cells and pioneer TFs like FOXA1 often results in strong growth dependency on these proteins, as revealed in the Cancer Dependency Map 26 , that further hinders their study by constitutive genetic disruption methods. Our understanding of the direct mechanisms by which pioneer TFs function in cells accordingly remain incomplete 23 .…”

Section: Introductionmentioning

confidence: 99%

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Redirecting the pioneering function of FOXA1 with covalent small molecules

Won,

Zhang,

Reinhardt

et al. 2024

Preprint

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Pioneer transcription factors (TFs) exhibit a specialized ability to bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic small molecules that stereoselectively and site-specifically bind the pioneer TF, FOXA1, at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the covalent ligands relax the canonical DNA binding preference of FOXA1 by strengthening interactions with suboptimal ancillary sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Redirecting the pioneering function of FOXA1 with covalent small molecules

Won,

Zhang,

Reinhardt

et al. 2024

Preprint

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“…S1). Cis-regulatory modules (CRMs) typically include an array of transcription factor (TF) binding sites, with the majority of TFs only binding to DNA sequence in open chromatin conformations [20–22]. Putative CRMs in ‘Fairchild’ were identified by mapping accessible chromatin regions (ACRs) using ATAC-seq of nuclei extracted from leaf tissue.…”

Section: Resultsmentioning

confidence: 99%

Haplotype phased genome of ‘Fairchild’ mandarin highlights influence of local chromatin state on gene expression

Diaz,

Ostovar,

Chen

et al. 2024

Preprint

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Background: Cis-regulatory sequences control gene expression through the coordinated action of transcription factors and their associated partners. Both genetic and epigenetic perturbation of cis-regulatory sequences can lead to novel patterns of gene expression. Phased genome assemblies now enable the local dissection of linkages between cis-regulatory sequences, including their epigenetic state, and gene expression to further characterize gene regulation in heterozygous genomes. Results: We assembled a locally phased genome for a mandarin hybrid named Fairchild to explore the molecular signatures of allele-specific gene expression. With genome phasing, genes with allele-specific expression were paired with haplotype-specific chromatin states, including levels of chromatin accessibility, histone modifications, and DNA methylation. We found that 30% of variation in allele-specific expression could be attributed to haplotype associated factors, with allelic levels of chromatin accessibility and three histone modifications in gene bodies having the most influence. Structural variants in promoter regions were also associated with allele-specific expression, including specific enrichments of hAT and MULE-MuDR DNA transposon sequences. Mining of cis-regulatory sequences underlying regions with allelic variation in chromatin accessibility revealed a paternally-associated sequence motif bound by ERF48, a target of the Polycomb repressive complex 2 (PRC2), and sequence similarity of this motif corresponded to local levels of H3K27me3, a signature of PRC2 activity. Conclusions: Using a locally phased assembly of a heterozygous citrus cultivar, we dissected the interplay between genetic variants and molecular phenotypes with the goal of revealing functional cis-regulatory sequences and exploring the evolution of gene regulation.

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“…Among these potential factors, nucleosomes have a major inhibitory effect on the binding of many TFs, and chromatin accessibility is therefore considered to be the key determinant of TF binding 12,[18][19][20] .A subset of TFs known as "pioneer factors" (PFs) can stably associate with nucleosomal templates by recognizing partial sequence motifs and/or interacting with histones 14,[21][22][23][24] . Inside cells, PFs can overcome the nucleosomal barrier by targeting nucleosome-embedded motifs and generating accessible chromatin, which enables the binding of other TFs and triggers transcriptional activation [25][26][27][28] . Given their ability to open chromatin in vivo and bind nucleosomal DNA in vitro, PFs should be able to access most, if not all, consensus motifs in the genome.…”

mentioning

confidence: 99%

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1

Xu,

Kleinschmidt,

Yang

et al. 2023

Preprint

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Despite the unique ability of pioneer transcription factors (PFs) to target nucleosomal sites in closed chromatin, they only bind a small fraction of their genomic motifs. The underlying mechanism of this selectivity is not well understood. Here, we design a high-throughput assay called ChIP-ISO to systematically dissect sequence features affecting the binding specificity of a classic PF, FOXA1. Combining ChIP-ISO within vitroand neural network analyses, we find that 1) FOXA1 binding is strongly affected by co-binding TFs AP-1 and CEBPB, 2) FOXA1 and AP-1 show binding cooperativityin vitro, 3) FOXA1’s binding is determined more by local sequences than chromatin context, including eu-/heterochromatin, and 4) AP-1 is partially responsible for differential binding of FOXA1 in different cell types. Our study presents a framework for elucidating genetic rules underlying PF binding specificity and reveals a mechanism for context-specific regulation of its binding.

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Pioneer factors — key regulators of chromatin and gene expression

Cited by 15 publications

References 42 publications

Redirecting the pioneering function of FOXA1 with covalent small molecules

Redirecting the pioneering function of FOXA1 with covalent small molecules

Haplotype phased genome of ‘Fairchild’ mandarin highlights influence of local chromatin state on gene expression

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1

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