Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Redirecting the pioneering function of FOXA1 with covalent small molecules

ABSTRACT: Pioneer transcription factors (TFs) exhibit a special 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 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Prostate Adenocarcinoma,Lymphoma

SUBMITTER: Sang Joon Won

LAB HEAD: Benjamin F. Cravatt

PROVIDER: PXD050685 | Pride | 2024-09-05

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20200827_22RV1_20uMWX2_V1to10_01.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_02.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_03.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_04.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_05.raw	Raw

Items per page:

1 - 5 of 89

Similar Datasets

Redirecting the pioneering function of FOXA1 with covalent small molecules [ChIP-seq]

Project description:Pioneer transcription factors (TFs) exhibit a special 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 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.

2024-03-26 | GSE261803 | GEO

Redirecting the pioneering function of FOXA1 with covalent small molecules [ATAC-seq]

2024-03-26 | GSE261801 | GEO

Redirecting the pioneering function of FOXA1 with covalent small molecules [ATAC-Seq]

2024-09-23 | GSE273817 | GEO

Redirecting the pioneering function of FOXA1 with covalent small molecules

2024-09-23 | GSE273816 | GEO

A quantitative metric of pioneer activity reveals that HNF4A has stronger in vivo pioneer activity than FOXA1

Project description:We and others have suggested that pioneer activity–a transcription factor’s (TF’s) ability to bind and open inaccessible loci–is not a qualitative trait limited to a select class of pioneer TFs. We hypothesize that most TFs display pioneering activity that depends on the TF concentration and the motif content at their target loci. Here we present a quantitative measure of pioneer activity that captures the relative difference in a TF’s ability to bind accessible versus inaccessible DNA. The metric is based on experiments that use CUT&Tag to measure binding of doxycycline (dox) inducible TFs. For each location across the genome we determine a “dox50,” the concentration of dox required for a TF to reach half-maximal occupancy. We propose that the ratio of a TF’s average dox50 between ATAC-seq labeled inaccessible and accessible binding sites, its Δdox50, is a measure of its pioneer activity. We measured Δdox50’s for the endodermal TFs FOXA1 and HNF4A and show that HNF4A has a smaller Δdox50 than FOXA1, suggesting that HNF4A has stronger pioneer activity than FOXA1. We further show that FOXA1 binding sites with more copies of its motif have a lower Δdox50, suggesting that strong motif content may compensate for weak pioneer activity. Our results suggest that Δdox50s, or other similar measures that assess the difference in TF affinity for inaccessible and accessible DNA, are reasonable measures of pioneer activity.

2022-05-27 | GSE204726 | GEO

A test of the pioneer factor hypothesis using ectopic liver gene activation [RNAseq]

Project description:The Pioneer Factor Hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (nonPFs) that activate batteries of silent genes. We tested the PFH by expressing the endodermal PF FoxA1 and nonPF Hnf4a in K562 lymphoblast cells. While co-expression of FoxA1 and Hnf4a activated a burst of endoderm-specific gene expression, we found no evidence for functional distinction between these two TFs. When expressed independently, both TFs bound and opened inaccessible sites, activated endodermal genes, and “pioneered” for each other, although FoxA1 required fewer copies of its motif to bind at inaccessible sites. A subset of targets required both TFs, but the mode of action at these targets did not conform to the sequential activity predicted by the PFH. From these results we propose an alternative to the PFH where “pioneer activity” depends not on the existence of discrete TF subclasses, but on TF binding affinity and genomic context.

2021-08-18 | GSE182190 | GEO

A test of the pioneer factor hypothesis using ectopic liver gene activation [CUTTag]

2021-08-18 | GSE182189 | GEO

A test of the pioneer factor hypothesis using ectopic liver gene activation [ATACseq]

2021-08-18 | GSE182188 | GEO

A test of the pioneer factor hypothesis using ectopic liver gene activation [0.05dox RNAseq]

2021-11-18 | GSE189020 | GEO

A test of the pioneer factor hypothesis using ectopic liver gene activation [0.05dox CUTTag]

2021-11-18 | GSE189006 | GEO