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Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203650 | GEO | 2024/04/28

REPOSITORIES: GEO

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Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [ChIP-seq]

Project description:To dissect the molecular mechanisms of the transcription factor FOXA2 accessing nucleosomal targets and controlling cell fates, we combined live-cell single-molecule imaging, genome editing, chromatin binding, chromatin accessibility, and RNA sequence analysis. Using the hESC differentiation cellular system to anterior primitive streak (APS) and definitive endoderm (DE), we demonstrated by RNA-seq that FOXA2 is a lineage-determining transcription factor for DE formation and that its intrinsically disordered C-terminal domain (CTD) is essential for its normal function. Through ChIP-seq and ATAC-seq at multiple time points of exogenous expression, we also showed that the CTD is required for FOXA2 effectively accessing targets in closed chromatin and altering chromatin accessibility. Together with the single-molecule kinetics captured by fluorescence microscopy, this study uncovers new mechanistic insights on the activity of lineage-determining transcription factors in engaging chromatin and accessing nucleosomal targets.

2024-04-29 | GSE203644 | GEO

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [ATAC-seq]

2024-04-29 | GSE203649 | GEO

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [RNA-seq]

2024-04-29 | GSE203640 | GEO

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells

Project description:Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells

| PRJNA841678 | ENA

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [ChIP-seq]

Project description:Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [ChIP-seq]

| PRJNA841668 | ENA

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [ATAC-seq]

Project description:Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [ATAC-seq]

| PRJNA841673 | ENA

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [RNA-seq]

Project description:Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells [RNA-seq]

| PRJNA841659 | ENA

Shaping Chromatin States in Prostate Cancer by Pioneer Transcription Factors.

Project description:The androgen receptor (AR) is a critical therapeutic target in prostate cancer that responds to antagonists in primary disease, but inevitably becomes reactivated, signaling onset of the lethal castration-resistant prostate cancer (CRPC) stage. Epigenomic investigation of the chromatin environment and interacting partners required for AR transcriptional activity has uncovered three pioneer factors that open up chromatin and facilitate AR-driven transcriptional programs. FOXA1, HOXB13, and GATA2 are required for normal AR transcription in prostate epithelial development and for oncogenic AR transcription during prostate carcinogenesis. AR signaling is dependent upon these three pioneer factors both before and after the clinical transition from treatable androgen-dependent disease to untreatable CRPC. Agents targeting their respective DNA binding or downstream chromatin-remodeling events have shown promise in preclinical studies of CRPC. AR-independent functions of FOXA1, HOXB13, and GATA2 are emerging as well. While all three pioneer factors exert effects that promote carcinogenesis, some of their functions may inhibit certain stages of prostate cancer progression. In all, these pioneer factors represent some of the most promising potential therapeutic targets to emerge thus far from the study of the prostate cancer epigenome.

| S-EPMC7299826 | biostudies-literature

Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming.

Project description:Pioneer transcription factors (TFs) access silent chromatin and initiate cell-fate changes, using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer TF, has a winged helix DBD that resembles linker histone and thereby binds its target sites on nucleosomes and in compacted chromatin. Herein, we compare the nucleosome and chromatin targeting activities of Oct4 (POU DBD), Sox2 (HMG box DBD), Klf4 (zinc finger DBD), and c-Myc (bHLH DBD), which together reprogram somatic cells to pluripotency. Purified Oct4, Sox2, and Klf4 proteins can bind nucleosomes in vitro, and in vivo they preferentially target silent sites enriched for nucleosomes. Pioneer activity relates simply to the ability of a given DBD to target partial motifs displayed on the nucleosome surface. Such partial motif recognition can occur by coordinate binding between factors. Our findings provide insight into how pioneer factors can target naive chromatin sites.

| S-EPMC4409934 | biostudies-literature

Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA.

Project description:Biomolecular condensation constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, the reported forces generated by protein-DNA co-condensation are typically below one piconewton (pN), questioning its physiological significance. Moreover, the force-generating capacity of these condensates in the chromatin context remains unknown. Here, we show that Sox2, a nucleosome-binding pioneer TF, forms co-condensates with DNA and generates forces up to 7 pN, exerting considerable mechanical tension on DNA strands. We find that the disordered domains of Sox2 are required for maximum force generation but not for condensate formation. Furthermore, we show that nucleosomes dramatically attenuate the mechanical stress exerted by Sox2 by sequestering it from coalescing on bare DNA. Our findings reveal that TF-mediated DNA condensation can exert significant mechanical stress on the genome which can nonetheless be attenuated by the chromatin architecture.

| S-EPMC9271091 | biostudies-literature

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