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Electrostatic properties of disordered regions control transcription factor search and pioneer activity [ATAC-Seq]

ABSTRACT: Electrostatic properties of disordered regions control transcription factor search and pioneer activity [ATAC-Seq]

PROVIDER: PRJNA1230563 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR32544780_1.fastq.gz	Fastqsanger.gz
	SRR32544780_2.fastq.gz	Fastqsanger.gz

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Electrostatic properties of disordered regions control transcription factor search and pioneer activity [ChIP-Seq]

Project description:Electrostatic properties of disordered regions control transcription factor search and pioneer activity [ChIP-Seq]

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Electrostatic properties of disordered regions control transcription factor search and pioneer activity [ChIP-Seq]

Project description:Transcription factors (TFs) recognize specific target sites within cis-regulatory regions to control gene expression. Prokaryotic TFs combine 1D and 3D diffusion mechanisms to efficiently locate their binding sites. In contrast, the determinants of target search efficiency of eukaryotic TFs within the chromatinized genome are poorly characterized. Here we combine in vivo and in vitro single molecule imaging to dissect the role of charged disordered regions of the mammalian Sox2 and Sox17 TFs in their ability to search for their binding sites. We demonstrate that the DBD flanking region of Sox2 (DFRSox2) dramatically enhances Sox2 search efficiency as compared to the negatively-charged DFRSox17 through distinct mechanisms on naked versus nucleosomal DNA. Enhanced search on naked DNA is primarily mediated by an increase in target recognition rate during 1D sliding. In contrast, target site recognition within nucleosomal DNA is mainly enhanced by increased nonspecific interactions with nucleosomes, facilitating binding to closed chromatin and reinforcing pioneering activity. These findings provide critical insights into the biophysical mechanisms governing TF target search beyond the DBD, and demonstrate how charged disordered regions modulate TF target search on the chromatinized genome.

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Defining the mechanisms and properties of post-transcriptional regulatory disordered regions by high-throughput functional profiling

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Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity

Project description:In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how low-complexity intrinsically disordered regions (IDRs) affect chromatin and control cell fate is unclear. Here, we report deletion of an IDR of the pioneer factor TCF-1, termed “L1”, leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1 deficient cells. Mechanistically, L1 is required for activation of T cell genes and de-repression of GATA2 driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes which are subject to repression as T cells develop. These data suggest TCF-1’s intrinsically disordered N-terminus maintains T cell lineage fidelity.

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