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Liquid condensation of reprogramming factor KLF4 with DNA provides a mechanism for chromatin organization.

ABSTRACT: Expression of a few master transcription factors can reprogram the epigenetic landscape and three-dimensional chromatin topology of differentiated cells and achieve pluripotency. During reprogramming, thousands of long-range chromatin contacts are altered, and changes in promoter association with enhancers dramatically influence transcription. Molecular participants at these sites have been identified, but how this re-organization might be orchestrated is not known. Biomolecular condensation is implicated in subcellular organization, including the recruitment of RNA polymerase in transcriptional activation. Here, we show that reprogramming factor KLF4 undergoes biomolecular condensation even in the absence of its intrinsically disordered region. Liquid-liquid condensation of the isolated KLF4 DNA binding domain with a DNA fragment from the NANOG proximal promoter is enhanced by CpG methylation of a KLF4 cognate binding site. We propose KLF4-mediated condensation as one mechanism for selectively organizing and re-organizing the genome based on the local sequence and epigenetic state.

SUBMITTER: Sharma R

PROVIDER: S-EPMC8458463 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Reversible chromatin condensation by the DNA repair and demethylation factor thymine DNA glycosylase.

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Liquid-Liquid Phase Separation of Histone Proteins in Cells: Role in Chromatin Organization.

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A di-acetyl-decorated chromatin signature couples liquid condensation to suppress DNA end synapsis

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-02-16 | GSE252296 | GEO

Diffusion-driven looping provides a consistent framework for chromatin organization.

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Reprogramming factor expression initiates widespread targeted chromatin remodeling.

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DNA-induced liquid phase condensation of cGAS activates innate immune signaling.

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Project description:In eukaryotes, higher-order chromatin organization is spatiotemporally regulated as domains, for various cellular functions. However, their physical nature in living cells remains unclear (e.g., condensed domains or extended fiber loops; liquid-like or solid-like). Using novel approaches combining genomics, single-nucleosome imaging, and computational modeling, we investigated the physical organization and behavior of early DNA replicated regions in human cells, which correspond to Hi-C contact domains with active chromatin marks. Motion correlation analysis of two neighbor nucleosomes shows that nucleosomes form physically condensed domains with ~150-nm diameters, even in active chromatin regions. The mean-square displacement analysis between two neighbor nucleosomes demonstrates that nucleosomes behave like a liquid in the condensed domain on the ~150 nm/~0.5 s spatiotemporal scale, which facilitates chromatin accessibility. Beyond the micrometers/minutes scale, chromatin seems solid-like, which may contribute to maintaining genome integrity. Our study reveals the viscoelastic principle of the chromatin polymer; chromatin is locally dynamic and reactive but globally stable.

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