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Chromatin Conformation Dynamics are essential to Control the Transcription of INK4/ARF locus

ABSTRACT: Chromatin Conformation Dynamics are essential to Control the Transcription of INK4/ARF locus

PROVIDER: PRJNA488260 | ENA |

REPOSITORIES: ENA

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Chromatin conformation dynamics are essential to control the transcription of INK4/ARF locus

Project description:Chromatin conformation dynamics are essential to control the transcription of INK4/ARF locus

| PRJNA490758 | ENA

Chromatin Conformation Dynamics are essential to Control the Transcription of INK4/ARF locus

Project description:The INK4/ARF (CDKN2A/B) locus has been identified as a hotspot for susceptibility to genetic changes associated with a vast variety of cancers and aging related diseases including coronary artery disease and type II diabetes. Using chromatin Capture-C technologies, we discovered a distal enhancer upstream INK4/ARF looped to CDKN2A, ARF and CDKN2B in human fibroblast cells IMR90 and cancer cell lines HCT116 and SEM, but absent in human fibroblast cell-derived induced pluripotent stem cells, which maintained an epigenetically silenced INK4/ARF locus. Bi-allelic deletion of the ~1.4 Kb core enhancer sequence by CRISPR/Cas9 technology in human HCT116 cells abrogated the long-range chromatin interaction, thereafter disrupting gene expression of these tumor suppressor genes. Moreover, cross-species conservation of the distal enhancer elements between human and mouse was observed.

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Chromatin conformation dynamics are essential to control the transcription of INK4/ARF locus

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A minimal DNA sequence within the ARF promoter represses p16INK4A expression via long-range chromatin interaction [Capture-C]

Project description:Loss of function of CDKN2A/B, also known as INK4/ARF [encoding for p16INK4A, p15INK4B, and p14ARF (mouse p19Arf)]), confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand molecular regulation of the locus, we knocked P2A-mCherry into the C-terminus of p16INK4A, and this construct faithfully recapitulated the endogenous transcription. Using this reporter cell line, we performed a noncoding tiling pooled screening targeting open chromatin regions spanning the approximately 500-kb region in the topological associated domain that includes p16INK4A. In both Cas9- and dCas9-KRAB–mediated screenings, we identified a 42-bp DNA sequence within exon 1β of the ARF gene, as the repressive element controlling p16INK4A expression. Chromatin conformation capture indicated that inactivating this element abolished the physical interaction between p15INK4B and ARF, thereby abolishing p16INK4A repression. This study has revealed a new mechanism of transcriptional regulation of p16INK4A by long-range chromatin interaction.

2019-12-17 | GSE125666 | GEO

A minimal DNA sequence within the ARF promoter represses p16INK4A expression via long-range chromatin interaction [Cut&Run ChiP-seq]

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An inter-dependent network of enhancers regulates INK4a/ARF locus

Project description:By functionally dissecting densest enhancer cluster in the gene desert at 9P21 locus, we identified a non-redundant inter-dependent enhancer network that functions over long distances, the perturbation in any enhancer in the network results in the complete collapse of entire enhancer cluster and target genes activity. The enhancer network can be targeted to regulate INK4a/ARF locus in associated pathophysiologies and cancers.

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Dishevelled-3 protein conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1

Project description:Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we developed the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein Kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.

2019-04-02 | PXD013085 | Pride

Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locus

Project description:Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locus

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The Ink4a/Arf locus operates as a regulator of the circadian clock modulating RAS activity

Project description:Upon perturbations by RAS and by shBMAL, differential effects on the circadian phenotype were observed in wild type and Ink4a/Arf knockout MEFs which could be reproduced by modelling simulations and correlated with opposing cell cycle fate decisions.

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2022-07-20 | PXD033382 | Pride

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