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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119947 | GEO | 2024/08/01

REPOSITORIES: GEO

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

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Chromosomal aberration of asbestos-induced malignant mesothelioma in rats

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Project description:The human CDKN2A locus encodes two distinct proteins, p16(INK4A) and p14(ARF) [mouse p19(Arf)], designated INK4A and ARF herein, that are translated from alternatively spliced mRNAs. Human ARF is implicated as a tumor suppressor gene, mainly in association with the simultaneous deletion of INK4A. However, questions remain as to whether loss of ARF alone is sufficient to drive tumorigenesis. Here we report that mice deficient for Arf are susceptible to accelerated asbestos-induced malignant mesothelioma (MM). MMs arising in Arf (+/-) mice consistently exhibit biallelic inactivation of Arf, but unexpectedly, do not acquire additional recurrent genetic alterations that we previously identified in asbestos-induced MMs arising in Nf2 (+/-) mice. Array CGH analysis was used to detect a recurrent deletion at chromosome 4C6. A candidate in this region, Faf1 (FAS-associated factor 1), was further explored because it encodes a protein implicated in tumor cell survival and in the pathogenesis of some human tumor types. We confirmed hemizygous loss of Faf1 and down regulation of Faf1 protein in a series of MMs from Arf (+/-) mice, and then showed that Faf1 regulates TNFalpha-mediated NFkappaB signaling, a mechanism previously implicated in asbestos-induced oncogenesis of human mesothelial cells. Collectively, these investigations divulge important information regarding the significance of Arf inactivation in MM pathogenesis, and implicate Faf1 as a key component in the TNFalpha/NFkappaB signaling node that has now been independently implicated in the asbestos-induced oncogenesis.

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