AI Article Synopsis
- Deregulated chromatin architecture, particularly due to the loss of CTCF, plays a significant role in cancer progression, especially in breast cancer.
- Loss of a single CTCF allele disrupts chromatin insulation, leading to enhanced cell invasion and altered chromatin structure, affecting oncogene expression.
- This reorganization creates new promoter-enhancer interactions that make cancer cells more sensitive to mTOR inhibitors, indicating a potential therapeutic target.
Article Abstract
The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9457068 | PMC |
| http://dx.doi.org/10.1073/pnas.2203452119 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Hypermethylation at 45S rDNA promoter in cancers.
PLoS One
January 2025
Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, Vietnam.
The ribosomal genes (rDNA genes) encode 47S rRNA which accounts for up to 80% of all cellular RNA. At any given time, no more than 50% of rDNA genes are actively transcribed, and the other half is silent by forming heterochromatin structures through DNA methylation. In cancer cells, upregulation of ribosome biogenesis has been recognized as a hallmark feature, thus, the reduced methylation of rDNA promoter has been thought to support conformational changes of chromatin accessibility and the subsequent increase in rDNA transcription.
View Article and Find Full Text PDFEscalation of genome defense capacity enables control of an expanding meiotic driver.
Proc Natl Acad Sci U S A
January 2025
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
From RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases.
View Article and Find Full Text PDFDivergent Contribution of Cytoplasmic Actins to Nuclear Structure of Lung Cancer Cells.
Int J Mol Sci
December 2024
Scientific Research Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia.
A growing body of evidence suggests that actin plays a role in nuclear architecture, genome organisation, and regulation. Our study of human lung adenocarcinoma cells demonstrates that the equilibrium between actin isoforms affects the composition of the nuclear lamina, which in turn influences nuclear stiffness and cellular behaviour. The downregulation of β-actin resulted in an increase in nuclear area, accompanied by a decrease in A-type lamins and an enhancement in lamin B2.
View Article and Find Full Text PDFChromatin-centric insights into DNA replication.
Trends Genet
January 2025
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, PKU-THU Center for Life Sciences, Peking University, Beijing 100871, China; Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, Sichuan 610213, China. Electronic address:
DNA replication ensures the precise transmission of genetic information from parent to daughter cells. In eukaryotes, this process involves the replication of every base pair within a highly complex chromatin environment, encompassing multiple levels of chromatin structure and various chromatin metabolic processes. Recent evidence has demonstrated that DNA replication is strictly regulated in both temporal and spatial dimensions by factors such as 3D genome structure and transcription, which is crucial for maintaining genomic stability in each cell cycle.
View Article and Find Full Text PDFMost genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and retinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!