Modeling epigenetic lesions that cause gliomas.
Gilbert J Rahme1, Nauman M Javed1, Kaitlyn L Puorro2
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Cell Biology and Pathology, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell
|July 26, 2023
Summary
Disrupting a CTCF insulator near PDGFRA in mouse cells increases proliferation. Combined with Cdkn2a tumor suppressor loss, this drives glioma formation, offering insights into cancer drivers.
Area of Science:
- Cancer biology
- Epigenetics
- Genomics
Background:
- Epigenetic alterations disrupting regulatory elements are potential cancer drivers.
- Experimental models are needed to validate the tumorigenic impact of these lesions.
- Isocitrate dehydrogenase-mutant gliomas show DNA hypermethylation, suggesting epigenetic drivers.
Purpose of the Study:
- To model epigenetic aberrations in isocitrate dehydrogenase-mutant gliomas.
- To investigate the role of a CTCF insulator disruption near PDGFRA in gliomagenesis.
- To understand the cooperation between insulator disruption and tumor suppressor gene silencing.
Main Methods:
- Modeling of CTCF insulator disruption in mouse oligodendrocyte progenitor cells (OPCs).
- Analysis of PDGFRA oncogene activation by an OPC-specific enhancer.
- Assessment of Cdkn2a tumor suppressor silencing and its cooperation with insulator loss.
- In vivo gliomagenesis studies.
Main Results:
- Disruption of the CTCF insulator in mouse OPCs led to PDGFRA activation and increased proliferation.
- Methylation-dependent silencing of Cdkn2a cooperated with insulator loss.
- Coordinate inactivation of the PDGFRA insulator and Cdkn2a drove gliomagenesis in vivo.
- Human-specific CpG richness in the insulator complicates mouse modeling but suggests a role in human glioma risk.
Conclusions:
- Recurrent epigenetic lesions can drive oligodendrocyte progenitor cell proliferation in vitro.
- Coordinated epigenetic alterations, including insulator disruption and tumor suppressor silencing, drive gliomagenesis in vivo.
- The study highlights the potential of epigenetic lesions as cancer drivers and the challenges in modeling human-specific epigenetic features.
Keywords:
CDKN2ADNA methylationIDH mutationPDGFRAcell of originchromatingenome topologygliomanuclear architectureoligodendrocyte progenitor cellsMore Related Videos
06:32Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures
Published on: January 9, 2019
7.9K
04:01Author Spotlight: Modeling Brain Tumors In Vivo Using Electroporation-Based Delivery of Plasmid DNA Representing Patient Mutation Signatures
Published on: June 23, 2023
1.7K
Related Concept Videos
02:21Cancers Originate from Somatic Mutations in a Single Cell
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
02:07Tumor Progression
Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
02:43Mouse Models of Cancer Study
Mice have long served as models for studying human biology and pathology because of their phylogenetic and physiological similarity with humans. They are also easy to maintain and breed in the laboratory, and hence, many inbred strains are now available for research. Studies on mice have contributed immeasurably to our understanding of cancer biology.
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
02:43Mouse Models of Cancer Study
Mice have long served as models for studying human biology and pathology because of their phylogenetic and physiological similarity with humans. They are also easy to maintain and breed in the laboratory, and hence, many inbred strains are now available for research. Studies on mice have contributed immeasurably to our understanding of cancer biology.
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...