Podcast
Questions and Answers
Combining DNA methylation inhibitors and ______ inhibitors is a clinically advanced epigenetic therapy.
Combining DNA methylation inhibitors and ______ inhibitors is a clinically advanced epigenetic therapy.
HDAC
Cytotoxic therapies directly kill rapidly dividing cells, including ______ cells.
Cytotoxic therapies directly kill rapidly dividing cells, including ______ cells.
cancer
Epigenetic therapies can help reverse the epigenetic ______ that leads to chemotherapy resistance.
Epigenetic therapies can help reverse the epigenetic ______ that leads to chemotherapy resistance.
silencing
Combining epigenetic therapies with conventional cytotoxic therapies can improve cancer treatment ______.
Combining epigenetic therapies with conventional cytotoxic therapies can improve cancer treatment ______.
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5-Aza-CR is known for reversing ______-mediated silencing.
5-Aza-CR is known for reversing ______-mediated silencing.
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Epigenetics refers to changes in gene activity that don't involve alterations to the ______ sequence itself.
Epigenetics refers to changes in gene activity that don't involve alterations to the ______ sequence itself.
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Key epigenetic mechanisms include DNA methylation, histone modifications, and ______ positioning.
Key epigenetic mechanisms include DNA methylation, histone modifications, and ______ positioning.
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DNA methylation involves adding a ______ group to a cytosine base in DNA.
DNA methylation involves adding a ______ group to a cytosine base in DNA.
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Histones are proteins that DNA wraps around, and they can be modified with various chemical ______.
Histones are proteins that DNA wraps around, and they can be modified with various chemical ______.
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In some cancers, histone modifications are ______, contributing to abnormal gene activity.
In some cancers, histone modifications are ______, contributing to abnormal gene activity.
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A global loss of DNA methylation (hypomethylation) in cancer cells leads to genomic ______.
A global loss of DNA methylation (hypomethylation) in cancer cells leads to genomic ______.
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5-Azacytidine and its deoxy derivative are approved drugs that act as DNA methylation ______.
5-Azacytidine and its deoxy derivative are approved drugs that act as DNA methylation ______.
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At higher doses, methylation inhibitors like 5-Azacytidine induce ______.
At higher doses, methylation inhibitors like 5-Azacytidine induce ______.
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Histone deacetylase (HDAC) inhibitors increase histone ______ levels, promoting gene reactivation.
Histone deacetylase (HDAC) inhibitors increase histone ______ levels, promoting gene reactivation.
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Lysine-specific demethylase 1 (LSD1) removes methyl groups from ______, affecting gene expression.
Lysine-specific demethylase 1 (LSD1) removes methyl groups from ______, affecting gene expression.
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EZH2 catalyzes H3K27 ______, which acts as a repressive mark.
EZH2 catalyzes H3K27 ______, which acts as a repressive mark.
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DZNep is a potential EZH2 inhibitor that depletes ______ components.
DZNep is a potential EZH2 inhibitor that depletes ______ components.
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MicroRNAs primarily act by binding to ______, leading to gene silencing.
MicroRNAs primarily act by binding to ______, leading to gene silencing.
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Dysregulation of miRNA expression is common in many diseases, including ______.
Dysregulation of miRNA expression is common in many diseases, including ______.
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The combined epigenetic therapies aim to tackle the disease on ______ fronts.
The combined epigenetic therapies aim to tackle the disease on ______ fronts.
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Current HDAC inhibitors often lack ______ and can lead to side effects.
Current HDAC inhibitors often lack ______ and can lead to side effects.
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Signaling pathways such as the PI3K/Akt pathway can modulate the activity of ______.
Signaling pathways such as the PI3K/Akt pathway can modulate the activity of ______.
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The mechanisms of miRNAs can lead to either mRNA ______ or translational repression.
The mechanisms of miRNAs can lead to either mRNA ______ or translational repression.
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The global hypomethylating effects can activate ______ and increase genomic instability.
The global hypomethylating effects can activate ______ and increase genomic instability.
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Azanucleosides' mechanism of action is dependent on DNA replication in the ______ phase of the cell cycle.
Azanucleosides' mechanism of action is dependent on DNA replication in the ______ phase of the cell cycle.
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DNA methylation levels can return to pre-treatment levels after the drugs are ______.
DNA methylation levels can return to pre-treatment levels after the drugs are ______.
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Histones are proteins that act as spools around which ______ winds.
Histones are proteins that act as spools around which ______ winds.
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Acetylation generally associates with gene ______.
Acetylation generally associates with gene ______.
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H3K4 methylation is typically associated with active ______.
H3K4 methylation is typically associated with active ______.
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Histone modifications contribute to the complex ______ code that influences gene expression.
Histone modifications contribute to the complex ______ code that influences gene expression.
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Phosphorylation, ubiquitylation, and sumoylation are examples of ______ modifications.
Phosphorylation, ubiquitylation, and sumoylation are examples of ______ modifications.
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Histone-modifying enzymes are considered potential therapeutic ______.
Histone-modifying enzymes are considered potential therapeutic ______.
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The basic units of chromatin, where DNA is compacted, are called ______.
The basic units of chromatin, where DNA is compacted, are called ______.
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Study Notes
Epigenetic Modifications as Therapeutic Targets
- Epigenetics involves changes in gene activity without altering DNA sequence. These changes are heritable and reversible, making them potential therapeutic targets.
- Key epigenetic mechanisms include DNA methylation, histone modifications, and nucleosome positioning.
- DNA Methylation: Adding a methyl group to a cytosine base often silences the associated gene. In cancer, tumor suppressor genes are frequently abnormally methylated, hindering their function.
- Histone Modifications: Histones package DNA. Modifications like acetylation or methylation affect DNA packaging, altering gene expression. Abnormal histone modifications contribute to some cancers.
- Nucleosome Positioning: The location of nucleosomes along DNA impacts which genes are accessible for transcription. Changes in nucleosome positioning contribute to disease.
- Epigenetic Abnormalities: Linked to a variety of conditions beyond cancer, including diabetes and neurological disorders.
DNA Methylation - Mechanism and Therapeutic Use
- Cancer is characterized by global hypomethylation (reduced DNA methylation) but specific promoter hypermethylation (increased methylation), often targeting tumor suppressor genes within CpG islands.
- 5-Azacytidine (5-Aza-CR) and 5-Aza-2'-deoxycytidine (5-Aza-CdR, decitabine) are approved DNA methylation inhibitors.
- These nucleoside analogs incorporate into DNA, inhibiting DNA methyltransferase (DNMT) enzymes, causing demethylation.
- Zebularine and S110 are other methylation inhibitors with potentially enhanced profiles.
- Challenges: Lack of specificity; global hypomethylation can activate oncogenes and increase genomic instability. Also, these drugs are dependent on DNA replication for activity (S-phase), limiting their effectiveness against slower-growing cancers.
Histone Modifications - The Basics
- Histones are proteins around which DNA is wound.
- Histone modifications, such as acetylation (adding acetyl groups) and methylation (adding methyl groups), are vital for gene expression regulation.
- Acetylation relaxes chromatin structure, promoting gene expression.
- Methylation can either activate or repress expression. Specific combinations of modifications form a complex 'histone code'.
- Other modifications include phosphorylation, ubiquitination, and sumoylation.
- Histone modifiers (e.g., HDACs, LSD1, EZH2) are potential therapeutic targets.
Therapeutic Targets - Inhibitors
- Histone Deacetylase (HDAC) Inhibitors: Inhibit HDACs (enzymes that remove acetyl groups), increasing histone acetylation, which often reactivates silenced tumor suppressor genes.
- Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Inhibit LSD1, which removes methyl groups from H3K4 and potentially H3K9, potentially restoring or altering gene expression.
- EZH2 Inhibitors: Inhibit EZH2, a component of PRC2, impacting H3K27 methylation, crucial for development of effective inhibitors.
- Inhibitors' specificities influence the spectrum of therapeutic targets.
Combining Epigenetic Therapies
- Cancers often involve multiple epigenetic alterations. Combination therapies offer a more comprehensive approach to treating multiple disease targets.
- Combining DNA methylation inhibitors with other epigenetic inhibitors (e.g., HDAC inhibitors) exhibits synergistic effects in various contexts and cancer types.
- Combining epigenetic therapies with conventional cytotoxic therapies can overcome epigenetic resistance mechanisms and improve efficacy. Epigenetic resistance can arise from drug-sensitivity gene silencing by epigenetics.
Reversibility and Continued Treatment
- DNA methylation levels can revert to pre-treatment levels after treatment discontinuation, indicating the need for continuous administration.
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Description
This quiz explores the crucial role of epigenetic modifications, such as DNA methylation, histone modifications, and nucleosome positioning, as potential therapeutic targets in various diseases. Understand how these epigenetic changes influence gene expression and their implications in conditions like cancer. Dive into the mechanisms driving heritable and reversible genetic activity.
