Week 2 CH 6 Review -- Pathophysiology

3 major types of Epigenetics

(1) DNA methylation, which results from attachment of a methyl group to a cytosine base that is followed by a guanine base (a CpG dinucleotide) (2) histone modification, which includes histone acetylation and alterations in chromatin (3) micro-ribonucleic acids (miRNAs or miRs), short nucleotides derived from introns of protein coding genes or transcribed as independent genes from regions of the genome whose functions, if any, remain poorly understood. MiRNAs regulate diverse signaling pathways.

Colon cancer (associated gene)

An inherited form of colon cancer is related to methylation of the promoter region of the MLH1 gene.

Epigenetics

Bridges DNA information and function by modifying gene expression Does not alter DNA sequence. Inheritable chemical modifications of DNA sequence Environmental factors, such as diet and exposure to certain chemicals, may cause epigenetic modifications.

Hypomethylation of oncogenes results in

Decreased methylation increases the activity of oncogenes. Hypomethylation increases as tumors progress from benign neoplasms to malignancy.

Differences between DNA sequence mutations and epigenetic modifications

Epigenetic modifications are REVERSIBLE

What could cause disease to manifest in one twin but not the other?

Epigenetic modifications can cause individuals with the same deoxyribonucleic acid (DNA) sequences (such as identical twins) to have different disease profiles.

Gene Silencing

Genes are silenced depending on which parent transmits them, is known as imprinting, and the transcriptionally silenced genes are said to be "imprinted."

Retinoblastoma (associated gene)

Hypermethylation of the promoter region on the RB1 gene is often seen in retinoblastoma.

Silenced gene of a gene pair

Imprinting Transcriptionally silenced genes are then said to be imprinted

What is the relationship between methylation and tumor progression

Methylation densities decline as tumors progress, which can increase the activity of oncogenes, causing tumors to progress from benign neoplasms to malignancy. Additionally, the promoter regions of tumor-suppressor genes are often hypermethylated. These elevated methylation levels decrease their rate of transcription at these critical genes, thus reducing the ability to inhibit tumor formation. Hypermethylation also is seen in miRNA genes and is associated with tumorigenesis.

Housekeeping genes

Necessary for the function and maintenance of all cells

Non-imprinted Allele

Not methylated, transcriptionally active gene

How do noncoding RNAs regulate gene expression?

RNA interference, gene co-suppression, gene silencing, imprinting, and DNA demethylation.

Renal cell carcinoma (associated gene)

Renal cell carcinoma in some cases is related to the VHL gene.

Breast cancer (associated gene)

The BRCA1 and BRCA2 genes are observed in some cases of inherited breast cancer.

transgenerational inheritance

The heritable transmission to future generations of epigenetic modifications

Imprinted Allele

Transcriptionally silenced genes, heavily methylated allele ex. Prader Willi syndrome

Russell-Silver syndrome.

Type of dwarfism Growth retardation, proportionate short stature, leg-length discrepancy, and a small, triangular-shaped face It involves hypomethylation of H19 and IGF2. Uniparental Disomy of chromosome 7

Demethylating agents

Unlike DNA sequence mutations, epigenetic modifications can be reversed through pharmaceutical intervention. For example, 5-azacytidine, a demethylating agent. Used in treatment of leukemia and myelodysplastic syndrome.

Aberrant/ malfunctioning of methylation

can lead to silencing of tumor-suppressor genes in the development of cancer.

miRNA methylation results in

cancer and/ or metastasis mRNA targets are over-expressed, and this over-expression has been associated with metastasis

Prader Willi Syndrome

ex of imprinting 4 million base pairs (Mb) of the long arm of chromosome 15. When this deletion is inherited from the father, the child manifests Prader-Willi syndrome. Genes are silenced depending on which parent transmits them, is known as imprinting, and the transcriptionally silenced genes are said to be "imprinted." Short stature, hypotonia, small hands and feet, obesity, hypogonadism, and mild-to-moderate retardation.

Angelman Syndrome

ex. of imprinting 4 million base pair deletion of chromosome 15 (same as Prader Willi), however, when inherited from the mother, causes Angelman syndrome. Genes are silenced depending on which parent transmits them, is known as imprinting, and the transcriptionally silenced genes are said to be "imprinted." Child has a characteristic posture, bouts of uncontrolled laughter, severe mental retardation, seizures, and an ataxic gait.

Russell-Silver syndrome

ex. of imprinting downregulation of IGF2 causes the diminished growth

Beckwith-Wiedemann syndrome

ex. of imprinting upregulation, or extra copies, of active IGF2 causes overgrowth Neonate presents with large size for gestational age, neonatal hypoglycemia, a large tongue, creases on the earlobe, and omphalocele.

micro-ribonucleic acids (miRNAs or miRs)

short nucleotides derived from introns of protein coding genes or transcribed as independent genes from regions of the genome whose functions, if any, remain poorly understood. MiRNAs regulate diverse signaling pathways. (block translation)

histone modification

which includes histone acetylation and alterations in chromatin Methylation, along with histone hypoacetylation and condensation of chromatin, inhibits the binding of proteins that promote transcription, such that the gene becomes transcriptionally inactive.

DNA methylation

which results from attachment of a methyl group to a cytosine base that is followed by a guanine base (a CpG dinucleotide) When a gene becomes heavily methylated the DNA is less likely to be transcribed into mRNA. As twins age, they demonstrate increasing differences in methylation patterns of their DNA sequences, causing increasing numbers of phenotypic differences. In studies of twins with significant lifestyle differences (e.g., smoking vs. nonsmoking), large numbers of differences in their methylation patterns are observed to accrue over time.