1. Epigenetics Abira Khan

2. What is Epigenetics?  Histone code: Modifications associated with transcriptional activation- primarily methylation and acetylation-would be recognized by enzymes that make the chromatin more accessible to the transcription machinery  DNA Methylation- CpG island  Epigenetic (that is, outside-the-genes, but heritable) alteration of the DNA 1. DNA methylation is an epigenetic modification of chromatin, the methylation pattern can be transmitted more or less faithfully through every round of DNA replication- An enzyme called maintenance methyltransferase acts preferentially on those CG sequences that are base-paired with a CG sequence that is already methylated 2. Histone acetylation is also considered to be an epigenetic modification 3. X Chromosome inactivation 4. Position-effect variegation

4. Imprinting  The phenomenon in which a gene’s expression depends on the parent that transmits it is known as genomic imprinting  In most cases of genomic imprinting, the copy of a gene inherited from one parent is transcriptionally inactive in all or most of the tissues in which the copy from the other parent is active  The term “Imprinting” signifies that whatever silences the maternal or paternal copy of an imprinted gene is not encoded in DNA sequence; rather it exercises its effect through some epigenetic alteration of the DNA or chromatin during gametogenesis  This epigenetic imprint remains throughout the life of the mammal, but it is erased and regenerated during each passage of the gene through the germ line into the next generation  For each gene, imprinting occurs in either the maternal or paternal line, never in both

6. DNA Methylation Pattern  Igf 2 gene is methylated in the female germ line but not in the male germ line  At fertilization, a methylated, maternally contributed Igf 2 gene is combined with an unmethylated, paternally contributed Igf 2 gene.  During embryogenesis, the methylated and unmethylated states are preserved each time the genes replicate  Because a methylated gene is silent, only the paternally contributed Igf 2 gene is expressed in the developing animal.  H19 gene, found just 70 kb downstream of Igf 2, is methylated in the male germ line but not in the female germ line.  For each, the methylation imprint is established in the parental germ line.  Methylated gene that was inherited from one sex can be unmethylated when it passes through an offspring of the opposite sex  Methylation imprints are reset each generation, depending on the sex of the animal

9. How it Works?  Researchers identified an enhancer region downstream of the H19 gene that can interact with promoters for both genes  In the region between the 2 genes lies a transcriptional regulation element called insulator.  A functional insulator stops communication between enhancers on one side of it with promoters on the other side  In the Igf 2-H19 region, the insulator DNA becomes functional by binding a protein called CTCF. The binding normally occurs on the maternal chromosome  As a result, the enhancer element on the maternal chromosome can only interact with the promoter of H19; this interaction, of course, turns on the H19 gene. In such a situation, the Igf 2 gene remains unexpressed  On the paternal chromosome both the insulator and the H19 promoter are methylated. Methylated insulator cannot bind CTCF and is not functional; so the enhancer downstream of H19 can activate transcription from the Igf 2 promoter  In addition, methylation of the H19 promoter suppresses transcription of the paternal H19 gene  Imprinting of the paternal chromosome by methylation thus turns on transcription of Igf 2 and prevents transcription of H19

11. Why Imprinting?  ~1% of the mammalian genome, roughly 500 genes will turn out to be imprinted  Most genes imprinted in one mammalian species are also imprinted in other species of mammals  Results are deleterious in some cases  So, why does it exist?

12. References  Principles of Genetics- Peter Snustad- 6th edition, Chapter 19  Genetics, from Genes to Genomes - Hartwell- 2nd edition, Chapter 17  Molecular Biology of the Cell- Alberts- 5th edition, Chapter 7