Introduction to Epigenetics. Manoj Kannan BITS-Pilani & NCI-Frederick. Recap of some familiar terms in genetics. Gene Allele Genotype Phenotype Gene expression Gene silencing Genome. Genome expression. Well-established paradigm of how genetic information is transcribed and translated
BITS-Pilani & NCI-Frederick
What do you think is the basis?
ALL THE MICE ARE GENETICALLY IDENTICAL!
May be from different parents?
Well, age difference…
Oh, okay - mutation in the pigment causing gene?
Most well-studied epigenetic tag/mark; best understood epigenetic cause of disease
Conserved across various kingdoms of life
SAM – S-adenosylmethionine
SAH – S-adenosylhomocystine
So, G, A, T, C…. and the fifth base, mC in mammalian genome
eg. housekeeping genes, tissue-specific genes
2 major classes of enzymes in mammalian systems
De novo methylases
Mouse knockouts of these genes tell us they are necessary for the survival and proper development of the organism.
Unmethylated (or hypomethylated) promoter allows gene transcription
Me-CpG binding proteins also preclude TF binding to the promoter region
Methylated CpGs block binding of TFs; hence, transcription blockedHow does DNA methylation affect gene transcription?
Other ways too…
Unless the genome is accessible by the transcription machinery of the cell, the genome cannot be functional!
Hence, the utilization of the biological information in the genome is dependent on the chromatin organization.
~146 bp DNA transcription
Histone octamer coreStructure of a nucleosome
A = acetylation
M = methylation
P = phosphorylation
U = ubiquitination
eg. Addition of acetyl groups (-ve) neutralizes the positive charge on lysine
=> affinity of the histone to bind tightly to DNA is reduced
=> chromatin becomes less compact
=> transcription of the associated gene is favored
Vice versa for deacetylation (the gene is repressed)
function as large, multiprotein complexes, eg. SAGA, ADA complexes (yeast), TFTC complexes (humans); associated with transciptional activation.
part of multiprotein complexes, eg.Sin3, NuRD; associated with transcriptional repression.
Comparing chromatin types transcription
DNA methylation transcription
Histone H3-K9 methylationCrosstalk between DNA methylation and chromatin modification
RNAi initiates heterochromatin formation in fission yeast and DNA methylation in plants.
Association with various cancers – stomach, kidney, colon, pancreas, liver, uterus, lung and cervix
Fragile X syndrome
“The Biology of Belief: Unleashing the Power of Consciousness, Matter and Miracles” is a recent book in the market on epigenetics!
Disclaimer: I haven’t read the book yet!