dna modifications and long-term patterns of gene expression epigenetics part 1 feb 19, 2015
TRANSCRIPT
The Wikipedia article is useful, howeveryou will have to research each topiccarefully, the article is provides summaries,but is short on detail.
http://en.wikipedia.org/wiki/Epigenetic
The metaphase chromosome on the upper left is DNA thatis condensed and packed together. Levels of RNA transcriptionfrom this DNA will be very low.
In women, the dormant X-chromosome (Barr body) showsvery little transcriptional activity. Portions of every chromosomeare like the Barr body, and essentially dormant.
ADDING A METHYL GROUP TO THECYTOSINE BASE LEADS TOWARDGENE SILENCING.
THIS IS A FUNDAMENTAL ANDIMPORTANT MECHANISM IN THEREGULATION OF GENE ACTIVITY.
ACTTGGCGCGATACGGGCGATCGATCC
TGAACCGCGCTATGCCCGCTAGCTACC
Transcriptionstart site
SEQUENCE IN PROMOTER OF A GENE WHICH IS BEING ACTIVELY TRANSCRIBED INTO RNA
ACTTGGCGCGATACGGGCGATCGATCC
TGAACCGCGCTATGCCCGCTAGCTACC
Transcriptionstart site
SEQUENCE IN PROMOTER OF A GENE WHICH IS IN A DORMANT STATE: NOT TRANSCRIBED
The RED cytosines (part of a CG pair) have been methylated
If you sequenced through this promoter, you would seethe difference.
ACTTGGCGCGATACGGGCGATCGATCC
TGAACCGCGCTATGCCCGCTAGCTACC
The human genome has about 30,000,000 methylcytosines.
There are about 3 billion base pairs, and about 1.2 billionC-G base pairs (40% of total), so methyl-cytosine that common,about 1.5% of all cytosine.
Cytosine ACTIVELYdemethylated
Methylation MAINTAINEDby enzyme Dnmt1
MECHANISMS OPERATE TO MAINTAINMETHYLATION DURING REPLICATIONOF DNA: SOME PATTERNS ARE STABLE.
1) Methyl binding domain (MBD)(part of Methyl-CpG-binding protein-2)binds to methyl-cytosine.
2) The transcription repressiondomain (TRD) recruits other proteins.
3) These proteins work together to convertDNA into condensed chromatin.
ACTIONS OF MeCP2
METHYLATION PATTERNS CAN BE CONTROLLED BY GENDER.IN THE MOUSE, THE MATERNAL GENE FOR INSULIN-LIKE GROWTH FACTOR (IGF-1) IS METHYLATED AT THE PROMOTER, AND DORMANT.THE PATERNAL COPY IS ACTIVE, AND THE ONLY GENE THAT CANPROVIDE THIS PROTEIN TO THE GROWING MOUSE.
THERE ARE PERHAPS 20 GENES IN HUMANS THAT ARE LIKE THIS.
WHAT CAN HAPPEN IF THERE IS A MUTATION IN THE AMINO-ACID SEQUENCE OF THE IGF-1 GENE FROM THE PATERNAL DNA?
DNA-methyl-transferase(DNMT) puts methylgroups on cytosinesnext to guanines
Methyl-binding-domainproteins (MBD) complexwith those sites
Histone-methyl-tranferases(HMT) add methyl groupsto SELECTED lysine chainsof histone proteins
The gene CONDENSES to becomeheterochromatin, and the gene becomesLARGELY dormant.
Histone deacetylase removesacetyl group from SELECTEDlysines of histrone protein
Histones, like most proteins, have side-chain lysines, that mighthave a positive charge (NH3+). But since DNA phosphate groupsgive DNA a negative charge, histones are strongly-associated withDNA and cover up the nucleotides.
What if the lysine is ACETYLATED? What happens to the positivecharge on the histone? Will it bind more/less strongly to DNA?
Acetylated histones, octameric proteins that organize chromatin into nucleosomes and ultimately higher order structures, represent a type of epigenetic tag within chromatin.[4] Acetylation removes the positive charge on the histones, thereby decreasing the interaction of the N termini of histones with the negatively charged phosphate groups of DNA. As a consequence, the condensed chromatin is transformed into a more relaxed structure that is associated with greater levels of gene transcription.
Phosphorylation (histone kinase) also makes histones more NEGATIVE, which moves histone AWAY from DNA and makes the DNA more open for transcription.