The human genome, epigenetics and chromatine remodelling Flashcards
describe the composition of the human genome
about 50% repetitive, 1-1,4% exons, 24% introns, rest unique intergenic sequences
(about 50% unique)
what are repetitive elements in the human genome?
retrotransposons, DNA-transposons, inverted repeats (hairpins, regulatory), highly repetitive DNA, telomeres, centromeres
describe the size of the human genome
6 billion bases per cell (6x10^9), length of all DNA in the human body more than 500x the distance between earth and sun
define “DNA”
macromolecule, contains all info necessary for development and function of a living organism
define “gene”
unit of inheritance (promoter, exons and introns)
define “chromosome”
organized structure of one long & coiled DNA (or two copies) and histones, visible in m-phase
define “genome”
total hereditary information of an organism (chromosomes & mitoDNA)
explain the structure of chromatin
naked DNA winding around histones=octamer - nucleosomes packed into 30 nm fiber (packed nucleosomes) - extended chromosome section (scaffolding proteins, form loops) - condensed chromosome section (condensin, loops form into coils), mitotic chromosome (cohesins - hold sister chromatides together)
what is euchromatin?
open, more accessible to nucleases and transcription factors, rich in actively expressed genes, replicated early in S-phase
what is heterochromatin?
closed, not accessible to TF, few genes, high content of repetitive DNA, replicated late in S-phase
facultative heterochromatin
can differ by cell type & time: tissue specific genes, gene silencing (inactive x-chromosome)
constitutive heterochromatin
same in all cell types, structural: telomeres, centromeres
define “epigenetics”
heritable changes in gene expression, no changes in DNA sequence
explain the function of DNA methylation
- silencing of genes: transcription repression of CpG-rich promoters & transposable elements
- > physically prevents binding of transcription factors, signal for other proteins to locate & silence genes, form heterochromatin
de novo DNA methyltransferase
put initial pattern of methyl groups on DNA sequence in development
maintenance DNA methyltransferase
copy methylation pattern from DNA template to new strand after replication in somatic cell division
how are DNA methylation patterns inherited from mother cell to daughter cell?
DNMT1 recognizes 5-met-C on parental strand and adds a methylation on new strand
active DNA demethylation
enzymatic process: TET-mediated oxidation of methyl group, base excision repair
passive demethylation
lack of maintenance methylation during replication, inhibition of DNMT1
what do histone tail modifications effect?
direct influence on overall chromatin structure, regulation of binding of effector molecules
writers in histone tail modification, give example
add modification to histone tails/DNA e.g. methyltransferases, acetyltransferases
readers in histone tail modification, give example
effector molecules that bind to modified histone tails e.g. chromodomain of HP1 binds to methylated region
erasers in histone tail modification, give example
remove modification, e.g. demethylase, deacetylase
describe histone methylation
lysine or arginine can be mono/di(tri)methylated, SAM as methyl donor, more repressive state
describe histone acetylation
Histone acetyltransferases (HATs) use acetyl-CoA to acetylate lysine, removes positive charge, opens chromatine (facilitate transcription factor access at enhancers/promoters)
describe the chromatin remodeling processes at the level of nucleosomes
enzyme-assisted, CRC=chromatin remodeling complexes for removal/insertion/sliding of nucleosomes, dimer exchange
what decides the outcome of epigenetic marks?
interplay between DNA methylation, histone marks and nucleosome position
how to epigentic modifications affect human disease in general?
abberant replacement of epigenetic marks and mutations in epigenetic machinery are involved in diseases like cancer, neurological disorders, autoimmunity
give examples how alteration of DNA methylation patterns inactivates tumor suppressors
- methylated CpG islands
- unmethylated gene body (transcription starts internally)
- unmethylated repetitive sequence (retrotransposon jumps and destabilizes DNA)
give an example of epigenetic therapy for cancer cells
HDAC inhibitors (messes around with specific gene expression outcome in cancer cells), for T-cell lymphoma
where is DNA usually methylated?
C before G (CpG regions, p = phosphate)
how can alterations in epigenetic modifications drive cancer development?
dysregulation of gene expression: upregulation of oncogenes and (most importantly) silencing of tumoursuppressors
discuss important functions of the non-protein coding parts of the genome
regulatory (regulate chromatin structure, transcription, splicing), non-coding genes, functional, structural and regulatory RNA (tRNA, rRNA, miRNA), structural (centromers, telomers)
