The cell in health and disease Flashcards
The genome
20,000 protein encoding genes.
non coding DNA
80% of the genome is transcribed - 80% associated with the regulation of gene expression.
Non protein coding DNA sequence
Promoter and enhancer regions that bind protein transcription factors
Non coding regulatory RNAs - of the 80% of the genome dedicated to regulatory function vast majority transcribed into RNAs (micro RNA and long coding)
mobile genetic elements
special structural regions
SNP and CNV
single nucleotide polymorphisms = variants at single nucleotide positions and almost always bi-allelic
1% in coding regions (what you’d expect by changes)
often occur in regulatory non coding areas
can be useful markers especially if coniherited “linkage disequilibrium”
CNVs: 50% of CNVs involve gene-coding sequences. (therefore may underlie a large portion of human phenotypic diversity)
HISTONES:
all cells in human body have the same genetic composition HOWEVER lineage specific programs of gene expression
1) chromatin organisation
- nucleosome 147 base pair wrapped around histone
2) DNA methylation - high level of methylation in gene regulatory elements generally results in chromatin condensation and transcriptional silencing (tightly regulates -
3) histone modifiying factors
- histone methylation: can either increase or suppress depending on which histone residue is markers
- histone acetylation: of lysine residues (histone acetyl transferase) tends to open up chromatin condensation
Micro RNA and Long coding RNA - another important mechanism of gene regulation.
MICRO-RNAS
primarily function to modulation the translation of target mRNAs into their corresponding proteins
conserved in all eukaryotes
less miRNAs than the protein coding genes- individual miRNAs may regulate multiple protein coding genes.
Dicer enzyme - snips into single standed miRNAS 20-30 nucleotides - miRNA associated with a multi protein aggregate called RISC - subsequent base bearing between the miRNA strange and it’s target mRNA directs the RISC to induce mRNA cleavage or repress it’s translation
siRNAs - synthetic version of of miRNAs
small interfering RNAs = short RNA sequences that can be introduced into cells.
interact with DICER and RISC
important in laboratories “knockout” technology
Long non coding RNA
lncRNAs modulate gene expression in lots of ways
can bind to chromatin restricting RNA polymerase access to coding genes within the region
1) gene activation
2) gene suppression
3) promote chromatin modification
4) may act as scaffolding to stabilise secondary or tertiary structrures and or multi=subunits complexes that influence gene activity.
CRISPR
clustered regulatory short palindromic repairs
CAs = CRISPR associated gene
usually CRISPRs are transcribed and processed into a RNA sequence that binds and directs the nuclease cas9 to a sequence (i.e a phage) leading to its binding and destruction
gene editing - artificial guide RNAs that bind cas9 and are complementary to a DNA sequence of interest
once directed to the target sequence - it induces double stranded DNA breaks
repairs of these highly specific cleavage sites can lead to random disruption mutations in the targeted sequences or the process introduction of new sequences of interaction
Golgi
assembly of new proteins
RER
new proteins are synthesised in the RER
proteins intended for the cytosol are synthesised on free ribosomes
smooth endoplasmic reticulum - (SER) may be abundant in certain cells types - site of steroid hormone and lipoprotein synthesis as well as the modification of hydrophobic compounds
Protoeomses
degrade denatured or otherwise tagged cytosolic proteins and release short peptides in some cases the peptides are then processed to be presents on MHC class one as part of the adaptive immune response. proteosomal degradation of regulatory proteins or transcription factors can trigger or shut down cellular signalling pathways
Lysosomes
intracellular organelles enzymes that digest enzymes
(vs. PEROXOMES - specialised organelles - containing catalase, peroxides and other oxidative enzymes. - role in breakdown of very long chain fatty acids genera hydrogen peroxidase in the process)
Mitochondrial
oxidative phosphorylation - makes most of the ATP which powers the cells
also important source of metabolic intermediates for anabolic metabolism
other things:
- synthesise certain macromolecules - haem
- contain important sensors of cell damage (in the process of apoptotic cell death)
Growth
The cell cycle and proliferation
the sequence of events resulting in cell division = the cell cycle.
G1 = pre syntheticgrowht
S = DNA synthesis
G2 (pre-mitotic)
M mitotic
G0 –> cellular quiescence
can progress to G1 from G0 are progress through there after mitosis
Cell cycle regulations
progression driven be proteins called cyclins
cyclin dependant kinases (are the enzymes associated cyclins)
checkpoints are another regulatory point in the cycle cycle.
Checkpoints in the cell cycle: sense DNA or chromosomal damage.
G1-S checkpoint = monitors the integrity of DNA before irreversibly committing cellular resources towards DNA replication.
G2 - M checkpoint ensures that there has been accurate DNA replication before the cell actually divides
when damage is sensed –> checkpoint activation –> leads to DNA repair mechanisms being activated
If the DNA damage is too severe the cell will actually undergo apoptosis or enter non replicative phase call senescence. (primarily through P53 dependant mechanism)
enforcing the cell cycle checkpoints is the CDK inhibitors - modulate the CDK-cycline complex activity
when growth occurs also stimulations changes cellular metabolism so that all of the cellular components to make two daughter cells are ready. chief among this is the WARBURG effect
Warburg effect
important concept particularly in cancer cell growth
concept that increased cellular uptake of glucose and glutamine and increased glucolysis and decreased oxidative phospphylaration …….
STEM CELLS:
totipotent stem cells can give rise to all types of differentiated tissues
in the mature organism adult stem cells in tissues can only replace damaged cells and maintain cell populatio
ns within the tissues they reside.
under homeostasis stem cells have two features
1) self renewal which permits them to maintain their numbers
2) Asymmetric division - cell replication which is cell replication where one daughter cell enters a differentiation pathway and gives rise to mature cells whereas the other remains undifferentiated and retains its self renewal capacity
in symmetric division both retain self renewal capacity. (such is seen in embryogenesis or under conditions of stress - such as in the bone marrow following chemotherapy)
embryonic stem cells - the least differentiates and limitless renewal capacity. “totipotent”
tissue stem cells are found in intimate associated with differentiate cells of a given tissue - have a limited repertoire of differentiate cells they can generate.
mesenchymal stem cells - multipoint cells that can differentiate in to a variety of stromal cells INCLUDING chondrocytes (cartilage) and osteocytes (bone), adipocytes (fat) and myocytes (muscle)
tissue stem cells are normallyprotected within specialised tissue environments called stem cell niches
such niches have been demonstrated in lots of regions……
Different stem cell NICHES
haematopoeitic stem cells - perivascular niche hair follicles - bulge region limbus of the cornea crypts of the gut canals of hering in the liver sub ventricular region of the brain
