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Regulation Of Gene Expression > Lesson 27 > Flashcards

Lesson 27 Flashcards

1
Q

genomic instability is the driving cause of many hallmarks of cellular aging located where?

A

downstream in both genomic DNA and mitochondrial DNA

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2
Q

what effect does aging have on telomeres?

A

progressive proliferation of cells causes the loss of these regions so we have a telomere shortening during aging

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3
Q

where do the majority of the epigenetic alterations occur?

A

not differences in the genetic sequences but in the epigenetic landscape

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4
Q

what is proteostasis?

A

the mechanisms that try to maintain the correct folding and assembly of proteins

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5
Q

what is another name for the downstream hallmarks?

A

antagonistic hallmarks

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6
Q

in what three ways can antagonistic hallmarks contribute to aging?

A
  • deregulated nutrient sensing
  • mitochondrial dysfunction
  • cellular senescence
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7
Q

what is deregulated nutrient sensing linked to?

A

where mTOR is a key regulator

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8
Q

what is mitochondrial dysfunction linked to?

A
  • the accumulation of damaged and mutations in the mitochondrial DNA
  • ROS accumulation within mitochondria leading to dyschromic stress
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9
Q

what is the result of cellular senescence?

A

cells don’t start to proliferate again

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10
Q

what are the two integrative hallmarks?

A

stem cell exhaustion and altered intercellular communication

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11
Q

what is transcriptional noise characterized by?

A

general loss of heterochromatin and (in specific regions) the re-activation of genes like poly combgenes - also a de-repression of the repeated region of the genome giving rise to the down regulation of some laminin proteins

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12
Q

what is the term used to refer to the progressive, complete change in heterochromatin state in particular to DNA de-methylation, that can be used to predict the age of the cell?

A

epigenetic clock → can be considered a progressive loss of chromatin like an epigenetic drift

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13
Q

what observed difference exists between young and old cells?

A

a more condensed and repressive state chromatin in young ones compared to the old ones, where chromatin
is more open, active, and so euchromatic state is more present and generally spread within the genome

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14
Q

what is an example of a gene that is repressed in its transcription and gives rise to the downstream regulation of a pathway?

A

Sirtuin genes or NuRD complexes

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15
Q

in terms of general concepts, during aging cells accumulate and reduce global methylation - in specific regions such as the polycomb locus or sirtuin, what occurs?

A

there is an increase of local methylation causing the repression of transcription

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16
Q

where do epigenetic changes occur?

A

upstream of many hallmarks

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17
Q

how is epigenetics linked to aging?

A

its linked to metabolism, and there is a very strict crosstalk since some of the metabolic products are use by acetyltransferase and, for example, NAD is used as a driver for histone deacetylase in sirtuins

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18
Q

name some intrinsic and extrinsic epigenetic factors?

A

intrinsic: nutrient sensing is linked to not only changes in DNA sequence but epigenetic landscape

extrinsic: environmental factors, stress factors, ROS

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19
Q

when caloric restriction is applied to animals, what is the effect?

A

normally, we have a down regulation of p16 (involved in senescence mechanisms) or the repression of sirtuins → after CR these mechanisms are reversed, and we promote the reverse of aberrant expression of these proteins and pathways

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19
Q

when caloric restriction is applied to animals, what is the effect?

A

normally, we have a down regulation of p16 (involved in senescence mechanisms) or the repression of sirtuins → after CR these mechanisms are reversed, and we promote the reverse of aberrant expression of these proteins and pathways

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20
Q

how does an impairment of glycolysis prolong lifespan?

A

an increase in glycolysis in cells give rise to an accelerating aging phenotype

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21
Q

what two things were found to potentially improve lifespan?

A

impairment of glycolysis and an over expression of fatty acid oxidation

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22
Q

what is NAD?

A

a co-factor for sirtuins that is a mitochondrial product used to control histone deacetylase

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23
Q

what does an increase in ⍺-ketoglutarate give rise to?

A

the activation of nuclear processes or the increase of ROS within the mitochondria de-regulation to change the expression of mitochondrial genes

24
Q

what causes the re-activation of some retro-transposons?

A

a general loss of heterochromatin → this can block activation and can ameliorate aging associated phenotype

25
Q

what is inflammaging?

A

all the changes that give rise to an accumulation of pro-inflammatory cytokines and epigenetic changes, inducing an inflammatory phenotype on the cells

26
Q

what is Werner syndrome?

A

a premature aging disorder caused by WRN protein deficiency

26
Q

what is the Werner protein associated with?

A

DNA processes and helices

27
Q

what is Werner syndrome caused by?

A

mutation of the WRN protein (chromosome 8) which is a DNA helicase, causing a downregulation of key processes of the DNA damage response

28
Q

what clinical signs are associated with Werner syndrome?

A

by accelerating aging, that gives rise to osteoporosis in a premature age, but also to a short status, hormonal defects, diabetes, blindness, and also premature death due to the accumulation of mutations that leads to malignancy

29
Q

what is a feature of senescence?

A

β-galactosidase

30
Q

what is the DNA damage response cascade?

A

cascade where some sensors are activated to highlight single or double strand breaks

31
Q

when phosphorylated, what histone acts like a marker of DNA damage?

A

𝛾H2AX

32
Q

in Werner KO cells, what did they notice about the level of chromatin present?

A

there is a reduced amount of chromatin in the inner nuclear membrane

33
Q

what is a inner nuclear membrane associated protein that is absent in WRN KO cells?

A

LAP2b

34
Q

when ChIP was performed on KO WRN cells, what did they discover?

A

there is a general enrichment of histone modifications and a decrease in H3K9me3

35
Q

when ChIP was used to analyze KO WRN cells, what was it looking for?

A

they wanted to consider in which regions there are accumulations of mutations and satellite regions

36
Q

when RNA-Seq was performed on KO WRN cells, what were they looking for?

A

they wanted to know the main regions of the regulated transcript expression and to see if most of the transcripts are associated with the maintenance of chromosome stability (in order to condense the chromosome state to the centromeric regions)

37
Q

what is at the crossroad of anabolic and catabolic choices within a cell?

A

mTOR

38
Q

what is mTOR?

A

a serine threonine protein kinase that is part of the PI3 kinase family → catabolic subunit for two different complexes that are in mTORC1 and mTORC2

39
Q

what is an inhibitor of mTORC1?

A

rapamycin

40
Q

what is mTORC1 involved with?

A

the cell cycle and cellular growth - metabolism and protein synthesis

41
Q

what are some factors that can either inhibit or promote mTORC1?

A

specific growth factors, nutrients, energy availability, oxygen and, on the other side as negative regulator, stress factors are acting on mTORC

42
Q

what is mTORC1 an inhibitor of?

A

autophagy

43
Q

what is the function of mTORC in mammals?

A

mTORC is a dimer complex with a megadalton size and it is composed by the catalytic part mTOR but also the FKBP12 that acts as a binding site for the inhibitor Rapamycin and the kinase activity is promoted by the binding to activator that is Rheb, that is a small GTPase

44
Q

the presence of energetic stress or hypoxia activates what?

A

TSC → has a role in the negative regulation of mTOR

45
Q

what is the status of mTOR in the cell usually?

A

maintained in an inactive or low active status

46
Q

what activates mTOR?

A

the conversion of GTP to GDP and the activation by Rheb GTPase activate it and this allow the expression of the specific transcriptional factors and nuclear function downstream

47
Q

what is one of the main functions of mTORC1?

A

the protein synthesis: acting on transcription initiation factors, mTORC1 has function both in translation and in ribosomes biogenesis, but it is a central player in anabolic stage

48
Q

what functions are positively regulated by mTORC1?

A

protein synthesis and metabolism

49
Q

what function is negatively regulated by mTORC1

A

catabolism: an inhibitory function both autophagy and on lysosome biogenesis

50
Q

where is mTORC maintained?

A

cytosolic factor → maintained in the cytosol and especially nearby lysosomes, but it can act on factors that can translocate to the nucleus

51
Q

in what ways is mTORC active in pathophysiological mechanisms?

A

in metabolic syndrome since mTORC is activated by insulin and growth hormone, obesity and type 2 diabetes has been associated to mTORC activity, but also neurodevelopmental or degenerative disorder

over 80% of cancer is associated with hyperactive mTOR

52
Q

how is mTOR related to aging?

A

mTOR activity is not specific for aging, but in general in aged cells there is an upregulation of mTOR activity

53
Q

what does BMEC-HSC crosstalk affect?

A

hematopoietic aging → it is not a cell autonomous effect but is due to the interaction

54
Q

how does mTOR inhibition by Rapamycin affect hematopoiesis?

A

negative effect

55
Q

what does mTOR inhibition of BMEC cause?

A

induces aging of HSCs → mechanism of aging can be intrinsic or extrinsic

56
Q

describe the mTOR activity in hematopoietic stem cells:

A

there is a reduction of the activation of mTOR and also a part of the signaling of mTOR, both in the hematopoietic system and in the endothelial cells

Regulation Of Gene Expression (28 decks)

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