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L3 Epigenetics > Molecular mechanisms of dosage compensation > Flashcards

Molecular mechanisms of dosage compensation Flashcards

1
Q

Why is dosage compensation required for the X chromosome? (2)

A
  • Males have XY, females have XX
  • If there was no mechanism to regulate X chromosome gene activity females would have twice as much X gene product as males
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2
Q

What is dosage compensation?

A

Mechanism to equalise gene expression from the X chromosome in males and females/hermaphrodites

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3
Q

What are the possible strategies for dosage compensation? (3)

A
  • Make the single X in males twice as active as each of the 2 X chromosomes in females
  • Inactivate 1 of the 2 X chromosomes in females
  • Make both X chromosomes in females (or hermaphrodites) half as active as the single X chromosome in males
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4
Q

Which dosage compensation mechanism is used in drosophila?

A

Make the single X in males twice as active as each of the 2 X chromosomes in females

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5
Q

Which dosage compensation mechanism is used in mammals?

A

Inactivate 1 of the 2 X chromosomes in females

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6
Q

Which dosage compensation mechanism is used in C. elegans?

A

Make both X chromosomes in females (or hermaphrodites) half as active as the single X chromosome in males

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7
Q

What is the critical factor in dosage compensation in drosophila?

A

Male specific lethal 2 (MSL2)

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8
Q

How does dosage compensation/sex determination work in drosophila? (5)

A
  • Msl2 is only produced in males
  • In female embryos sufficient Sxl (X-linked) protein is produced from 2 X chromosomes to bind to MSL2 transcripts and prevent translation
  • SXL causes formation of Dsx female isoform which causes sexual differentiation
  • In male embryos there isn’t enough Sxl protein produced from 1 X to prevent MSL2 transcription so Msl2 accumulates, also causes formation of Dsx male isoform
  • MSL2 boosts single X activity to match that of XX
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9
Q

What is the function of MSL2 protein in male drosophila? (2)

A
  • MSL2 production allows assembly of the MSL complex on the male X chromosome
  • Complex can’t form in females without the MSL2 protein
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10
Q

What are the components of the MSL complex? (7)

A
  • MSL1
  • MSL2
  • MSL3
  • MLE
  • MOF
  • roX1
  • roX2
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11
Q

What kind of protein is MSL2? (3)

A
  • Ubiquitin ligase
  • Ubiquitinates histone H2B, significance not fully understood
  • Required for MSL complex assembly
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12
Q

What kind of protein is MSL3?

A

Has a chromodomain which binds H3K36me3 which is present in actively transcribed exons

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13
Q

What kind of protein is MLE?

A

RNA/DNA helicase

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14
Q

What kind of protein is MSL1?

A

Scaffolds the MSL complex

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15
Q

What kind of protein is MOF? (2)

A
  • Histone acetyltransferase specific for H4K16
  • H4K16ac stimulates expression on already active genes, further boosting of activity
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16
Q

What is the function of roX1 and roX2? (2)

A
  • Non-coding RNAs of different sizes and sequences
  • Stimulate recruitment and spreading of the MSL complex on the C chromosome
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17
Q

What are polytene chromosomes? (3)

A
  • Chromosomes in drosophila salivary glands
  • Multiple rounds of endoreplication without mitosis and sister chromatid separation makes the ploidy 1024n so they can be visualised under light microscope
  • Use of fluorescently labelled antibody for MSL3 shows localisation on the X chromosome
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18
Q

What is the distribution of MSL3 on the X chromosome?

A

Present along the whole length but concentrated at H3K36 methylation (specifically recognises with its chromodomain)

19
Q

What are MREs? (4)

A
  • MSL recognition elements
  • Repetitive DNA sequences on the X chromosome that initiate MSL complex binding to chromatin, lateral spreading then occurs
  • Mechanism of localisation isn’t understood
  • Core sequence is GAGCGAGA
20
Q

What is the structure of the roX non-coding RNAs? (4)

A
  • 3’ stem loop
  • Series of repetitive GUUNUACG roX box sequences
  • roX1 much longer than roX2
  • Structures are required to stimulate MSL complex localisation to the X chromosome and stimulate MOF H4K16 acetylation activity
21
Q

What is a Barr body?

A

Darkly staining body at the periphery of the somatic nucleus observed in female cells which is the condensed, transcriptionally inactive X chromosome

22
Q

How is the fur of tortoiseshell cats explained? (4)

A
  • X-linked gene for fur pigment
  • Heterozygous for X-linked mutation so one X produces red/brown pigment, other X produces black pigment
  • All somatic tissues in female mammals are mosaic for X inactivation, clones of cells inactivate the same X
  • Causes tortoiseshell fur pattern
23
Q

Which X is inactivated in mammals? (2)

A
  • Inactivation of an X chromosome in any cell in early female embryo is random and permanent
  • Means that female mammals are mosaic for X inactivation
24
Q

What is Xic? (2)

A
  • The X inactivation centre
  • Cis-acting master switch locus for initiation of X inactivation
25
Q

What are the components of the Xic? (4)

A
  • Xist
  • Tsix
  • Rex1
  • Rnf12
26
Q

What is the function of Xist? (2)

A
  • Non-coding RNA which decorates the entire length of the X chromosome from which it is transcribed
  • Prevention of diffusion to the other X chromosome is not understood
27
Q

What is the function of Tsix? (2)

A
  • Complementary to Xist RNA
  • Expression of one inactivates the other
28
Q

How does Xist cause X inactivation?

A

The first chromosome to accumulate above a threshold amount of Xist is the one that is inactivated

29
Q

What is the function of Rnf12? (3)

A
  • Ubiquitin ligase encoded by Xic locus
  • Degrades Rex1
  • More Rnf12 production means more Xist production and less Tsix production
30
Q

What is the function of Rex1? (2)

A
  • Autosomally derived protein
  • Transcriptional repressor of Xist RNA
31
Q

How is X inactivation propagated and maintained beyond the Xic? (3)

A
  • YY1 transcription factor binds to Xist RNA
  • Triggers further accumulation of YY1 binding to Xist with hnRNPU RNA binding protein
  • Complex spreads along the chromosome to allow decoration with Xist
32
Q

What are the events which follow Xist inactivation of the X chromosome? (10)

A
  • Xist decorates the inactive X
  • Core histone acetylation is decreased
  • Core histone H3K4 methylation is decreased
  • Core histone H3K27 methylation is increased (polycomb)
  • Core histone H2A ubiquitination of lysine 119 is increased (H2AK119Ub)
  • PRC2 and PRC1 binding is increased
  • H3K9 methylation is increased
  • HP1alpha binding is increased
  • CpG DNA methylation is increased
  • All causes condensation of inactive X into the Barr body which can’t be transcribed
33
Q

What are the 2 sexes in C. elegans?

A
  • Males (XO)
  • Hermaphrodites (XX)
34
Q

What is the difference between C. elegans males and hermaphrodites? (2)

A
  • XX hermaphrodites have germ cells producing eggs which are fertilised by its own sperm to produce embryos
  • XO males have germ cells producing sperm only
35
Q

What is the critical factor in dosage compensation in C. elegans?

A

XOL-1 protein kinase

36
Q

How does dosage compensation/sex determination work in C. elegans? (6)

A
  • Autosomal signal elements promote expression of XOL-1
  • X chromosome signal elements inhibit expression of XOL-1
  • Hermaphrodites have XX so have twice as much XOL-1 inhibition as males (XO)
  • XOL-1 repression results in high SDC-2
  • Results in low HER-1 expression which causes hermaphrodite
  • XOL-1 expression = high HER-1 = male sexual differentiation
37
Q

What is the function of XOL-1?

A

Inactivate SDC-2

38
Q

What is the difference in SDC-2 levels in males and hermaphrodites C. elegans? (2)

A
  • Low in males
  • High in females
39
Q

What is the function of SDC-2? (2)

A
  • Assembles dosage compensation complex (DCC)
  • Targeted to the X chromosome where it suppresses transcription of X-linked genes to make each X chromosome in hermaphrodites half as active as the single male X
40
Q

How is the DCC targeted to the X chromosome? (3)

A
  • SDC-2 assembles the DCC and targets it to rex sites (specific DNA sequences on the X chromosome)
  • Rex-bound DCC recruits additional DCCs to spread across the X chromosome
  • DCC promotes H4K20me1 on both X’s which reduces X-linked gene transcription
41
Q

How is dosage compensation achieved in drosophila?

A

MSL complex catalyses H4K16 acetylation to boost transcription of the single male X chromosome

42
Q

How is dosage compensation achieved in mammals? (2)

A
  • Xist RNA decorates the X from which it is transcribed and recruits YY1 and hnRNPU
  • 1 X is silenced by decreasing H3K4 methylation and histone acetylation and promoting H3K27 and H3K9 methylation , polycomb complex, HP1alpha recruitment and DNA methylation
43
Q

How is dosage compensation achieved in C. elegans? (3)

A
  • SDC-2 is active in hermaphrodites due to X-linked genes repressing XOL-1 causing recruitment of DCC to both X chromosomes
  • DCC promotes H4K20me1 which reduces gene transcription of both X’s in hermaphrodites
  • SDC-2 is inactive in males because only 1 X chromosome so XOL-1 remains active and represses SDC-2

L3 Epigenetics (15 decks)

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