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Molecular Biology I: Nucleic Acid Metabolism SC/BIOL 3110, 2020 S1

The document provides a recap of the last lecture of a molecular biology course. It discusses topics like histone methylation, position effect variegation, heterochromatin formation, differential histone methylation marks, the histone code paradigm, and potential therapeutic uses of epigenetic drugs like Brd4 inhibitors.

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Ann Than
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102 views14 pages

Molecular Biology I: Nucleic Acid Metabolism SC/BIOL 3110, 2020 S1

The document provides a recap of the last lecture of a molecular biology course. It discusses topics like histone methylation, position effect variegation, heterochromatin formation, differential histone methylation marks, the histone code paradigm, and potential therapeutic uses of epigenetic drugs like Brd4 inhibitors.

Uploaded by

Ann Than
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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MOLECULAR BIOLOGY I: NUCLEIC ACID METABOLISM

SC/BIOL 3110, 2020 S1

Bonus Lecture: Last recap

1
Course Announcements:

• Just a reminder: today (Jun 23) is the last day to submit an online course
evaluation. You can use the following URL to complete the evaluation.

http://courseevaluations.yorku.ca/

• Also, final exam is this Friday (Jun 26) from 7 to 10 pm.

• The final exam format will be similar to the midterms. Make sure you have a
calculator ready.

• ~ 65% of the final exam will focus on the last 3rd of the course.

• I will not be using proctortrack because it is not possible to ensure all students
have webcams in such a short time; however, that means I will be using the
same sequential exam question method as before.

• I will post more details on the Moodle page (e.g. how many questions in MC vs.
short answer sections and the marks distribution of the sections) by Friday
morning.

2
Recap of last lecture:

Histones methylation:

• A number of lysines on histone proteins are methylated.

• Note: individual lysines can either be methylated, acetylated or ubiquitylated, but


each lysine can only be modified by one type of PTM at a time.

• Also note that arginines on histones can also be methylated à only mono- or di-
methylated
3
Recap of last lecture:

Position Effect Variegation (PEV):

• See https://smallscienceworks.com/2015/01/28/fifty-shades-of-red-the-superhot-
history-of-pev/ for blog post explaining the history of position effect variegation, and
the identification of Su(var) genes and pathway leading to heterochromatin
formation.

• Started with Muller using X-


rays to mutagenize flies
and cataloguing various
phenotypes, including
red/white/variegated eyes.

• Others performed additional


forward genetic screens to
search for Suppressor and
Enhancer mutations.

4
Recap of last lecture:

Position Effect Variegation (PEV):

5
Recap of last lecture:

Position Effect Variegation (PEV):

• Very simplistically: Su(var) genes code for proteins that help make heterochromatin
whereas E(var) genes code for proteins that antagonize heterochromatin formation

6
Recap of last lecture:

Constitutive heterochromatin formation (simplified):

Step 1: Establishment of Step 2: Recruitment of HP1 Step 3: Propagation of


H3K9-methylation (via it’s chromodomain) heterochromatin

Su(var) 2-1 = HDAC1

Su(var) 3-9 = H3K9 HMT

Su(var) 2-5 = HP1

7
Recap of last lecture:

Constitutive heterochromatin formation:

• In mouse, binding of HP1 brings in more SUV39H1 (via chromoshadow domain) to


methylate neighbouring nucleosomes (i.e. co-operativity) à spreading of
heterochromatin.

• Spreading of heterochromatin is stochastic (i.e. no fixed end site) unless stopped by


defined boundary element (e.g. insulator).

8
Recap of last lecture:

Differential H3methylation marks distinct chromatin domains:

constitutive facultative
euchromatin heterochromatin heterochromatin

K4-methylated H3 K9-methylated H3 K27-methylated H3

9
Recap of last lecture:

Differential histone methylation form distinct types of chromatin:

• Different methylated residues on histone H3 and H4 and methyl-H3/H4 binding


proteins:

Trx/MLL = H3K4 HMT


Su(var) 3-9 = H3K9 HMT
E(Z)/EZH2 = H3K27 HMT

SET domain-
containing proteins
10
Recap of last lecture:

Histone code paradigm:

• Variety of inhibitors of histone modification-writers/erasers/readers have been developed


and used in clinical trials for different diseases such as different types of cancer.

11
Recap of last lecture:

Using/developing epigenetic drugs:

• Many small molecule inhibitors designed to target DNA methylation or histone code
writers/erasers/readers are currently being developed and tested against various
diseases such as cancer.

e.g. HDAC inhibitors (SAHA)


histone methyltransferase inhibitors
Brd4 inhibitors

12
Recap of last lecture:

Brd4 – Ac-H4 reader important for transcriptional activation:

• Brd4 contains tandem bromodomains that bind to acetylated-H4. Binding of Brd4 to


regulatory elements (e.g. enhancers/promoters) in turn recruit TFs and other factors
(e.g. PTEFb) that promote/facilitate transcription elongation.

BET family members: all have double BDs


and all inhibitied by JQ1

13
Epigenetics and chromatin regulation:

Potential therapeutic uses of the Brd4 inhibitor JQ1 (and similar compounds)?

BRDT
Other uses?

14

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