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Printable Handouts
Navigable Slide Index
- Introduction
- Chromosomal translocation and the MLL gene
- Blood cells in acute leukemia
- MLL translocations cause acute leukemia in children
- Studies from the Shilatifard lab
- Histone modification and transcription
- Histone lysine methylases
- Balanced gene expression during development
- (Poly)combing the cancer genome
- MLL translocations result in leukemogenesis
- MLL translocations & hematological malignancies
- AFF4 is a core component of the MLL-chimeras
- Biochemical isolation of the AFF4 complex
- A molecular mechanism for MLL-based leukemia
- AFF4 is recruited to MLL target genes Hox a9, a10
- MLL-chimera target gene expression needs AFF4
- Transcriptional elongation checkpoint control
- The function of MLL within the chimeras
- Yeast Set1 is related to human MLL
- Purification of yeast Set1/COMPASS
- COMPASS family of H3K4 methylases
- COMPASS structure from yeast to human
- COMPASS family mutations in cancer (1)
- The many MLL4 mutations in cancer (1)
- Division of labor by the COMPASS family
- Chromatin bivalency
- Bivalency & key developmental genes in ES cells
- Active and repressive marks in ES cell promoters
- The histone code: cause or cog
- Which COMPASS family is involved in bivalency?
- The conserved Hox cluster
- The MLL2/COMPASS family & bivalency
- Genome-wide role of MLL2/COMPASS
- Rapid developmental induction bivalency absence
- Promoter bivalency and transcriptional induction
- Bivalency not a transcription induction prerequisite
- Developmental promoter readiness/responsiveness
- Elongation complexes: SEC & LEC
- The ELL family of Pol II elongation factors
- Characterization of ELL3
- ELL3 is associated up/downstream of TSS
- ELL3, p300 & H3K4me1 co-localize on enhancers
- The ABCs of transcription in ES cells
- ELL3-dependent Pol II occupancy
- ELL3 on Hox gene enhancers
- ELL3 and Pol II occupancy on homeotic genes
- ELL3 and SEC in Hoxa cluster activation
- A model for the enhancer-associated ELL3
- H3K4me1 as a mark of enhancers
- COMPASS family member & enhancer H3K4me1
- Drosophila Trr
- Trr complex reduction & chromatin modifications
- Trr-dependent pattern of histone modifications (1)
- Trr-dependent pattern of histone modifications (2)
- Trr required for enhancer-promoter interaction
- Trr interacts with the ct enhancer
- MLL3/4/Trr COMPASS-like complexes
- Human MLL3/4 homologues of Drosophila Trr
- Mammalian MLL3 and MLL4 are methyltransferase
- MLL3/4 associate with enhancer regions
- Trr/MLL3-4-dependent enhancers
- COMPASS family mutations in cancer (2)
- The many MLL4 mutations in cancer (2)
- Enhancer/promoter looping
- Look back at MLL4 mutations
- Enhancer malfunction & tumor suppressor gene
- Enhancer malfunction & oncogene expression
Topics Covered
- MLL genes and their pathogenic translocations
- Yeast, mammalian and Drosophila systems for studying leukaemia pathogenesis
- Proteins and protein complexes that regulate chromatin modifications, transcription initiation, and transcription elongation
- What is the function of MLL?
- Why do translocations of MLL with so many different partners result in leukemogenesis?
- The AFF4 complex and Hox genes
- COMPASS family of H3K4 methylases and their mutations in cancer
- Chromatin Bivalency
- The ELL family of Pol II elongation factors
- Drosophila Trr
- Enhancer/promoter interactions, malfunctions and their outcomes
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Shilatifard, A. (2014, April 2). Enhancer malfunction in cancer [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/MNQV1947.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Ali Shilatifard has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Oncology
Transcript
Please wait while the transcript is being prepared...
0:00
Hello.
My name is Ali Shalati.
I'm going to share with you the
recent stories from the laboratory
and the function of enhancer in
regulation of promoter activity,
and how malfunction
enhancer properties
resulting pathogenesis
of human cancer.
0:16
For over 20 years now, the
burning question in my laboratory
has been why chromosomal
translocation involving the MLL
gene results in pathogenesis
of hematological malignancies.
MLL gene which encoded by about
4,000 amino acid containing protein
undergoes frequent translocation
with large number of translocation
partners as shown here
on the right hand side.
And translocation of MLL to many
of these translocation partners
result in pathogenesis of
hematological malignancies.
As shown in the bottom here,
there are several examples
of MLL translocation, an 11-4
translocation on the left hand side
of the screen and a couple
of 11-19 translocations
on the right hand
side of the screens.
And most of these
translocations are detected
in children upon cytogenetics.
And analysis of blood from the kids
shows that there's a high level
of white blood cell
exist in these patients.
1:11
Normally, we have about 1% of
white blood cells in our system.
Looking at blood analysis
from leukemic patients,
some of these patients have
over 80% of white blood cells
in their system, which
complications of infiltration
of these white blood cells
in many tissues and organs
result death for these children.
1:30
MLL translocations mostly
afflicts young adults,
early adolescents and infants.
And very little is known about
why these translocation causes
pathogenesis of
hematological malignancies.
So a true understanding
of molecular properties
of MLL translocational leukemia
is going to be very important
for development of
targeted therapeutics.