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- Genetics of Developmental Disorders
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1. Imprinting disorders associated with molecular changes on chromosome 11p15
- Prof. Rosanna Weksberg
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2. Chromatin genes and disease
- Prof. Richard Gibbons
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3. Heterochromatin, epigenetics and gene expression
- Prof. Joel C. Eissenberg
- Cardiopulmonary Disease
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4. Transcription factors and complex disease development
- Dr. Ines Pineda-Torra
-
5. Molecular genetics of pulmonary arterial hypertension
- Prof. Richard C. Trembath
- Neuromuscular System Diseases
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6. Gene therapy for the muscular dystrophies
- Prof. Jeff Chamberlain
-
7. RAS pathway and disease: neurofibromatosis and beyond
- Prof. Eric Legius
-
8. Congenital syndromes of pain and painlessness
- Prof. Geoff Woods
- Prof. James Cox
- Endocrinology and Metabolism
-
9. Changing lives: stratified medicine in monogenic diabetes
- Prof. Andrew Hattersley
-
10. Genetics of monogenic obesity 1
- Prof. Dr. Johannes Hebebrand
- Prof. Dr. Anke Hinney
-
11. Genetics of monogenic obesity 2
- Prof. Dr. Johannes Hebebrand
- Prof. Dr. Anke Hinney
- Cancer Genetics
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13. Inherited predisposition to breast cancer
- Prof. Diana Eccles
-
14. Genetics of breast and ovarian cancer
- Prof. Jeffrey Weitzel
-
16. NF2-related Schwannomatosis and Gorlin Syndrome
- Prof. D. Gareth R. Evans
-
17. The genetic basis of kidney cancer
- Dr. W. Marston Linehan
- Oligogenic and Complex Diseases
-
18. Ciliopathies and oligogenic phenomena
- Prof. Nicholas Katsanis
- Therapy
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19. Mismatch repair deficient cancers & Lynch syndrome
- Prof. Sir John Burn
- Archived Lectures *These may not cover the latest advances in the field
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20. Mismatch repair deficient cancers: diagnosis, treatment and prevention
- Prof. Sir John Burn
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21. NF2 & Gorlins
- Prof. D. Gareth R. Evans
Printable Handouts
Navigable Slide Index
- Introduction
- Outline
- Transcription: basic concepts
- Transcription factors (TF) & biological processes
- Transcription factors and disease
- Changes in TF affect multifactorial diseases
- Outline: CVD and Type 2 diabetes
- Approaches for identification of gene variants
- PPAR subfamily
- Positive gene regulation by PPARgamma
- Cofactor-receptor dynamic cycle
- PPARgamma and metabolic homeostasis
- Missense mutations in human PPARgamma
- TF variants in coding regions: in vitro studies
- TF transcriptional activity testing: luciferase assay
- TF DNA binding activity testing: gel shift assay
- Pro12Ala PPARgamma: functional studies
- Functional studies for PPARgamma variants (1)
- Functional studies for PPARgamma variants (2)
- Functional studies for PPARgamma variants (3)
- Studies for PPAR gamma variants: in vitro
- Pro12Ala PPAR gamma: in vivo studies
- Summary so far
- Variation in non-coding DNA
- Variation in distant-acting enhancers
- Identification of distant-acting enhancers
- ChIP-chip and ChIP-seq
- Validation of enhancer activity in vitro: luciferase
- Validation of enhancer activity in vivo
- Genome wide approaches
- Genomic variants, TCF7L2 and diabetes risk
- Beta-catenin and TCF7L2 in pancreatic cells
- TCF7L2 and diabetes risk
- TCF7L2 variation in non-coding regions
- Isolation of active regulatory elements: FAIRE
- FAIRE-seq in human pancreatic cells
- Enhancer activity of the risk allele
- TCF7L2 variant and chromatin accessibility
- TCF7L2 & diabetes risk in animal models (1)
- TCF7L2 & diabetes risk in animal models (2)
- TCF7L2 and diabetes risk: summary
- Genome-wide approaches: Sort1
- Sort1 expression & lipoprotein metabolism (1)
- Sort1 expression & lipoprotein metabolism (2)
- Sort1 expression & lipoprotein metabolism (3)
- Summary
Topics Covered
- Transcription factors (TFs): function and role in disease
- Identified transcription factor variants and impact on CVD and Type 2 diabetes disease risk
- Traditional approaches (gene candidate studies, e.g. PPARgamma)
- Contemporary approaches (genome wide association studies, e.g. TCF7L2, SORT1)
- Study of functionality of transcription factor mutations
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Pineda-Torra, I. (2014, January 5). Transcription factors and complex disease development [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 14, 2024, from https://doi.org/10.69645/XHAK1437.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Ines Pineda-Torra has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Clinical Practice
Transcript
Please wait while the transcript is being prepared...
0:00
My name is Ines Pineda Torra,
and I work in the Division of Medicine at University College London in the UK.
This talk will focus on the role of transcription factors
in the development of complex diseases.
0:15
I will first briefly introduce what transcription factors are
and discuss why polymorphisms in these proteins
play an important role in the development of disease.
Then I will give some examples on how variation in transcription factors
has been shown to affect multifactorial diseases,
such as cardiovascular disease and Type 2 diabetes.
I will cover both variance of transcription factors
identified by traditional gene candidate approaches,
as well as variance identified by more contemporary genome-wide approaches.
In addition, I will describe how the functionality of these transcription factor variants is assessed
using various molecular biology techniques.
0:57
Let me first introduce what transcription factors are
and explain why they are important in disease development.
As their name indicates, transcription factors are a class of DNA-binding proteins
that are responsible for the transcription of genes,
which is the conversion of a double-stranded sequence of DNA
into a copy of single-stranded RNA,
thereby regulating the expression of genes.
This conversion into RNA is catalyzed
by an enzyme called RNA polymerase II, or Pol II.
Transcription is a tightly-regulated process.
It is needed to ensure the correct expression
of a specific set of genes at a specific time,
in response, for instance, to metabolic, developmental, or differentiation demands.
Transcription factors are just one of the diverse groups of proteins
that are crucial for the successful transcription by Pol II in eukaryotic cells.
These proteins include general transcription factors, or GTFs,
cofactors, and histone-modifying enzymes.
General transcription factors bind to sequence elements,
for instance, a TATA box located in the core promoter.
These factors are involved in the formation of the transcription of the pre-initiation complex
and in the subsequent recruitment of Pol II.
Cofactors are also important layers in this process
as they modulate the activity of the transcription factor.
These cofactors are often associated with histone-modifying enzymes,
such as histone acetyltransferases or histone methyltransferases.
These enzymes, by modifying the acetylation of histones
or methylation of histones or DNA,
are going to mediate changes in the accessibility of the chromatin to the transcription factors.
Also key players in this process are DNA-binding transcription factors,
which binds to specific DNA sequences located near the core promoter of the gene.
In this case, then, these sequences are referred to as proximal sides.
They can also bind to the existing regulatory regions called enhancers.
I will give more details of these enhancers later on in my talk.
Transcription factors can either act as activators or repressors,
depending on whether they facilitate or prevent, respectively,
the binding of Pol II and GTFs to the core promoter.
Cofactors, transcription factors, the GTFs, and Pol II
can interact with or affect each other in many different ways.
This is indicated here by the double-ended arrows.
For instance, cofactors can interact with the general transcription machinery,
or they can bind to nucleosomes with various histone modifications,
thereby stabilizing the cofactor binding to the gene.