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.
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.
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.