Enhancer malfunction in cancer

Published on April 2, 2014   41 min

Other Talks in the Series: Epigenetics, Chromatin, Transcription and Cancer

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.
1:52
My laboratory for over 20 years now has been taking advantage of genetic and biochemistry multiple model system including Saccharomyces cerevisiae, Drosophila melanogaster, mouse, and also tissue sample and human cell lines that we have been working in the laboratory in the hope of understanding why translocations of MLL results in leukemic pathogenesis. There will be a little emblem on the bottom that tells you what model system I'm talking about in a given slide, and our work rapidly moves between model system trying to define the role of the factors that Ive been studying in leukemic pathogenesis.
2:30
There's a great deal of interest in the scientific community to understand how the two meter long naked DNA is packaged within the tiny space within eukaryotic nucleus. And what we have learned is that t histone proteins play a very important role in this process and that post-translational modification of histone proteins, such as methylation by Set 1 compass is shown in here, and crosstalk between these histone modifications plays a very important role in directing the basal transcription machinery to the transcription start sites and regulation of gene expression throughout development. Therefore, misregulation of these properties of identification of the transcription binding sites, recruitment of the basal machinery by these factors could result in pathogenesis of human diseases.
3:19
So about a year and a half ago, there were about six KMTs, lysine methylases that have been identified. The KMT-IIs shown in the green signs, it's a product of the enyzmatic machinery named compass, which was identified by our laboratory. It's associative and active process of transcription. KMT-6 family which is involved in methylation of lysine 27 of histone H3 associates with repressed transcription.
3:46
The KMT-2 family, or trithorax family, and the KMT-6 family, or the Polycom family work together in regulation of development. It's truly the balance between the triothorax and the Polycom group that is involved in regulation of many different processes, including cell fate determination, tumor genesis, cellular memory, and stem cell renewals.
4:10
Recently, a beautiful study from Saint Jude Children's Hospital showed that out of large number of patients that have been sequenced for the genome with the brain tumor, over 70% of them have a single point mutation in H3K27 and these mutations are lysine to methanine mutations. Exact molecular mechanism for this process is not clear at this time, but what's clear is that single point mutation in histones can result in pathogenesis of human cancer. And this is regarding to the site that is methylated by the Polycom group.
4:44
Our interest has been in the trithroax group of family of transcription factors. And for many years, the field has been asking why do translocation of MLL to so many unrelated genes results in leukemic pathogenesis? For past 20 years, we have taken two approaches to address these questions. Number one is that we would like trying to find out how is it that the translocation partners of MLL are involved in leukemic pathogenesis? And number two is what is the function of the MLL itself? But most importantly, we would like to understand why MLL translocation to so many unrelated gene results in pathogensis of leukemia. Well we have shown that ELL is an RNA polymerase to elongation factor, and we proposed over 16 years ago that translocation of MLL into the translocation partners such as ELL results in misregulation of elongation properties of RNA polymerase to the cells bearing the translocation. And this could be the major cost for leukemic pathogenesis. And we have shown during the past 15 years that actually many of these MLL translocation partners are found in leukemia with MLL. They're all found within one macromolecular complex regulating the rate of transcription elongation.
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Enhancer malfunction in cancer

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