September 21

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C. David Allis (Rockefeller U.) 2: Epigenetics in Development and Disease

By heheals

September 21, 2020




https://www.ibiology.org/genetics-and-gene-regulation/epigenetics/#part-2

In the first of his videos, Dr. Allis introduces the concept of epigenetics; a change in a cellular phenotype that is not due to DNA mutation but due to chemical modifications of proteins that result in changes in gene activation. In the nucleus, DNA is wrapped around proteins called histones to form chromatin. How tightly the chromatin is packaged determines whether genes are active or not. This switch between the “on and off” state of chromatin is regulated by chemical modification of histones. Allis describes work from his lab and others that identified the enzymes that add, remove and recognize the histone modifications. Changes in histone modification can cause a number of diseases including cancer. A key difference between genetic mutations and epigenetic modifications is that epigenetic changes are reversible making them an attractive drug target.

Dr. Allis focuses on the role of epigenetics in development and disease in his second talk. Histones can be modified on a number of amino acids, particularly lysines, by the addition of acetyl or methyl groups. Combinatorial patterns of these modifications act to enhance or repress gene expression. Allis describes work from his lab and others, which demonstrates that mutations in histone (for instance a lysine to methionine mutation) may block these modifications and, thus, impact gene expression. Sadly, these “onco-histone” mutations have been identified as the cause of many diseases including pediatric brain tumors and pancreatic neuroendocrine tumors.

Speaker Biography:
C. David Allis is the Joy and Jack Fishman Professor and Head of the Laboratory of Chromatin Biology and Epigenetics at The Rockefeller University. Allis’ lab studies how modifications to histones, the proteins that package DNA, influence gene expression and the implications these changes have for human disease.

Allis has been honored with many awards for his pioneering research including the 2015 Breakthrough Prize in Life Sciences, the 2014 Japan Prize, the 2007 Canada Gairdner International Award and many others. Allis is a member of the National Academy of Sciences USA, the American Academy of Arts and Sciences and the French Academy of Sciences.

Allis received his BS in biology from the University of Cincinnati and his PhD in biology from Indiana University and he was a post-doctoral fellow at the University of Rochester.

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  1. I learned a lot and it's a history of great work, but from the beginning of the first lecture to the end of the second, the focus keeps narrowing from "epigenetics in development and disease" to a few rare cancers. Anyone interested in large public health problems like the global epidemic of type 2 diabetes and the racial and social disparities in COVID-19 severity would appreciate a mention of the known causal role of epigenetics in susceptibility to diabetes and, by extension, COVID-19.

  2. I wonder if there's really something that makes mutations of H3.3K27 → I harder to happen than H3.3K27 → M. Or, is there something that makes K27 → M mutations more destructive that K27 → I?

    It also makes sense that damaging one amino acid in the region that controls the enabling and disabling of a gene would be a lot more impactful than damaging one amino acid in a protein used for other purposes. If you permanently disable all the codons wrapped around a nucleosome, or can't control when they should stop being expressed, you've pretty much impacted all the hundreds of codons around that nucleosome, or, perhaps, even the whole gene. (Also, how is enabling and disabling of all the nucleosomes that are part of the same gene coordinated?)

    It also makes intuitive sense that being unable to regulate the expression of a gene can result in uncontrolled growth. E.g., if you can't produce a signal that plays a role in telling the cell, or other cells to stop dividing, you'd expect to get uncontrolled tissue growth.

  3. Very nice and interesting data, relevant to some rare human cancer diseases, eventhough initial research was literally based upon yeast models! I admire Dr. Allis and his co-workers. He's one of the best in epigenomics research, hands down.

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