Link discovered between MEN1 and much-studied Hedgehog signal pathway

Menin Epigenetically Represses Hedgehog Signaling in MEN1 Tumor Syndrome
-Xianxin Hua, MD, PhD, Buddha Gurung, PhD, Perelman School of Medicine, University of Pennsylvania
Cancer Research April 15, 2013 73:2650-2658; Published OnlineFirst April 15, 2013;

Link discovered between MEN1 and much-studied cell pathway
A research team led by Xianxin Hua, MD, PhD, associate professor of Cancer Biology at the Abramson Family Cancer Research Institute, report in Cancer Research that menin suppresses signaling in the much-studied Hedgehog pathway in endocrine organs.

• "This study uncovered a new layer of regulation of pro-proliferative genes by menin via the Hedgehog signaling pathway," Hua says.
  
• "These pro-replication genes are regulated through GAS1 and PRMT5."
  
• The GAS1 protein promotes Hedgehog signaling.
  
• Menin interacts with the methylating enzyme PRMT5, and binds to the promoter of the Gas1 gene, inhibiting Gas1 gene transcription.
  
• By inhibiting Gas1 expression, menin and PRMT5 inhibit the pathway's tendency towards cell proliferation.
  
• Mutant menin proteins are impaired in their ability to interact with PRMT5, and lead to increased Hedgehog signaling and cell proliferation.
  
• Hua's team found that treating a mouse model of human MEN1 with a Hedgehog pathway inhibitor called Erivedge reduced proliferation of tumor cells and blood insulin levels. Hua says that this suggests a potential new treatment for MEN1 patients.
  

DNA - A Graphic Guide to the Molecule that Shook the World

DNA - A Graphic Guide to the Molecule that Shook the World
-Rosenfield I, et al. 2011 Columbia University Press. ISBN 978-0-231-14270-0

• Don't let the 'comic book' design of this book fool You. This book is a great introduction to DNA and genetics! It's well written -even fun- and it has been extremely helpful in learning the basics of DNA structure, gene transcription, and more. Recommended.

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas
-Henriett Butz, et al. InTech, February 2012, ISBN 978-953-307-879-3.

Multiple endocrine neoplasia type 1: a chromatin writer’s block

Multiple endocrine neoplasia type 1: a chromatin writer’s block -Dreijerink, K. M. A., Lips, C. J. M. and Timmers, H. T. M. (2009). Journal of Internal Medicine, 266: 53–59. doi: 10.1111/j.1365-2796.2009.02115.x

• Menin is important for the writing of histone H3K4 trimethylation.
• In MEN1 tumors, writing of H3K4me3 on specific target genes is blocked.
• Compounds that interfere with the removal of the histone methylation mark are being developed.
• Specific targeting of menin-HMT to treat tumors poses a great challenge for future research.

DNA methylation

Allfrey in 1964 described methylation as a chemical mark upon histones.^[Ref.1] According to newer sources, methylation also takes place on some CpG sequences of the DNA itself.^[Ref.11] CpG denotes a cytosine base next to a guanine base, a combination that tends to occur frequently. A methyl group (CH₃) may attach to the cytosine in a CpG pair, forming Me-CpG. DNA methylation is associated with the regulation of gene expression.

In human DNA about 80%-90% of CpG sites are methylated, but there are certain areas known as CpG islands where none of the sites are methylated. These are associated with the promoters of 56% of mammalian genes, including all ubiquitously expressed genes. ⁽¹⁾

MEN1 is a ubiquitously expressed gene^[Ref.6], so it would seem that we should take a closer look at methylation.
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⁽¹⁾Methylation. Wikipedia.

The Molecule that Shook the World

I've been reading a short book on DNA and genetics, and it has really surpassed my expectations. "DNA - A Graphic Guide to the Molecule that Shook the World", by Israel Rosenfield, Edward Ziff, and Borin Van Loon (2011, Columbia University Press), is designed much like a comic book. At first glance I didn't know whether to take the book seriously, but halfway through this little book I think it's a winner!

250 pages of serious material presented clearly and in a very readable, even entertaining form. DNA, replication, the genetic code, gene expression, chromosomes, epigenetics, the Human Genome Project, and much more... and every page illustrated to illuminate the material and to keep the reading brisk and with a sense of (occasionally bawdy) humor. This is a layman's book, a self-described "popular work" and "graphic novel". But unless You're a seasoned expert in the field, You may find this book very informative and enjoyable. Highly recommended.

This book may be one of the best, first sources to read for a layman who wants to begin to understand genetics and MEN1 a little more deeply.

A chromatin writer's block

Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. This material includes histones, the core proteins around which are tightly wound DNA. I used to think all the information that genetically defines organisms is contained in DNA. Apparently this is not the case. The core histones also are capable of storing epigenetic information. They can written upon, read, and erased by other molecules. These messages affect the expression and silencing of genes without altering the underlying nucleotide sequence.

• MLL (mixed-lineage leukemia) is a writer of H3K4me3, the histone H3K4 trimethylation mark.
• Menin is important for the writing of H3K4me3.
• Menin contains a LLWLL amino acid motif, which "is in fact a nuclear receptor interaction domain."
• Reduction of menin mRNA levels... results in reduced levels of H3K4 trimethylation on hormone responsive genes and decreased transcription of these genes.
• In MEN1 tumors, writing of H3K4me3 on specific target genes is blocked.
• Loss of H3K4 trimethylation appears to contribute to MEN1 tumor development.
• As loss of menin function leads to reduced H3K4me3 levels on target genes an inhibitor of H3K4 demethylase activity, causing persistence of remaining H3K4 trimethylation, could be an effective approach. Compounds that interfere with the removal of the histone methylation mark are being developed.
• Histone deacetylase inhibitors (HDACis) are a well-known class of histone modification regulating drugs, with very promising effects in preclinical and clinical studies.
• Specific targeting of menin-HMT to treat tumors poses a great challenge for future research.

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Multiple endocrine neoplasia type 1: a chromatin writer’s block. Dreijerink, K. M. A., Lips, C. J. M. and Timmers, H. T. M. (2009). Journal of Internal Medicine, 266: 53–59. doi: 10.1111/j.1365-2796.2009.02115.x
Mixed-lineage lukemia. Wikipedia