Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin

Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin in the Regulation of Genes Implicated in MEN1-Like Tumors
-S Agarwal, R Jothi
PLoS ONE 7(5): e37952. doi:10.1371/journal.pone.0037952

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.

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.

Cells use DNA methylation to control gene expression

• "Methylation of DNA (not to be confused with histone methylation) is a common epigenetic signaling tool that cells use to lock genes in the 'off' position."
• DNA methylation occurs at the cytosine bases of eukaryotic DNA, which are converted to 5-methylcytosine by DNA methyltransferase (DNMT) enzymes.
• ...methylation near gene promoters varies considerably depending on cell type, with more methylation of promoters correlating with low or no transcription.
• Although patterns of DNA methylation appear to be relatively stable in somatic cells, patterns of histone methylation can change rapidly during the course of the cell cycle. Despite this difference, several studies have indicated that DNA methylation and histone methylation at certain positions are connected.
• Tumor suppressor genes are often silenced in cancer cells due to hypermethylation.

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The Role of Methylation in Gene Expression. Theresa Phillips, Ph.D. 2008, Nature Education.

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.

Chemical marks on histones

Chemical 'marks' that can be written upon histones include:

• acetylation
• methylation
• ubiquitination
• phosphorylation

The possible combinations of histone marks are nearly unlimited, and are referred to as the 'histone code'.
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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
Acetylation and Methylation of Histones and Their Possible Role in the Regulation of RNA Synthesis. Allfrey VG, et al. Proc Natl Acad Sci USA. 1964 May; 51(5): 786–794. PMCID: PMC300163.

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

Packing six feet of DNA into every cell

Human DNA strands are approximately 6 feet in length (7). To store them compactly within cells they are tightly wound around proteins called histones.Read more: /wiki/Histone
(photo from http://en.wikipedia.org/wiki/Histone)


A single DNA strand is wrapped around multiple histones, in a beads-on-a-string structure. These are then compacted, forming the 30nm fiber, then further compressed onto scaffold proteins to form chromosomes.
Read more: /wiki/Nucleosome
(photo from http://en.wikipedia.org/wiki/File:Chromatin_Structures.png)