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

How does DNA replicate?

An animated presentation on DNA replication, by John Kyrk: http://www.johnkyrk.com/DNAreplic.swf

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)

Is a cure possible?

If Your life is touched by MEN1 it's important not to give in to fear. It's a serious condition, but effective treatments are available for many of its manifestations. Medical science is advancing rapidly in this area, driven especially by research in the areas of cancer and genetics. There is good reason to hope for continued advances in MEN1 research and treatment ...and someday a cure.

But first things first. If You or a loved one has MEN1, You'll want to seek out the best treatment available. MEN1 is complex, and in order to find the best available treatments it will help to learn more about MEN1 and better understand what You're up against.

I am not a physician, nor any kind of medical professional. But I've got a loved one with MEN1, and we want to make sure she gets the best care possible. So I want to learn more.

On this website we plan to offer resources for those who want to learn more about MEN1. It is our firm belief that MEN1 patients, their loved ones, and friends, can help overcome the challenges of MEN1 by better understanding the condition, its treatments, and something of the research surrounding it. If knowledge is power, then learning about MEN1 improves our ability to secure the best treatment for the MEN1 patients we care for. And in some way, to learn is to join our efforts -even if only in a fraternal sense- with those involved directly in medical research and treatment, and with families around the world who face the challenge of MEN1. This is no small thing.

With our study, prayers, and if possible, financial support of ongoing research, let's help pave the path to a cure.

Will You join in me in learning about MEN1? In promoting MEN1 education, treatment, and research? In supporting those who are fighting this disorder? And in working -and, yes, praying- for a cure?

Brainstorming for a cure

Suppose we could design a virus or bacteria that attacks and kills any cell that is unable to produce menin, but has no effect on other cells. This would seem to prevent MEN1 tumors from developing. But how would this really work? Do we design the virus so that it is unable to harm cells containing menin? Perhaps the virus is able to infect all types of cells, but is inactivated in the presence of menin.

But this would seem to depend on there always being at least some minimum level of menin production in all normal cells. I don't know whether this is the case. It has been reported that menin "is ubiquitously expressed in tissues examined, although its expression levels are variable among different tissues"(3). If we're lucky, we develop a virus that is able to destroy individual menin-deficient cells surrounded by cells that are not menin-deficient, and the result is that any cells unable to produce menin are destroyed, and all other cells are unaffected.

If we're not quite so lucky, maybe we find that normal cells sometimes produce very little or no menin during part of their life cycle, and we wouldn't want them destroyed by our hypothetical virus. But in this case perhaps there is a different method our virus could use to detect cells whose MEN1 genes are both nonfunctional.

What is MEN1?

Multiple Endocrine Neoplasia Type 1 is a genetic disorder that greatly increases the risk of developing multiple cancerous and noncancerous tumors in glands such as the parathyroid, pituitary, and pancreas. These endocrine tumors may produce excessive levels of hormones that lead to secondary disease.

Individuals with MEN1 are born with one mutated copy of the MEN1 tumor suppressor gene in each cell. Cells that later develop a mutation in the remaining copy of the MEN1 gene then are left unable to produce menin, an important tumor suppressor protein. With no functional MEN1 gene, such cells may divide uncontrollably, resulting in the development of tumors.

MEN1 is also known as: MEN Type 1, MEN-1, Multiple Endocrine Adenomatosis Type 1, MEA Type 1, MEA 1, Wermer's syndrome.

references:
http://www.mayoclinic.org/men1/
http://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1

Why promote MEN1 awareness?

MEN1 isn't very common: only about 1 in 30,000 people have this genetic disorder. But that's 10,000 in the United States, and more than 250,000 worldwide.

When a disease is "rare" and unknown to our family and friends we tend not to think much about it... But when it strikes a loved one, "rare" no longer has much meaning.

We want to promote greater awareness, research, and improved treatment of MEN1.