Knockdown of Menin Affects pre-mRNA Processing

Knockdown of Menin Affects pre-mRNA Processing and Promoter Fidelity at the Interferon-gamma Inducible IRF1 Gene
-Auriemma L, et al. Epigenetics & Chromatin 2012, 5:2 doi:10.1186/1756-8935-5-2.

• MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing.
• IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells.

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1
-Wikipedia

• An overview of MEN1.

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.

Expression analysis of endogenous menin

Expression analysis of endogenous menin, the product of the multiple endocrine neoplasia type 1 gene, in cell lines and human tissues
-Wauto V, et al.
Int J Cancer. 2000 Mar 15;85(6):877-81.

The amino acid sequence of menin

The human gene MEN1 (also the name of the disorder associated with a mutant MEN1 gene) encodes the protein menin. UniProt specifies three isoforms of menin, Isoform 1 being called the 'canonical' sequence.¹ It is 615 amino acids in length, the others being 610 and 575 amino acids in length, respectively.

Menin Isoform 1:

        10         20         30         40         50         60
MGLKAAQKTL FPLRSIDDVV RLFAAELGRE EPDLVLLSLV LGFVEHFLAV NRVIPTNVPE

        70         80         90        100        110        120 
LTFQPSPAPD PPGGLTYFPV ADLSIIAALY ARFTAQIRGA VDLSLYPREG GVSSRELVKK 

       130        140        150        160        170        180 
VSDVIWNSLS RSYFKDRAHI QSLFSFITGW SPVGTKLDSS GVAFAVVGAC QALGLRDVHL 

       190        200        210        220        230        240 
ALSEDHAWVV FGPNGEQTAE VTWHGKGNED RRGQTVNAGV AERSWLYLKG SYMRCDRKME

       250        260        270        280        290        300 
VAFMVCAINP SIDLHTDSLE LLQLQQKLLW LLYDLGHLER YPMALGNLAD LEELEPTPGR 

       310        320        330        340        350        360
PDPLTLYHKG IASAKTYYRD EHIYPYMYLA GYHCRNRNVR EALQAWADTA TVIQDYNYCR 

       370        380        390        400        410        420
EDEEIYKEFF EVANDVIPNL LKEAASLLEA GEERPGEQSQ GTQSQGSALQ DPECFAHLLR 

       430        440        450        460        470        480 
FYDGICKWEE GSPTPVLHVG WATFLVQSLG RFEGQVRQKV RIVSREAEAA EAEEPWGEEA

       490        500        510        520        530        540 
REGRRRGPRR ESKPEEPPPP KKPALDKGLG TGQGAVSGPP RKPPGTVAGT ARGPEGGSTA

       550        560        570        580        590        600
QVPAPTASPP PEGPVLTFQS EKMKGMKELL VATKINSSAI KLQLTAQSQV QMKKQKVSTP

       610 
SDYTLSFLKR QRKGL 

The table contains standardized single-letter codes for the various amino acids. Wikipedia offers a table describing these codes.²
For example, the "Q" at amino acid position 64 represents glutamine, which is encoded either by codons CAA or CAG.³
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¹ UniProt entry on "MEN1_HUMAN"
² http://en.wikipedia.org/wiki/Amino_acid#Table_of_standard_amino_acid_abbreviations_and_properties (Wikipedia: Amino Acid).
³ http://en.wikipedia.org/wiki/Genetic_code#RNA_codon_table (Wikipedia: Genetic Code).

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.

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