“Epigenetic molecular genetics in Multiple Myeloma”


Dr. Regkli Areti, Konstadinedes Polidoros, Mallis Panayiotis, Matsis Konstadinos, Constadinides Ioannis and Panagoula Kollia.








In most higher eucaryotic genomes,including those of mammalian cells,approximately 5 percent of the C residues are modified by methylation at the 5 position of the cytokine ring.Such methylations occur almost exclusively at  sequences to yield mCpG (mC=5-methylcytosine) and appear symmetrically on both stands of the DNA (since the CpG dinoucleotide is always base-paired with another CpG sequense in the antiparallel double helix).Curiously,CpG sequences are themselves underrepresented in genomes that contain mC ,being present at only about one-third the expected frequency 1.

                What has become apparent in recent years is that certain CpG sites in the vicinity of many genes are undermethylated in tissues where the gene is expressed, compared to tissues where the gene is inactive.The use of particular restriction enzyme pairs has provided a convenient and simple assay for assessing the state of methylation of some subsets of CpG sequences.Demethylation of active genes is not complete1,2.Up to 30 percent of the CpG sequences in transcribed regions are methylated,

compared to about 70 percent methylation of all CpG sequences in animal cell DNA.As with Dnase sensitivity,undermethylation is usually detected over a significantly larger region than the transcribed portion of a particular gene and is often found in tissues where the gene is not (yet) active but potentially activatable.1,2,3,4

                Although demethylation and expression are not coupled for every gene that has been examined,in most cases the correspondence is quite striking.This prompt the question of whether changes in DNA methylation are the cause or effect of gene activation.Methylation could regulate

gene expression in two main ways.First,addition of a 5-methyl group and proteins such as repressors and activators ,for the 5-methyl to cytosine could increage or decreage the interaction between the

specific DNA –protein recognition often takes places.Second because DNA Group protrudes into the major groove of the double helix where the addition of a 5-methyl group to C leads to molecular crowding in the major groove,methylation tends to shift the conformational equilibrium of the DNA away from the standard B-form toward other forms .Since DNA binding proteins are generally sensitive to the configuration of the sugar –phosphate backbone as well as to the base sequense at their

recognition sites,such conformational changes could dramatically alter repressor (or avtivator ) binding .2,3Some evidence that demethylation may indeed induce gene activation comes from studies using 5-azacytidine (5 azaC),an analog of C.Strikingly ,5 –aza C induces differentiation (turning on

the genes) in cultured mouse embryo cells.Similarly in the case of a number of cloned genes that have been reintroduced into mammalian cells  the unmethylated form proves to be more active than the deliberately methylated gene.However there are also examples where demethylation lags behind gene expression.Thus the exact relationship berween methylation and gene expression remains unclear,perhaps because only a few of the potential methylation sites in DNA are critical for gene control.Also nuclear is how selective demethylation of a critical site might be accomplished when gene

activation is desired.A final puzzle arises from the realization that some eucaryotic organisms regulate their genes perfectly well without any DNA  methylation whatsoever1,2,3,4.


The epigenetic rhythm is determined by the change which provokes the gene expression, and which the realization, with changes, such as modification of histones, changes in methylation and acetylation of the DNA.         





Histone Acetyltransferases-HATS


The acetylation of histones in eykariotic organisms  was discovered quite a few years ago, and the identification as well as the characterization of enzymes which create it have revealed their remarkable diversity in different organisms.

                Histone Acetyltransferases-HATS, is the name for factors which allocate enzyme activation in the transportation of an acetylation team from the acetyl-CoA to the e-amino of the group of amino-acids lysine, that are  usually found in the basic region of  N-terminal end of histones. The total number of enzymes-HATS  are separed in two categories:type A 19 found in the core and type B found in cytoplasme  9,93. The HATS of type B are considered to catalyse the acetylation of newly- composed proteins in the cytoplasme , while the HATS of type A are considered that they participate in the nuclear acetylation of the histone related with the transcription, as well.

The acetyltransferase of type B, HAT1, was discovered in sacharomyces 57 and it acetylizes the lysin 5 and 12 of  histone 4 (H4) in vitro, amino-acids which were known to be found acetylated , in the newly synthesized Η4 10. The enzyme HAT1 constitutes a part of a multifactor complex whose subunits includes also 14 proteins HAT2 and CAF1 which have been connected with the redevelopment and the aggregation of  the components of the chromatin, respectively 82,55. Despite the particular significance attached to HAT1, the transformation or HAT2 has not presented any problems in the incorporation of H4 to the chromatin 82, which clearly indicates that its action can be replaced by other enzymes when the HAT1 is absent or cannot act.

Many of the proteins with HAT activity can acetylized  free histones  when  used in vitro, while others such as the nuclear ones, cannot acetylized   their physiologic substrate as they are but only when they are found in the whole complex  with other factors, that appear that they are essential for their activity .

Another family of acetylates   that has been found  is the one of  MYST, which was named after and shaped by the strong resemblance they bear with the concatenation of proteins MOZ, Ybf/Sas3, Sas2 and Tip60 22. The Esa1 of Sacharomyces, the MOF of Drosofilla  and the human HBO1 and MORF 76  constitute newer members of family MYST which was discovered later.

The strong relationship between the transcriptional  activation and acetylation of the histones  was clearly indicated when it was discovered that the larger subunit of the complex factors that is connected with TVR (TVR Associated factors-TAFs), Taf1-taf250, allocates the enzyme activity  in the acetylation of histones 73. The complex  TFIID can band  to the DNA via the TVR factor that recognizes special sequenses, athough it has been discovered that even TFIID that does not carry TVR it can transcript in vitro .

The acetylotransferases are involved in the transcriptional  regulation not only via the acetylation of histones  but also by transcriptional  factors 25.




Histone Deacetylases-HDACS 


The acetylation of the histones is a reversal procedure, as the acetyl group can be removed from the action of special enzymes called apocetylase histones- (HDACS), the existence of which was discovered shortly afterwards the presence acetylases 102  The deacetylase are categorized in families and the enzymes of human class I, II and III are homologe to the ones of the sacharomyces Rpd3, Hda2 and Sir2, respectively 103. Deacetylase hitones are divided in units in which some of the subunits function and regulate the enzyme activation. Apocetylase together with the histone acetylases contribute to the acetylation of certain histones as well as the regulation and the differentiation of different megafactors which are responsible for their modification. The interaction between megafactors which advance to specific alleles, has as a result their located action in instigators, which in turn regulate the amount of quantity and the availability of the enzyme ¶¶ 4 63



Histone Methyltranferases-HMTs


The methylation histones is performed by specific enzymes, the methylase histones, HMTs. Recently other enzymes that methylate the histones in specific residues have been discovered and it has contributed in the discovery of the transcription mechanism, as when the histones are methylated show significant differences from the methylation known up to the moment as post-translational.

The methylation of the histone does not change the total charge of protein and it appears to be stable modification, concurrently certain enzymes that remove methylgroup have been discovered, but present special action 99,28,111. The methylation of histones can be classified in two groups, those that methylate the lysine residues18,100  and those methylated the arginine residues, such as the family of PRMT. The amino-acid arginin can undergo only - or di-methylation. The enzymes that end up in the methylation Arginin residues are separated in two categories: Type I, which leads to a single and asymmetrical di-methylation and Type II, which leads to a single  and symmetrtical di-methylation. There are  five enzymes which involved in the methylation reaction of arginin, and present high degree of maintainance of catalytic region  18, that are named prmt1-5. The methylation histone is involved in the regulation of transcription mechanisms as much as in the control of suppressive activity on the transcription. The role of methylating histones during transcription is characterized by an additional degree of complexity,  the number methylated groups on a residue is related to different attributes. 66 <>




The Methylation of the aminoacid  lysine of histone


The histone lysine that undergo methylation are the Lysine 4,.9,.27 and 36 and 79 on histone the 3 and lysine 20 on histone the  4. The enzymes that are involved in this the specific transformation bring characteristic region SET, and the characteristic regions that are rich in cytokines that precede, PRESET and follow, Post-set, respectively,to the region where there is enzyme activity. The enzymes that methylated lysine of the histones can be categorized in four large families: the SET1, which includes enzymes which methylate the K4 of H3, the SET2, which includes the enzymes which methylate the K36 of H3, the RIZ and the family SUV39, which is consists of enzymes that can methylate the K9 and K27 of H3 18 

 The methylation the K79 of H3 is an exception since the enzyme that is responsible for the modification, DOT1, does not brings the characteristic SET region 36. The methylation of K79 is related to the activity of the transcription and  is considered  participate in preventing the spread Heterochromatosis. The first methylated lysine which was discovered in from mammals and brings upon itself an active methylated of K9 of H3 is Suv39h1, counterpart of Su (var) the 3-9 Drosofila 52 

 In certain cases where there is a later expressive modification of factors from enzymes which modify the chromatin during methylation of arginin or acetylase have been found and their fuction appears in biological reactions, such  as translation 25,38 But for the enzymes from the methylated lysine family with characteristic domain SET, the only known are the histones. Recently other enzymes that methylate the K4 of H3, including the MLL, the ALL, hSET1 and hSMYD3 this 72,75,117,48  have been excluded from humans. These proteins are usually part of mcromolecule structures, which include more the one enzyme activity that modifiy the chromatin. In contrast with heterochromatin situation which was mentioned, the potential role of the modification of the histone in the consseration of the active translational chromatins has not being dified. If the modifications of the histone press for some reaction to the controversial of the translational, the methylation works as aactivation means for the gonads, because contrary to the acetylation, the maethylation of the lysine is stable. In addition, sugnificant levels of methylation of H3-K4 have been observed in the genes of region of b-globulin and in the NF-4 during the cell diffentiation, before the translation, showing that tis specific modification is involved in the resolution and the conservation of one strong active chromatin 49,48








Μοριακή Λειτουργία


p15 ή CDKN2B


        Λειτουργία της κινάσης

        Πρόσδεση πρωτεϊνών

        Εξαρτώμενη από την κυκλίνη πρωτεϊνική πρόσδεση κινάσης

p16  ή CDKN

Chr9:21.96-21.98 Mb

        Πρόσδεση DNA

        Εξαρτώμενη από την κυκλίνη πρωτεϊνική πρόσδεση κινάσης

        Πρωτεϊνική δραστηριότητα


Chr5:10.73-10.81 Mb

        Επαγωγή της  απόπτωσης  με εξωκυτταρικά σήματα



Chr16:11.26-11.26 Mb

        Δραστηριότητα πρωτεϊνικού υποδοχέα κινάσης

        Πρόσδεση υποδοχέα αναπτυξιακού παράγοντα ομοίου ινσουλίνης

        Πρόσδεση πρωτεϊνών



Chr19:54.15-54.16 Mb

        Πρόσδεση πρωτεϊνών

        Επικρατούσα περιοχή πρόσδεσης ΒΗ3







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