Luis Arbaiza
dnarb9000@hotmail.com
http://luisbertrandarbaiza.blogspot.com/
UNMSM
1.-INTRODUCTION
A sperm and an ovum are genetically equal, but epigenetically different.
This difference is calls imprinting. There being a mother imprinting and paternal other one.
The union of two gametes, one with imprinting mother and paternal other one allows the normal development of the embryo.
The imprinting means that determined of genes, involved in this process, are extinguished or lit according to a typical and standard patter, in function if they are in the mature sperm or in the ovum.
The genes that are ignited in a gamete are extinguished in another type of gametes.
And this makes them functionally different. In general the genes expressed in the paternal imprinting raise the foetal development whereas the maternal one limits it.
( Paolini 2004)
The union of gametes with the same imprinting, leads to diverse faults epigenéticos and makes the embryonic development unviable.
Immature it of this process makes epigenetic faults.
But what causes its epigenetic difference?
Even one cannot answers completely to this question.
The motivation of this bibliographical investigation is to elaborate a hypothesis on the reason of the imprinting and chance to find experiences that sustain the experimentally above mentioned hypothesis.
JUSTIFICATION
The genetic imprint is a requirement for the normal development of the embryos
This one is realized in the germinal line, his mistake must take mistakes that prevent the successful development of the embryos.
Especially in those procedures like the ICSI that "jump" steps of the epigenetics processes in the masculine gamete.
It could explain by that major percentage of epigenetic diseases has been demonstrated in children conceived by ICSI
And why some found faults in the metilación of the genes H19 and MEST in oligozospermic patients (C.J. Marquess 2008) This might explain also the appearance increased of the syndrome Silver-Russell in children with hiccup - metilación of the gene H19 born of ART. (C.J. Marquess 2008)
In addition a fall metilación of the site of union might lead to an unactivation of the gene IGF2 paternal and to be related to the low embryonic quality and under weight, associated often in ART (artificial reproduction thecnologuies). (C.J. Marquess 2008)
3.-DELIMITING OF THE PROBLEM
For to the develop of a hypothesis on the reason of the imprinting is necessary to cross diverse areas still badly investigated of this phenomenon, which can be grouped in investigations that answer to certain questions, none with a complete and sufficient response:
3,1 what genes are these?
3.2 When are they modified?
3.3 The one who modifies them?
3,4 since it modifies them?
3.5 Which is the reason not caused of the imprinting? Is it genetic or epigenética?
3.6 Which is the relation with the gene Sry that obviously is the only difference between masculine and feminine genome and ah of being the point of item of this differentiation?
MATERIALS AND METHODS
I analyze the existing bibliography in topics related to try to answer the questions of the investigation for what one acceded to virtual libraries and to computer programs of managing byline, as well as the virtual communication with investigators in area.
http://luisbertrandarbaiza.blogspot.com/
RESULTS
3,1 WHAT GENES ARE THESE?
There is a genome of the imprinting, approximately 156 possible new genes, and the status of imprinting-gene can be predicted by his sequence (Luedi, P.P. et to. (2007). The classic mechanism of genetic stamp of a gene is the metilación but it is not the only one and not necessarily it means unactivation.
Here a relation of some known genes like involved in the human imprinting.
Chromosome location GENE State in the sperm State in the ovum Activator function
1 NOEY2
I activate (suppressing of tumors)
IGF2 active Control independent from the demas, his change drags numerous genes more
7p12 (GRB10) in growth factor recipient protein 10
7 q21 PEG10 unactivated assets Probably it is a new gene for imprinting
7q31.3 MEST isoformas 1 and 2,
8 KCNK9 (I activate in the brain it causes cancer, two-pole and epilepcia)
8p23 DLGAP2 (possible suppressing of tumors of bladder)
DLGAP2
Associated protein-2 (Dlgap2).
Was excluded seize the gene responsible for EPMR.
11 H19
Inactive assets Rna not codificante
Role in cancer
To member of the AP2 transcription factor family
E2F1 transcription factor
Possibly uan control different from those of the demas
His change arrastar other genes mas
11 p57, Kip2 CDKN1C
Assets
14 q MEG3,
15 q11-q13 active SNRPN (ribonucleoproteína nuclear small, polypeptide N)
15 q11-q13 IPW Not polypeptide
Functions RNA.
Predominantly in brain
15 UBE3A cause Angelman syndrome. on the mother's chromosome
19q13.4 Possible main key
X active XIST
Inactive
Idice that this metilacion removes in the spermatogenesis Xist (is in mouse)
NESP55
ATP10A
PHLDA2
NDN
MAGEL2
Inactive SNRPN
PEG3
KCNQ1
KCNQ1OT1
CDKN1C
TP73
IGF2R
WT1
SLC22A18
3.2 WHEN DOES IMPRINTING HAPPEN?
During the development of primordial germinal cells the imprinting pattern resigns. Probably on having entered to the gonad.
ESPERMATOGENESIS
It is completed in the phase haploide (meiosis) in the man it happens before the meiosis so soon as when the spermatogonia proliferate; according to some authors it is intrinsic and cell-autonomous.
OVOGÉNESIS
The imprinting happens in ocytes about the time of the first meiotic division, the metilación in the woman happens in the development post natal when the ooccites are in diplotene prophase I, the mother imprinting in constant established in the ripeness of the oocytes.
But the metilación can be in different moments for different genes (Paolini 2004)
There has been verified that it does not owe to the influence of the somatic cells of the genital comb or the environment of the gonad in the basic cells. (Paolini 2004)
IMPRINTING AND DEVELOPMENT
0 ZYGOTO
THE DIFERENCE OF THE IMPRINTING IS EXAGGERATED
The paternal metilación desmetila brief after the fertilization, the mother one suffers metilaciones of novo
4 hours
In mouse the paternal pronucleo is desmetiled in 4 a.m. later to the fertilization
4 hours
A global desmetilacion happens in the morula at 4 a.m. h of fertilization.
5 days
In the blastocist it re-establishes the metilación in the inner cell mass but not in the trophectoderm. In the blastocist reestablesce the metilación in the inner cell mass but not in the trophectoderm. (Kierszenbaum TO. 2002)
MASH2 regulates the development of spongiotrophoblast
Igf2 he has been in labyrinthine trophoblast
ASCL2 it expresses in spongiotrophoblast and labyrinthine
3-4 weeks Basic germ cells seize PGCs have imprinting mother - paternal they migrate Basic germ cells inherit an imprinting bialelic of father and mother, and erase his imprinting to begin one of novo during the gametogenesis. (Kierszenbaum TO. 2002)
The cells they germinate basic they express these genes: Blimp1, Oct3/4, Fragilis, Stella, c-kit, Mvh, Dazl and Gcna1 (Deshira Saiti 2000)
H19 and Igf2 they express in endoderm and mesoderm, (Andrea L. Webber1 1998)
6 week Embrionic germ cells
They do not have imprinting or this is desregulated, already they are in gonad
They destine to be 40 basic cells a gonad induced by exra-embryonic fabrics hipotetized that this cells suppress the program of somatization
Blimp1 (or Prdm1), that is an oppressor of tarscripcion help to this foundation (Yasuhide Ohinat 2005)
On having been born and in a few months the paternal imprinting is completed
Puberty I Initiate of speramatogenesis. The paternalisation is a constant process in the mitotically-dividing spermatogonial stem cell and meiotically-dividing spermatocyte progeny derivative (Kierszenbaum TO. 2002)
Dnmt3L, and Dnmt3b, they interact with Dnmt2a and Dnmt3b and it is needed for a correct espermatogenesis. (Kierszenbaum TO. 2002)
MATURITY The imprinting already I mature this one in the stem cell in the línea germinal (C.J. Marquess 2008)
Spermatogonia is germ cells immature does mitosis
Some of them differ even primary spermatocytes.
After the first meiosis 2 turn secondary spermatocytes
These do meiosis 2 and form 2 espermatidas
spermatogonya (diploid) These in spermatozoids already this metilated H19
3.4 THE ONE WHO MODIFIES THEM?
The genes to imprint generally are metiled in his promoter, what them inactive. (The metilation is the incorporation of a group metil in a coal of the nucleotide)
The metilación not always is turn down
The metilatión changes structure of cromatine
A patter of metilación is the result of:
1.-D and novo metilaciones
2.-Maintenance
3.-Desmetilacion
( Paolini 2004)
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The promoters of the genes to improntar are rich in islands CpG
The enzimas that do this metilación are 3 DNA methyltransferases:
DNMT 1
Dnmt3a
Dnmt3b
For example DNMT 1 catalyzes the transfer of a group methyl (CH3) from S-adenosylmethionine (SAM) to the coal 5 of the citosina turning out to be one 5-Methylcytosine.
These islands metilated are capable of uniting to proteins (for example MECP2 " methyl CpG-binding protein 2)
Dnmt3a and Dnmt3b give metilations of novo
Dnmt1 on the dna having be divided daughter produces a new metilación in the fiber
The desmetilacion happens in absence of Dnmt1 with continuous cycles of replication of the DNA (desmetilatión passive), but also actively (without replication of the DNA). The nature of the desmetilases is even unknown.
DNMT3L attends the metilation of novo
DNMT3a and DNMT3b seem to be those that bosses give of metilación in the early embryo
DNMT1 is the one that this pattern of cell supports mother to daughter (both copies)
3.5 WHICH IS THE REASON NOT CAUSED OF THE IMPRINTING?
It is of supposing that provided that the genes to imprint are numerous (probably hundreds) and that not they all modify simultaneously, there is a chains of reactions that takes this modification gradually up to his total ripeness.
The bibliographical information realizes of certain stages of this process in waterfall without being able to glimpse the start this total phenomenon. Though there is reasonable that goes back to the absence or presence of gene sry, the only gene that differentiates the feminine and masculine genomes and that would determine in last instance the gametogénesis or the ovogénesis.
FRAGMENTS OF THE PROCESS OF IMPRINTING
The expression of the gene KCNQ1OT1 of the chromosome 11p15.5, it is essential for the imprinting of certain regions. The mechanism can be a gene is activated in an environment let's say ováric or spermatic and this one produces the imprinting in chain reaction in other one genes.
Studying his factors of transcrition there might manage be known which the first cause of the imprinting
IG-DMR The ergenic germline-derived differentially methylated region (IG-DMR) is candidate for region control of the chromosome 12
It is a cluster that it contains:
Paternally expressed protein-coding genes Dlk1 and Dio3 and different odd number - coding RNAs, of expression maternal included Gtl2 and C/D snoRNAs.
To retrotransposon-like gene (Rtl1) is expressed from the paternal chromosome and is an antisense transcript expressed from the maternal chromosome containing two microRNAs with full complementarity to Rtl1
IG-DMR's Delección of the mother chromosome causes the loss of the imprinting in all the genes of the cluster
The paternal delectión makes the imprinting intact
19q13.4 A few women lack a piece of chromosome: 19q13.4 and his pattern of imprinting in his ova is paternal
EXPERIENCES THAT GIVE INDIRECT EVIDENCE ON THE REASON OF THE IMPRINTING
Some experiments carried out with other purposes to the search of the reasons of the imprinting can give experimental evidence on some aspects of this one
His analysis can take to make hypothesis and / or to sustaining experimentally in an indirect way
EXPERIMENT 2 MOTHERS
In 2004 Japanese investigators there obtained mice babies of two mothers females.
The ZYGOTE they did it with a mature genome and immature other one (Tomohiro Kono 2004) The not developed oocite was of a mouse mutant with a delection of 13-kilobases
The not developed one is (ng)
And the developed one (fg)
But in the ng I do not alter H19 and Igf2
To block H19 in ng I use a mouse with a deletión in this gene
The embryos were born to 17.5 days
I confirm to him that these embryos do not happen of the 17.5th
The 2 were born with retarded growth they had a little developed liver
Igf2 and H19 As well as Dlk1 and Gtl2 Are printed by them in the spermatogenesis.
Of this we can conclude that the mother metilation happens in the ripeness of the oocite and that the immature occite is a counterpart to a sperm epigenetically speaking.
And that, on the other hand the imprinting of the genes H19 and Igf2 is independent and they find his reason in the region of 13-kilobases
Of the experiment of the mice with two mothers it is possible to deduce the following things:
- it is possible to conclude that an immature oovocite is like a sperm except for 2 genes (igf2 and h19)
- Ii we annul one of them (h19) to obtain the sperm
- therefore so much a sperm is like an immature ovocite except for 2 genes
- if one adds the factors of ripeness of the ovum and is annulled igf2 it might turn a sperm into ovum.
Apparently they weigh fewer ivf, he speaks it that gain the mother genes bony that the paternal genes are incomplete
ARTIFICIAL MODIFICATION OF THE IMPRINTING
Some substances as the synthetic estrogen, diethylstilbestrol (DES) can change the pattern of metilatión of the DNA. (John A. McLachlan, 2001)
The expression of the imprinted genes and the development of the fetus is influenced by the addition of foetal whey of veal to the culture (Paolini 2004)
It is not known as this way affects the imprinting
Probably it removes the groups methyls, going to uncompleting or when the pattern erasing of imprinting. (Paolini 2004)
ICSI AND IMPRINTING
The children of the ICSI weigh less (Paolini 2004)
EXPERIMENT OF THE FEMININE SPERM
First Cells mother turned into sperms
( Nayernia K 2006)
Cells of marrow change in cells they germinate masculine there was expression of scoreboards of cells they germinate (Nayernia K. 2007)
The born mouse tape-worm faults and I use special chemists and vitamins
PRODUCING WOMAN OF SPERMS
There is a locus for you like idatiform 19q13.4. They examined the metilación in the daughters and in it her likes
The mutation I inherit of the mother grandfather for what one concludes that the mistake does not owe one to itself erased of the brands of imprinting if not rather to the reestablishment of mother brands in the ovogénesis or in his post-cigotic maintenance (El-Maarri Or 2003)
If there is a mutation that turns the mother genome in paternal:
1.-A simple element determines the paternity or maternity of the genome
2. - this healthy gene feminize the sperms.
3.-The partenisatión of the genome needs not activation or the suppression of this gene or factor.
The normal condition probably is paternal
First it is necessary to erase and later stamp
We can hypotetizer that the factor of development folicular besides a silence of the gene igf2 can change the paternal imprinting of the sperms to mother
IG-DMR's Delección of the mother chromosome causes the loss of the imprinting in all the genes of the cluster what it indicates as a gene cause of imprinting.
The paternal delectión makes the imprinting intact
A few women lack a piece of chromosome: 19q13.4
This healthy gene feminizaría ova. It might feminized the sperms
H19 and Igf2, apparently, they are printed by a mechanism independent from this one.
If there is achieved the correct expression of igf2 and of ha19 a wide number of other genes puts well (bony of mother it happens to paternal)
CONCLUSION
Of the analysis one could have generated follow hypothesis
HYPOTHESIS
There exist two mutually independent mechanisms that initiate the chain reaction of events that take the pattern of imprinting paternal or mother.
1.-A gene in 19q13.4 is responsible of feminized a very significant number of genes to stamping
And it would alter other one H19 and Igf2
DISCUSSION
There are apparently two mechanisms conduct on that the imprinting depends these mechanisms they must be related to the presence or absence of the gene SRY though the above mentioned relation still is cloudy.
It is known that some enzyme the genes are responsible of metilation to imprint, besides the fact that these genes are rich in islands CpG but provided that in a gamete they are metilated and in other one not, being equal it is necessary to ask since it knows this enzyme that genes metiled and which not? And in addition, since it knows when metilation if this one in a sperm or in an ovum?. Something besides these enzymes would indicate a different or it activates these enzymes
The mechanism can be a gene is activated in an environment let's say ováric or spermatic and this one produces the imprinting in waterfall in other one genes.
It should study abortions of icsi and of art to see since they are epigenetically when technical these alter the normal ripeness of the imprinting in the gametes. Already there is evidence of a major cup diseases epigenetics in ARTs
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