THE CAUSE OF IMPRINTING IN HUMAN GAMETES
Luis Arbaiza
UNMSM
1 .- INTRODUCTION
A sperm and an egg are genetically identical, but epigenetically different.
This difference is called imprinting. Having a maternal and a paternal imprinting.
The union of two gametes, one maternal and one paternal imprinting allows normal development of the embryo.
The imprinting means that certain genes, involved in this process, are turned off or pinned by a typical pattern and standard, depending if in the sperm or the egg mature.
genes that are turned in a gamete are off in the other gamete. And this makes
functionally different. In general, the genes expressed in the parental imprinting elevate fetal development while it limits the maternal.
(Paolini 2004)
The union of gametes with the same imprinting, leads to different epigenetic defects and embryonic development unviable.
The immaturity of this process cam epigenetic defects.
But what causes et epigenetic difference?
still can not completely answer this question.
The motivation for this research literature is to develop a hypothesis about the cause of imprinting and perhaps find experiences that support this hypothesis experimentally. JUSTIFICATION
genetic imprinting is a prerequisite for normal development of embryos
As this takes place in the germ line, the error must carry errors that prevent the successful development of embryos.
Especially in ICSI procedures such as those that "jump" steps of epigenetic processes in the male gamete.
This could explain why it has been shown greater percentage of epigenetic diseases in children conceived with ICSI
and nurse found that defects in the methylation of the H19 gene and MEST in oligozospermicos (CJ Marques 2008) This might also explain the increased occurrence of Silver-Russell syndrome in children with hypo-methylation of the H19 gene ART born. (CJ Marques 2008)
addition, a low methylation of the binding site could lead to inactivation of the paternal IGF2 gene and linked to low embryo quality and low weight, often associated with ART (artificial reproduction thecnologuies). (CJ Marques 2008)
3 .-
For delimitation of the problem to develop a hypothesis about the cause of imprinting must travel several areas still poorly investigated this phenomenon, which can be grouped investigations that respond to certain questions, none with a complete and sufficient answer:
genes
3.1 What are these?
3.2 When you change?
3.3 Who the changes? 3.4
how the changes?
3.5 What is the uncaused cause of imprinting? Is it genetic or epigenetic?
3.6 What is the relationship with the Sry gene which is obviously the only difference between male and female genome, and uh be the starting point of this differentiation? MATERIALS AND METHODS
literature was analyzed in subjects related to try to answer the research questions to what was agreed virtual libraries and software for data management and virtual communication with researchers in the area. RESULTS
3.1 WHAT ARE THE GENES?
A genome imprinting, about 156 potential new genes, and imprinting status-gene can be predicted by its sequence (Luedi, PP et al. (2007). The classic mechanism of genetic imprinting is a gene methylation but is not the only and does not necessarily mean inactivation.
Here is a list of some genes known as imprinting involved in the human.
State Chromosome location GEN sperm into the egg state active role 1 NOEY2
active (tumor suppressor)
active IGF2 Independent control of others, the change carries many more
7p12 genes (GRB10) in growth factor receptor protein PEG10 10
7 q21 active inactivated may be a new gene imprinting
7q31.3
MEST isoforms 1 and 2, 8 KCNK9
(active in the brain causes cancer, bipolar and epilepcia)
DLGAP2 8p23 (possible bladder tumor suppressor)
DLGAP2
associated protein-2 (Dlgap2). WAS
Excluded as the gene responsible for EPMR.
11
inactive H19 noncoding RNA active role in cancer
a member of the AP2 transcription factor family
Transcription factor E2F1 may uan
different from control of others
His other genes change more
drag
11 p57, Kip2 CDKN1C active
MEG3
14 q, 15 q11-q13
active SNRPN (small nuclear ribonucleoprotein, polypeptide N) 15 q11-q13
IPW functions not
polypeptide RNA. Predominantly in brain
15 Causes UBE3A Angelman syndrome. on the mother's chromosome 19q13.4
passkey
Possible active XIST
inactive X
Idica that methylation is removed in spermatogenesis Xist (is in mice)
NESP55
ATP10A
PHLDA2
MAGEL2
SNRPN NDN
inactive PEG3
CDKN1C KCNQ1
KCNQ1OT1
TP73
IGF2R
WT1
SLC22A18
3.2 What HAPPENS WHEN IMPRINTING?
During the development of primordial germ cells imprinting pattern is deleted. Likely to enter the gonad. SPERMATOGENESIS
Completes in the haploid phase (meiosis) in man before meiosis occurs as soon as when spermatogonia proliferate, according to some authors is intrinsic and cell-Autonomous. Oogenesis
ocytes The imprinting occurs around the time of the first division meiotic, methylation occurs in women in the postnatal development when ooccitos are diplotene prophase I, the maternal imprinting continuously established in the maturation of oocytes.
But methylation may be at different times for different genes (Paolini 2004)
has been found not due to the influence of somatic cells of the genital ridge or gonad environment in primary cells. (Paolini 2004)
IMPRINTING AND DEVELOPMENT STAGE TIME Time IMPRINTING STATUS OF SPERMATOGENESIS oogenesis
0 Zygote
exaggerates the imprinting DIFERENCAI
demethylated paternal methylation shortly after fertilization, the mother undergoes de novo methylation
4 hours
In mouse paternal pronucleus is demethylated within 4 hours after fertilization
4 hours
A global demethylation occurs in the morula at 4 h of fertilization .
5 days
In the blastocyst restores methylation in the inner cell mass but not in the trophectoderm. In the blastocyst reestablesce methylation in the inner cell mass but not in the trophectoderm. (Kierszenbaum AL. 2002)
MASH2 regulates the development of spongiotrophoblast
Igf2 has been found in labyrinthine trophoblast expresses
ASCL2 spongiotrophoblast and labyrinthine in 3-4 weeks
as PGCs Primordial germ cells have migrated paternal and maternal imprinting The Primordial germ cells inherit a biallelic imprinting father and mother, and delete your imprinting to start a de novo during gametogenesis. (Kierszenbaum AL. 2002)
primordial germ cells expressing these genes: Blimp1, Oct3 / 4, Fragilis, Stella, c-Kit, MVH, DAZL and Gcna1 (Deshira Saiti 2000)
H19 and Igf2 are expressed in endoderm and mesoderm (Andrea L. Webber January 1998)
6 weeks Embrionic
germ cells have no imprinting or is deregulated, and gonad are primordial cells
40 are intended to be gonad Exra-induced tissue embryonic cells is hypothesized that somatization stifle
Blimp1 program (or Prdm1), a repressor that foundation helps tarscripcion (Yasuhide Ohinata 2005)
at birth and within months is completed Parental imprinting
esperamatogenesis puberty started. The paternalisacion is an ongoing process in-Dividing mitotically and meiotically spermatogonial stem cell-derived progeny Dividing spermatocyte (Kierszenbaum AL. 2002)
Dnmt3L and Dnmt3b interact with Dnmt2a and Dnmt3b and is required for proper spermatogenesis. (Kierszenbaum AL. 2002)
MATURITY The imprinting is already mature in the stem cell line in germinal (CJ Marques 2008)
Spermatogonia are immature germ cells do mitosis
Some differ to primary spermatocytes.
After the first meiosis spermatocytes become secondary
2
These are meiosis 2 and form 2 spermatids
Spermatogonia (diploid) are in speramtozoides already methylated H19
THE AMENDING 3.4 Who?
to imprint genes are usually methylated in its promoter, making them inactive. (Methylation is the addition of a methyl group on a Carbon nucleotide)
methylation silencing is not always
Methylation chromatin structure changes
A pattern of methylation is the result of: 1 .-
de novo methylation maintenance
2 .- 3 .- demethylation
(Paolini 2004)
promoters imprinting genes are rich in CpG islands
The enzymes that make this methylation are 3 DNA methyltransferases, DNMT 1
Dnmt3a Dnmt3b
For example DNMT 1 catalyzes the transfer of a methyl group (CH3) from S-adenosylmethionine (SAM) to carbon 5 of cytosine resulting in a 5-methylcytosine.
unmethylated
These islands are susceptible to bind to proteins (eg MECP2 "methyl CpG-binding protein 2)
Dnmt3a and Dnmt3b are de novo methylation Dnmt1
when divided by a new DNA methylation in the daughter strand
The demethylation occurs in the absence of Dnmt1 with continuous cycle of DNA replication (passive demethylation) but also active (no DNA replication .) The nature of the demethylases is still unknown. Dnmt3L
assists
novo methylation of Dnmt3a and Dnmt3b appear to be the giving patterns of methylation in the early embryo
DNMT1 is what keeps this pattern of mother cell to daughter (two copies)
3.5 What is
CAUSE NO CAUSE OF IMPRINTING?
Presumably because imprinting genes are numerous (perhaps hundreds), and not all are modified simultaneously, there is a cascade of reactions that leads this change gradually until fully matured.
bibliographic information realizes certain stages of this cascade could not envision the total trigger of this phenomenon. Although it is reasonable to lift the absence or presence of sry gene, single gene that differentiates male and female genomes, and ultimately determine gametogenesis and oogenesis.
FRAGMENTS OF MATURATION PROCESS OF IMPRINTING
cause consequence
KCNQ1OT1 The expression of the gene on chromosome 11p15.5, is essential for the imprinting of certain regions. The mechanism may be a gene is active in a ovarian or spermatic say this cascade occurs in other imprinting genes.
studying their transcricion factors could be achieved by knowing what the root cause of imprinting
IG-DMR The ergenic germline-derived differentially methylated region (IG-DMR) is candidatopara control region of chromosome 12
is a cluster that contains:
paternally Expressed protein-coding genes Dlk1 and DIO3 and several non-coding RNAs, including maternal expression of Gtl2 and C / D snoRNAs.
A retrotransposon-like gene (Rtl1) is Expressed from the paternal chromosome and has an antisense transcript from the maternal chromosome Expressed containing two microRNAs with full Complementarity to Rtl1
Deletion of IG-DMR of the maternal chromosome causes loss of imprinting on all cluster genes
The deletion leaves intact paternal imprinting
19q13.4 Some women do not have a piece of chromosome: 19q13.4 and its imprinting pattern in their eggs is paternal
EXPERIENCES GIVING EVIDENCE ON THE CAUSE OF INDIRECT
IMPRINTING Experiments conducted with other aims at finding the causes of imprinting can provide experimental evidence on some aspects This
Their analysis may lead to you hypotheses and / or indirectly sustain
experimentally
EXPERIMENT MOTHER OF 2
In 2004, Japanese researchers obtained mice female offspring of two mothers.
The zygote genome did so with a mature and an immature (Tomohiro Kono 2004) The oocyte was not developed a mouse mutant with a deletion of 13-kilobase
The undeveloped is (ng)
and development (fg)
But in the ng was not altered
H19 and Igf2 H19 To block ng was used in a mouse with a deletion in the gene
The embryos were born to 17.5 days
was confirmed that these embryos do not spend the day 17.5
The 2 were born growth retardation had a poorly developed liver Igf2 and H19
As Dlk1 and Gtl2 are printed on spermatogenesis.
From this we can conclude that the maternal methylation occurs in oocyte maturation and the Occitan immature sperm is homologous to epigenetically speaking.
And, on the other hand the imporntin of H19 and Igf2 genes is independent and find their cause in the region of 13-kilobase
IMPRINTING Modification
Some substances such as synthetic estrogen, diethylstilbestrol (DES) can turn DNA methylation pattern. (John A. McLachlan, 2001)
The expression of imprinted genes and fetal development is influenced by the addition of fetal calf serum culture medium (Paolini 2004)
is not known how this medium affects the imprinting Perhaps
removes methyl groups, leading to incomplete or delete the pattern of imprinting. (Paolini 2004)
E IMPRINTING
ICSI ICSI Children weigh less (Paolini 2004)
EXPERIMENT
First female sperm stem cells turned into sperm that impregnated
(Nayernia K 2006)
marrow cells were transformed into male germ cells were expressing germ cell markers (Nayernia K. 2007)
born mouse had defects and will use special chemicals and vitamins
PRODUCER OF SPERM WOMAN
A idatiformes molas locus 19q13.4. Examined the methylation the daughters and the mola
The mutation is inherited from the grandfather or maternal grandfather so we conclude that the error is not due to an erased imprinting marks if not quite the re-establishment of native brands in oogenesis or in post-cigotic maintenance (El-O Maarri 2003)
CONCLUSION This analysis has been able to generate hypotheses
síguete
HYPOTHESIS Two mutually independent mechanisms that initiate the cascade of events leading to the pattern of paternal or maternal imprinting .
1 .- A gene in 19q13.4 is responsible for feminizaría a significant number of genes to print
And another alter H19 and Igf2
DISCUSSION There are apparently two mechanisms locomotive upon which the imprinting of these mechanisms must be related to the presence or absence of SRY but that relationship is still nebulous.
is known that some methylating enzyme is responsible for imprinting genes, these genes also are rich in CpG islands but because in a gamete are methylated and not in another, still the same question arises how this enzyme known to methylate genes and which are not? And as you know when methylated if a sperm or an egg. Some of these enzymes also signal a different or activates these enzymes
The mechanism may be a gene is active in a ovarian or spermatic say this produces cascade to other imprinting genes.
abortions should study what ICSI and art to see how they are epigenetically by altering these techniques the normal maturation of imprinting in the gametes. There is already evidence of increased disease epigenetic ARTs cup
Deletion of IG-DMR of the maternal chromosome causes loss of imprinting on all cluster genes that marks it as a locomotive gene imprinting.
The deletion leaves intact the parental imprinting
Some women do not have a piece of chromosome: 19q13.4
This healthy gene feminizaría eggs.
sperm could feminize H19 and Igf2, apparently, are printed by a mechanism independent of this. If
achieved the correct expression of IGF2 and ha19 a large number of other genes is well placed (maternal bone becomes father)
The experiment of mice with two mothers can deduce the following:
"We conclude that an immature oocyte and sperm except for 2 genes (IGF2 and H19)
-one was nullified (h19) to get the sperm
-hence a sperm is like an immature oocyte except for 2 genes
"If add the egg maturation factors and vanishes IGF2 could turn sperm into eggs.
weigh less ivf Apparently, that talks about winning the bony maternal genes that paternal genes are incomplete
WOMEN PRODUCERS
MDE SPERM
If there is a mutation that makes the maternal genome paternal
1 .- A simple element determines parenthood
2.-genome that healthy gene feminizaría sperm. 3 .- partenisación
genome requires no activation or suppression of this gene or factor.
The normal state is paternal
may first have to delete and then print
We hypothesize that the factor of follicular development as well as IGF2 gene silencing can change the parental imprinting of the sperm mother
Arie Look
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