Epigenetic Modification Is Central to Genome Reprogramming in Somatic Cell Nucle - 《stemcells》干细胞学杂志干细胞之家



免疫细胞治疗专区	欢迎关注干细胞微信公众号

12 3 4 5 6 7 8 9 10 ... 28 下一页

返回列表

查看: 641415\|回复: 272	go Epigenetic Modification Is Central to Genome Reprogramming in Somatic Cell Nucle [复制链接]

江边孤钓

版主

Rank: 7 Rank: 7 Rank: 7

积分: 0
威望: 0
包包: 483

楼主

发表于 2009-3-5 00:08 |只看该作者 |倒序浏览 |打印

作者：Lyle Armstronga,b, Majlinda Lakoa,b, Wendy Deanc, Miodrag Stojkovica,b作者单位：a Centre for Stem Cell Biology and Developmental Genetics andb Institute of Human Genetics, University of Newcastle, Central Parkway, Newcastle upon Tyne, United Kingdom;c Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom
   6 c! L: [& n; o

      , @) A& M/ V4 \2 v8 ^: V! h1 F
                       _9 Q; v, u6 Q  t) Z( ]! i
         5 @0 x; K7 @8 o9 ]; D- `8 |1 C

         , }7 A+ [7 B) [6 B6 |
         7 V" L  v# d9 M% W2 V/ S; z
                  2 |* t* E2 m- M7 G
      0 U9 A& C3 b9 n4 L0 }3 x
      2 n) ]. E& A; Q

      【摘要】! C6 z2 o& i$ q7 D( Y. s. L
   The recent high-profile reports of the derivation of human embryonic stem cells (ESCs) from human blastocysts produced by somatic cell nuclear transfer (SCNT) have highlighted the possibility of making autologous cell lines specific to individual patients. Cell replacement therapies have much potential for the treatment of diverse conditions, and differentiation of ESCs is highly desirable as a means of producing the ranges of cell types required. However, given the range of immunophenotypes of ESC lines currently available, rejection of the differentiated cells by the host is a potentially serious problem. SCNT offers a means of circumventing this by producing ESCs of the same genotype as the donor. However, this technique is not without problems because it requires resetting of the gene expression program of a somatic cell to a state consistent with embryonic development. Some remodeling of parental DNA does occur within the fertilized oocyte, but the somatic genome presented in a radically different format to those of the gametes. Hence, it is perhaps unsurprising that many genes are expressed aberrantly within "cloned" embryos and the ESCs derived from them. Epigenetic modification of the genome through DNA methylation and covalent modification of the histones that form the nucleosome is the key to the maintenance of the differentiated state of the cell, and it is this that must be reset during SCNT. This review focuses on the mechanisms by which this is achieved and how this may account for its partial failure in the "cloning" process. We also highlight the potential dangers this may introduce into ESCs produced by this technology.

AN OVERVIEW OF THE CLONING PROCESS+ |' I$ v) V4 X. b" F
: {: m: G0 C# A& {8 V
It has long been known that certain invertebrate species can be "duplicated" or "cloned" simply by dividing them into two pieces and allowing the separated halves to grow into a complete organism. However, this cannot be applied to vertebrates.( l. C, u1 Y$ _2 V- A

It is more than 50 years since the groundbreaking studies of Briggs and King .# |" x4 |, B+ g% R, {

Figure 1. The method used to create "Dolly" the sheep. The nuclear material was removed from an oocyte taken from an adult female and replaced by that of a somatic cell from another animal. Fusion and activation of this reconstructed zygote gave rise to an embryo that was surgically transferred to a surrogate mother wherein development to term was completed.
- _8 _( o& z# p* r/ d/ ^0 t
Clearly, there are still many problems associated with SCNT. The majority of cloned embryos (irrespective of species) do not survive to birth, whereas those that do often demonstrate a variety of defects that greatly reduce the probability of their survival to adulthood . In this review, we will concentrate on the mechanisms that establish a normal epigenotype and consider the critical areas in which these differ between SCNT-derived and naturally fertilized embryos. 2 _8 e4 n6 E6 p& Z& v; b3 W
      【关键词】 Embryonic stem cells Genome reprogramming Epigenetic modification Somatic cell nuclear transfer- k0 S2 X! J/ d& {3 F( R6 O# |
   HOW IS SCNT ACHIEVED?0 D( i: n& H3 |. c2 j+ C
' v5 F3 c- x' K4 E! O+ ?' M
There are two basic strategies for the cloning of mammals by SCNT that are able to produce embryos capable of development to term. Both of these techniques require the removal of the nuclear material from the oocyte and differ only in the way in which the nuclear material of the donor cell is introduced and the subsequent activation of the reconstructed embryo. Enucleation of the MII oocyte may be achieved by a number of techniques; the most popular is capillary incision of the zona pellucida, using a micromanipulator followed by removal of the polar body and adjacent metaphase chromosomes by suction into a glass pipette  (the so-called "handmade" cloning method). Although this technique has the advantage of simplicity, it does remove more oocyte cytoplasm and therefore it may reduce the amounts of proteins needed for reprogramming and early embryonic development.
4 v2 b4 [6 |  c$ }' f4 A
Introduction of the donor nucleus can be performed using a variety of methods that aim to optimize the successful production of offspring by altering several factors. These techniques rely on either microinjection of the donor cell or its isolated nucleus into the oocyte cytoplasm, or fusion of the donor cell with the enucleated oocyte is achieved through appropriately timed electrical pulses. Of key importance is cell cycle synchrony of the donor cells. Full-term cloned animals have been obtained most consistently from donor cells in a quiescent state (G0 or G1), which may be induced in cultured cells by serum starvation .

Not all cells that would normally be nondividing are useful donors for SCNT. Neurons and other types of terminally differentiated cells are generally rather poor candidates for cloning studies; this may reflect the lack of developmental plasticity of their genomes. Such cells are believed to repress many more genes than cycling or less differentiated cells and as such are thought to be extremely difficult to reprogram .% _2 G- l9 H$ x
% H% _1 |6 f  E& P2 B7 ~  s; b
However, other types of cells that are not terminally differentiated may make better donors. There is considerable evidence to suggest that the use of ESCs as nuclear donors gives rise to viable offspring with greater efficiency than many somatic cell types . Interestingly, these cells seem to offer little advantage (in terms of development to term) over more readily accessible cell types such as skin fibroblasts.& L, o( |+ K) f$ s+ _5 v" x

Whichever method is used to transfer the donor nucleus, it undergoes disassembly in response to the high levels of maturation promoting factor (MPF) found in the MII-stage oocyte cytoplasm. Reassembly of the nucleus occurs after artificial activation of the reconstructed oocyte. An extension of the time between introduction of the donor nucleus and activation may be beneficial to the development of live clones , which resulted in higher rates of progression to blastocysts (83%) and 57% development of offspring to term. It has been suggested that such serial transfer allowed more time for reprogramming of the metaphase nucleus to take place (i.e., the initial reprogramming undertaken in the enucleated oocyte and up to the four-cell stage is augmented by another passage of the donor nucleus through another round of early embryonic development). It would be tempting to speculate that a serial transfer technique would be capable of solving many of the problems associated with cloning in mammals by more effectively removing the somatic "memory" of the donor nuclei. However, it has yet to be established that this technique offers any advantages for the isolation of ESC lines for therapeutic applications. Of course, the use of twice the number of oocytes would be a major obstacle for use in human studies in which oocyte availability is limited. Even if this obstacle were removed, it is essential to ensure that any human ESC lines produced by SCNT are capable of use in cell replacement therapy with minimal potential risk to the patient. For this reason, it is essential to increase our understanding of the nature of genome reprogramming in both normal and SCNT embryos.# y( M2 X5 w2 |+ s; J3 G' Z) h

EPIGENETIC MODIFICATION IS CENTRAL TO REPROGRAMMING

Upon transfer of a somatic nucleus to an oocyte during the cloning process, several essential changes must ensue. First, the somatic nucleus must cease to express its unique repertoire of gene products. Second, that nucleus must become subject to the instructions provided by the oocyte cytoplasm to unfold a new pattern of development-specific gene transcripts, and third, the heritable memory endowed by the chromatin that ensured the characteristics of the donor tissue must be erased. All these changes involve a remodeling, not of the underlying genetic sequences that comprise the genome, but of the epigenetic features that overwrite the gene sequences and find interpretation in new gene expression .

Epigenetic reprogramming is an essential feature of normal development and is associated with the erasure of some of the epigenetic modifications inherited from the gametes . The pattern of DNA methylation is an indicator of the differentiation state of the cell although there is a paucity of information concerning the rules governing this pattern.

Imprinted genes are a unique group of genes that are important for fetal growth and development, especially in the placenta, as well as for postnatal behavior and cognition. The expression of imprinted genes does not follow a mendelian pattern of inheritance but instead depends on the parent-of-origin to dictate its expression . This high error rate may represent a potentially fundamental obstacle and preclude the use of NT to derive patient-specific ESCs even though such cells may appear to be pluripotent under our current definitions of their ability to differentiate into multiple cell lineages. Cells may be derived from these lines which have the morphological and immunological characteristics that define them as therapeutically useful types, but these may not be able to function in the same way as similar indigenous cells when introduced into a patient if they are unable to express certain genes at their correct levels.
9 n2 E  [; n, A
A contrary viewpoint could be that because many of the epigenetic errors that result from NT affect imprinted genes typically involved in extra embryonic development, they would be less likely to affect the inner cell mass (ICM) of the blastocyst from which ESCs are derived. However, it would be surprising if imprinted genes were the only loci affected by incomplete epigenetic reprogramming given its genome-wide role in controlling gene expression. Indeed, there is evidence to support this latter view; microarray analysis has demonstrated that approximately 4% of a panel of 10,000 murine genes showed abnormal expression levels in the placenta of NT mice. Perhaps surprising was that although the livers of cloned animals also showed gene dysregulation, this was less extensive than in the placenta, affecting a different set of genes . In a companion study, gene expression patterns of NT clones derived from ESCs were compared with clones derived from cumulus cells as the somatic donors. This study found that a smaller subset of genes were affected in clones derived from ESCs compared with clones derived from cumulus cells, in keeping with the earlier suggestion that embryonic cells may require less reprogramming to reestablish totipotency. The fact that such errors occur at all in the ICM should make us exercise an element of caution when considering the use of NT-derived ESCs in regenerative medicine.$ r- C( u% A& [7 O! @! [* D

EPIGENETIC REPROGRAMMING IN NORMAL AND NT EMBRYOS
3 _' ]; y  [# t8 H. n
An understanding of the mechanisms that govern epigenetic reprogramming during normal development and how they might differ in the context of SCNT is central to our ambition to derive epigenetically normal ESCs.; S& ?( W: F5 I. T( X4 B/ U

Upon fertilization, there is a series of events that involve the incoming sperm as it encounters the egg cytoplasm. The initial event after fertilization is the decondensation of the sperm nucleus, resulting in the unwinding of the tightly packaged sperm DNA held in a unique, almost toroidal, conformation by the sperm-specific protamines (Fig. 2) .4 d$ l1 m/ \  X! D2 H: L# d3 Z& _

Figure 2. Remodeling of paternal chromatin after fertilization until the first cell division. Sperm DNA is highly compacted due to association with protamine. Removal of protamine is followed by binding of the DNA by acetylated histones that help to maintain the newly formed chromatin in an "open" conformation. Reprogramming of the genome by progressive demethylation of DNA is accompanied by histone modifications, loss of oocyte-specific histone H1oo, and recruitment of nonhistone proteins to prepare DNA for transcription.: @, c; Z# D1 d! Z+ `" M
3 F1 v" G, i. k1 B/ \
This remodeling of the sperm nucleus into an accessible, transcriptionally competent chromatin configuration is coincident with the formation of the pronuclear membrane and demethylation of the paternal genome. As the end of telophase approaches, centromeric proteins A and B, which function as part of the kinetochore complexes, are assembled onto the DNA. Upon completion of active demethylation, and with the initiation of S phase, transcription factors (e.g., TATA box protein and Sp1) bind to prime the genome for transcription late in the first cell cycle  (Fig. 3).

Figure 3. Methylation levels throughout pre-implantation development of normal and nuclear transfer-derived embryos. The paternal genome (purple) of normally derived embryos undergoes rapid active demethylation, whereas the maternal genome (yellow) undergoes passive demethylation until the morula stage of pre-implantation development, when de novo methylation commences. Cloned embryos (turquoise) undergo a reduced passive demethylation.2 B# `+ h* {' z& ~

The exact nature of the active demethylation is not well understood. Active demethylation is operatively defined as loss of methylation in the absence of DNA replication. The speed with which this process occurs strongly suggested that it is mediated enzymatically. Identification of a putative demethylase enzyme(s), especially the active demethylase in the oocyte, has met with some controversy. As yet, the origin of this activity has not been unequivocally assigned to either the oocyte cytoplasm or the sperm itself; however, indirect evidence of partial demethylation on SCNT points to the activity residing in the oocyte cytoplasm. Demethylation of up to five supernumerary male pronuclei obtained by polyspermic fertilization of zona-free mouse oocytes suggests a high abundance of this activity .7 ]% Q/ N" J2 u5 a& o
& A7 c* a7 `* V1 Y+ E8 Q5 u
Mechanistically, the loss of a methyl group poses a considerable enzymatic challenge, and these activities and their epigenetic regulation are a research "hotspot" at present. Why the embryo needs to actively demethylate the paternal genome so rapidly after fertilization remains a mystery. It has been suggested that de-repression of a number of paternal alleles is required to accommodate the burst of transcriptional activity that occurs at the end of the first cell cycle .$ v# `$ D. M2 k- M
& A- _1 r2 n9 K9 H
PASSIVE DEMETHYLATION

The rapid genome-wide loss of 5-methylcytosine from the paternal genome, with the exception of some elite sequences (e.g., imprinted genes centromeric satellites and some endogenous retroviruses . As yet, no underlying biochemical mechanism has been described to link these histone modifications to any specific means for maintenance of chromatin states in imprinted and nonimprinted regions alike.& X3 |4 z. [9 H6 b- v
4 K, E, q1 d) i$ `
EPIGENETIC INFORMATION FIDELITY FAILS DURING CLONING
; e! _+ x' P6 j0 q; Q) u  L
Imprinted DNA methylation of loci is very often disrupted in NT embryos, affecting the extra-embryonic tissues more frequently than those of the embryo. However, although this may have certain consequences for embryonic survival and/or growth, imprinted loci do not represent the bulk of the mammalian genome, with more than 70 imprinted loci known to date , and in most cases the level of methylated DNA remains much higher than in normal embryos (Fig. 3), a state more reminiscent of somatic cells.% T# z& s, \) i& J

In addition to reduced passive loss of DNA methylation, the onset of de novo methylation frequently begins much earlier (four-cell stage) than in normal embryos, suggesting that incomplete remodeling of the donor nucleus impairs the normal temporal progression of epigenetic reprogramming leading to transcriptional misregulation. One might expect that given the apparent abundance of demethylating activity in the oocyte, the somatic genome would be rapidly demethylated; clearly, this is not the case. A number of explanations may account for inadequate epigenetic remodeling of the donor nucleus. First, the enucleation process may remove significant essential components intimately associated with the MII chromosomes which are required for demethylation. Precedence for an essential component of the mitotic apparatus has been reported in non-human primates .
! A6 C& K* X2 y: w+ l3 y
The suggestion of a "histone code" controlling the expression or repression of genes by altering the conformation of the chromatin has gained widespread attention , so it seems that lysine trimethylation represents stability of either expression or silencing. It is uncertain whether the oocyte has the capability to reprogram these types of chromatin modifications.
3 H) Y+ y& _. Q; [
The pattern of asymmetric DNA methylation in the newly fertilized mouse oocyte is also observed for some methylated states of K9 and K27 residues . Perhaps successful reprogramming during NT relies upon inducing histone modifications targeted to critical genomic regions more readily associated with germ-line resetting and not ordinarily expressed in the oocyte.
/ u- x' f  w! r
At present, it is not yet clear whether the oocyte is uniquely competent to remodel and reprogram the wide variety of chromatin modifications, both nucleosomal and otherwise, in a more efficient manner. Perhaps the focus of attention should continue with presenting inherently more compatible donors during SCNT. Irrespective of the limitations to reprogramming, a low number of NT embryos do survive, suggesting that in rare cases it is capable of at least partial resetting of the genome. It may be the case that the reprogramming activity is simply overwhelmed by the enormous task of having to modify or replace somatic histones, remove polycomb complex proteins, and demethylate areas of the genome that may be a lot less accessible than the corresponding areas in gamete-derived genomes. Alternatively, it may be that such reprogramming is actually "forbidden" for the genomes of somatic cells and it is only when the mechanism controlling this malfunctions that successful clones arise.% q: J2 ^) @2 s* `9 o% i

EPIGENETIC ALTERATIONS REMODEL SOMATIC NUCLEAR DONORS
4 [0 g& Q5 p2 u0 F
Studies in Xenopus have indicated that such repressive complexes do not disassemble easily .
& m& k$ F5 M0 y( ~! l/ B, g% j
FUTURE PROSPECTS
4 v! ?; q: _; g; Z. a
The use of SCNT to produce patient-specific ESC lines holds great promise for the development of individually "tailored" cell replacement therapy and regenerative medicine. However, we must proceed carefully, establishing the balance in which the potential benefits will consistently far outweigh prospective risks.

It is clear that significant improvements must be made in understanding the ordinary process whereby an oocyte remodels a sperm nucleus, restoring totipotency to the diploid zygote. We must apply this basic information to understand the extraordinary situation when the oocyte, challenged with a somatic nucleus, attempts to erase somatic epigenotypes to initiate development. It may even be possible to design strategies for epigenetic intervention which give the reprogramming process a "helping hand" by partially resetting the epigenotype of the somatic donor cell to a more embryonic state. It is to hoped that ultimately the investigation of epigenetic reprogramming in NT will give us sufficient understanding to manipulate this process in somatic cells by an "epigenetic engineering" approach so that we can produce therapeutically useful pluripotent cells directly.$ l' \1 {4 p% m% J( h; z9 h" U. E
1 I& A9 y+ Z7 Z% i
ACKNOWLEDGMENTS) D9 m8 |/ K* \! v* t; M7 `
; G3 |( [1 w# q. t9 Z
This work was supported by Medical Research Council UK, One North East, Biotechnology and Biological Sciences Research Council, the Leukemia Research Foundation, and the UK Department of Health (Life Knowledge Park).
: `7 T9 A$ S  b
DISCLOSURES/ [9 O1 l1 F8 l! E0 m% y& z

The authors indicate no potential conflicts of interest.
      【参考文献】

Briggs R, King TJ. The transplantation of living nuclei from blastula cells into enucleated frog¡¯s eggs. Proc Natl Acad Sci U S A 1952;38: 455¨C463.9 o. j8 F2 F" A4 R! G% v$ V$ M% x

Briggs R, King TJ. Factors affecting the transplantability of nuclei of frog embryonic cells. J Exp Zool 1953;122:485¨C506.
4 K) T/ T4 |. C
Briggs R, King TJ. Changes in the nuclei of differentiating endoderm cells as revealed by nuclear transplantation. J Morphol 1957;100:269¨C312.

Briggs R, King TJ. Nuclear transplantation studies on the early gastrula (Rana pipiens). Dev Biol 1960;2:252¨C270.5 J4 t+ f% |* T7 u( w; K
6 \) L- S0 V3 Y9 H
Chesne P, Heyman Y, Peynot N et al. Nuclear transfer in cattle: Birth of cloned calves and estimation of blastomere totipotency in morulae used as a source of nuclei. C R Acad Sci III 1993;316:487¨C491.
1 C! L; R. y* @* L, l  y
Shoukhrat M, Mitalipov RR, Yeoman KD et al. Rhesus monkey embryos produced by nuclear transfer from embryonic blastomeres or somatic cells. Biol Reprod 2002;66:1367¨C1373.4 Q! d8 @9 M/ J& [

Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 1962;10: 622¨C640.
# U: d+ u: x' U) c1 k8 s
Wilmut I, Schnieke AE, McWhir J et al. Viable offspring derived from fetal and adult mammalian cells. Nature 1997;385:810¨C813.
! b: v; N$ w/ q! U4 C3 C' g
Forsberg EJ, Strelchenko NS, Augenstein ML et al. Production of cloned cattle from in vitro systems. Biol Reprod 2002;67:327¨C333.. n3 g/ ?% X8 p. D- t$ a! D3 |

Gao S, McGarry M, Priddle H et al. Effects of donor oocytes and culture conditions on development of cloned mice embryos. Mol Reprod Dev 2003;66:126¨C133.* N/ l& F1 N; ~' C, C3 S5 E
0 o3 D8 L2 u& m# g
Walker SC, Shin T, Zaunbrecher GM et al. A highly efficient method for porcine cloning by nuclear transfer using in vitro-matured oocytes. Cloning Stem Cells 2002;4:105¨C112.+ ?4 {4 i2 B% O0 \

Wen DC, Yang CX, Cheng Y et al. Comparison of developmental capacity for intra- and interspecies cloned cat (Felis catus) embryos. Mol Reprod Dev 2003;66:38¨C45.0 `  t' w1 z% C

Hwang WS, Ryu YJ, Park JH et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 2004;303:1669¨C1674.

Hwang WS, Roh SI, Lee BC et al. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science 2005;308:1777¨C1783.

Hochedlinger K, Rideout WM, Kyba M et al. Nuclear transplantation, embryonic stem cells and the potential for cell therapy. Hematol J 2004;5(suppl 3):S114¨CS117.  f- W8 y7 a$ k, B, M6 A% t* ?

Lanza R, Moore MA, Wakayama T et al. Regeneration of the infarcted heart with stem cells derived by nuclear transplantation. Circ Res 2004;94:820¨C827.! L5 A( [7 ]/ R+ Y/ g

Amano T, Kato Y, Tsunoda Y. Full-term development of enucleated mouse oocytes fused with embryonic stem cells from different cell lines. Reproduction 2001;121:729¨C733.

Sakai RR, Tamashiro KL, Yamazaki Y et al. Cloning and assisted reproductive techniques: Influence on early development and adult phenotype. Birth Defects Res C Embryo Today 2005;75:151¨C162.
* v2 `$ i( }( h+ Y& Z2 ^' O
Hill JR, Burghardt RC, Jones K et al. Evidence for placental abnormality as the major cause of mortality in first-trimester somatic cell cloned bovine fetuses. Biol Reprod 2000;63:1787¨C1794.

Shi W, Zakhartchenko V, Wolf E. Epigenetic reprogramming in mammalian nuclear transfer. Differentiation 2003;71:91¨C113./ E% _  d2 b& f! R8 g7 g5 t
/ v. Y: U7 Y" J1 ], r7 q
Tian XC. Reprogramming of epigenetic inheritance by somatic cell nuclear transfer. Reprod Biomed Online 2004;8:501¨C508.

Hosaka K, Ohi S, Ando A et al. Cloned mice derived from somatic cell nuclei. Hum Cell 2000;13:237¨C242.

Tatham BG, Dowsing AT, Trounson AO. Enucleation by centrifugation of in vitro matured bovine oocytes for use in nuclear transfer. Biol Reprod 1995;53:1088¨C1094.) S; W( E0 d: Y3 y' A& Q

Vajta G, Lewis IM, Hyttel P et al. Somatic cell cloning without micromanipulators. Cloning 2001;3:89¨C95.

Vajta G, Lewis IM, Trounson AO et al. Handmade somatic cell cloning in cattle: Analysis of factors contributing to high efficiency in vitro. Biol Reprod 2003;68:571¨C578.' ?$ J: Y" R0 }" s

Vajta G, Bartels P, Joubert J et al. Production of a healthy calf by somatic cell nuclear transfer without micromanipulators and carbon dioxide incubators using the Handmade Cloning (HMC) and the Submarine Incubation System (SIS). Theriogenology 2004;62:1465¨C1472.& o( |' b& X' ^, d$ M

Campbell KH, McWhir J, Ritchie WA et al. Sheep cloned by nuclear transfer from a cultured cell line. Nature 1996;380:64¨C66.

Santos F, Zakhartchenko V, Stojkovic M et al. Epigenetic marking correlates with developmental potential in cloned bovine pre-implantation embryos. Curr Biol 2002;13:1116¨C1121.9 A7 ^/ m' B/ x5 ~2 N5 D
2 ?4 ^1 |! h4 {& a% H1 ^2 W
Baxter J, Sauer S, Peters A et al. Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes. EMBO J 2004;23:4462¨C4472.
/ |* K: c& @! Z+ S
Mullins LJ, Wilmut I, Mullins JJ. Nuclear transfer in rodents. J Physiol 2003;554:4¨C12.5 Z0 {, d2 y" c: `

Eggan K, Baldwin K, Tackett M et al. Mice cloned from olfactory sensory neurons. Nature 2004;428:44¨C49.; @5 U. {1 j4 ?
4 b" P- P7 ?) R6 o
Ohi S, Hosaka K, Ohkawa M et al. Cloned murine fetuses produced by nuclear transfer using metaphase-arrested embryonic stem cells. Hum Cell 2001;14:317¨C322.* ?" k1 W) s2 a2 w% m1 s, [

Saito S, Liu B, Yokoyama K. Animal embryonic stem (ES) cells: Self-renewal, pluripotency, transgenesis and nuclear transfer. Hum Cell 2004;17:107¨C115.' V* j; P! b) v& ~/ D2 C  Q

Yamazaki Y, Mann MR, Lee SS et al. Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proc Natl Acad Sci U S A 2003;100:12207¨C12212.9 e9 A/ b+ k4 b: x& g8 b( u
6 m" i+ F6 u. S# n4 R
Kato Y, Imabayashi H, Mori T et al. Nuclear transfer of adult bone marrow mesenchymal stem cells: Developmental totipotency of tissue-specific stem cells from an adult mammal. Biol Reprod 2004;70:415¨C418./ U  D! E- @. `  W* g; L
! _4 V5 Y! t; `7 Y( o2 C3 b3 }
Yin XJ, Cho SK, Park MR. Nuclear remodelling and the developmental potential of nuclear transferred porcine oocytes under delayed-activated conditions. Zygote 2003;11:167¨C174.

Downs CS, Mullinger AM, Johnson RT et al. Inhibitors of DNA topoisomerase II prevent chromatid separation in mammalian cells but do not prevent exit from mitosis. Proc Natl Acad Sci U S A 1991;88: 8895¨C8899.
0 V+ [4 g7 J+ i. T4 O; h
Fulka J Jr, Moor RM. Noninvasive chemical enucleation of mouse oocytes. Mol Reprod Dev 1993;34:427¨C430.
( c3 S; A- }& y* v( R+ C
Campbell KH, Ritchie WA, Wilmut I. Nuclear-cytoplasmic interactions during the first cell cycle of nuclear transfer reconstructed bovine embryos: Implications for deoxyribonucleic acid replication and development. Biol Reprod 1993;49:933¨C942.

Akagi S, Adachi N, Matsukawa K et al. Developmental potential of bovine nuclear transfer embryos and postnatal survival rate of cloned calves produced by two different timings of fusion and activation. Mol Reprod Dev 2003;66:264¨C272.; N+ h1 o2 c0 x3 @5 ^, G# |
/ u& e: B  m6 V1 z
Zhang LS, Jiang MX, Lei ZL et al. Development of goat embryos reconstituted with somatic cells: The effect of cell-cycle coordination between transferred nucleus and recipient oocytes. J Reprod Dev 2004; 50:661¨C666.

Boiani M, Gentile L, Gambles VV et al. Variable reprogramming of the pluripotent stem cell marker Oct4 in mouse clones: Distinct developmental potentials in different culture environments. STEM CELLS 2005; 23:1089¨C1104.

Hiiragi T, Solter D. Reprogramming is essential in nuclear transfer. Reprod Dev 2005;70:417¨C421.
9 [3 l5 `' z8 [
Lei L, Liu ZH, Wang H et al. The effects of different donor cells and passages on development of reconstructed embryos. Yi Chuan Xue Bao 2003;30:215¨C220.  }% G8 t; O3 V/ h$ \: o
/ \, `% I- t9 E# N! r1 ?  A0 u
Dean W, Santos F, Stojkovic M et al. Conservation of methylation reprogramming in mammalian development: Aberrant reprogramming in cloned embryos. Proc Natl Acad Sci U S A 2001;98:13734¨C13738.4 ~2 ]. ~, c5 d1 n# z

Wakayama S, Cibelli JB, Wakayama T. Effect of timing of the removal of oocyte chromosomes before or after injection of somatic nucleus on development of NT embryos. Cloning Stem Cells 2003;5:181¨C189.
9 k6 v9 G( Q' I4 P2 Y! G7 n8 _% Q
Kwon OY, Kono T. Production of identical sextuplet mice by transferring metaphase nuclei from four-cell embryos. Proc Natl Acad Sci U S A 1996;93:13010¨C13013.: F) }! `$ s; H- J( C" i

Surani MA. Reprogramming of genome function through epigenetic inheritance. Nature 2001;414:122¨C128.& Y5 S4 F4 z* U' ~& q! K: k
) |) \  {2 M, ?: ~
Oswald J, Engemann S, Lane N et al. Active demethylation of the paternal genome in the mouse zygote. Curr Biol 2000;10:475¨C478.

Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet 2000;1:11¨C19.1 s$ j9 J+ ^1 K
7 H: r. q% ~9 n% f+ h0 r+ ~; X
Bestor TH. The DNA methyltransferases of mammals. Hum Mol Genet 2000;9:2395¨C2402.

Heard E. Recent advances in X-chromosome inactivation. Curr Opin Cell Biol 2004;16:247¨C255.! R* `3 }% c% x6 U
% m+ ?2 m/ h1 o5 F) V9 l3 D- O3 x
Mermoud JE, Popova B, Peters AH et al. Histone H3 lysine 9 methylation occurs rapidly at the onset of random X chromosome inactivation. Curr Biol 2002;12:247¨C251.
0 D, K: u  w2 m' Y  b
Constancia M, Hemberger M, Hughes J et al. Placental specific IGF-II is a major modulator of placental and fetal growth. Nature 2000;417: 945¨C948.

Frank D, Fortino W, Clark L et al. Placental overgrowth in mice lacking the imprinted gene Ipl. Proc Natl Acad Sci U S A 2002;99:7490¨C7495.
+ ], J/ }# E. Y- B
Lin S, Youngson N, Takada S et al. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat Genet 2003;35:97¨C102.+ A3 ?0 [1 z0 r6 N3 o- e
; A# G, C! d2 Y
Ferguson-Smith AC, Surani MA. Imprinting and the epigenetic asymmetry between parental genomes. Science 2001;293:1086¨C1089.) a$ }# q' T5 j( [# u  K6 B
& H& T, Y( N* f- `: Q# U
Doherty AS, Mann MR, Tremblay KD et al. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 2000;62:1526¨C1535.

Khosla S, Dean W, Brown D et al. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol Reprod 2001;64:918¨C926." n3 Q9 E( r9 X' R. e8 _& L

Mann MR, Lee SS, Doherty AS et al. Selective loss of imprinting in the placenta following preimplantation development in culture. Development 2004;131:3727¨C3735.: h3 S. z8 f& D8 F% f

Humpherys D, Eggan K, Akutsu H et al. Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus nuclei. Proc Natl Acad Sci U S A 2002;99:12889¨C12894.
; c5 u# C/ ^$ y7 N6 w% R; p
Shiota K, Yanagimachi R. Epigenetics by DNA methylation for development of normal and cloned animals. Differentiation 2002;69:162¨C166.

Han YM, Kang YK, Koo DB et al. Nuclear reprogramming of cloned embryos produced in-vitro. Theriogenology 2003;59:33¨C44.

Braun RE. Packaging paternal chromosomes with protamine. Nat Genet 2001;28:10¨C12.
* g1 J1 X( h3 y1 C: q% w
Nakazawa Y, Shimada A, Noguchi J et al. Replacement of nuclear protein by histone in pig sperm nuclei during in vitro fertilization. Reproduction 2002;124:565¨C572.

McLay D, Clarke HJ. Remodelling the paternal chromatin at fertilisation in mammals. Reproduction 2003;125:625¨C633.! h$ I4 P% k$ b7 g+ @4 o) A# f
' Y3 O# V1 B6 Q% K
Tanaka M, Kihara M, Meczekalski B. H1oo: A pre-embryonic H1 linker histone in search of a function. Mol Cell Endocrinol 2003;202:5¨C9.

Worrad DM, Ram PT, Schultz RM. Regulation of gene expression in the mouse oocyte and early preimplantation embryo: Developmental changes in Sp1 and TATA box-binding protein, TBP. Development 1994;120:2347¨C2357.: E  U& }/ F* i" @  P7 S5 G: q, v; z% \
3 q) S1 D# B3 v- ~) I) k
Santos F, Dean W. Epigenetic reprogramming during early development in mammals. Reproduction 2004;127:643¨C651.

Cedar H, Verdine GL. Gene expression. The amazing demethylase. Nature 1999;397:568¨C569.
. L( i5 {2 f3 f( Y0 R2 V5 i
Hendrich B, Guy J, Ramsahoye B. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev 2001;15:710¨C723.! _3 I) |2 P% J- l# m  @. a. b
8 D0 o- ~, O( G
Klimasauskas S, Kumar S, Roberts RJ. HhaI methyltransferase flips its target base out of the DNA Helix. Cell 1994;76:357¨C369.* q& U* ]$ Q; j1 x2 T  P# x. w
5 ]; R! R0 v3 u2 u  X9 U' ?
Wu P, Qiu C, Sohail A et al. Mismatch repair in methylated DNA. Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4. J Biol Chem. 2003;278: 5285¨C5291.

Morgan HD, Dean W, Coker HA. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: Implications for epigenetic reprogramming. J Biol Chem 2004;279:52353¨C52360.
, Q* q, X8 V) {
Ram PT, Schultz RM. Reporter gene expression in G2 of the 1-cell mouse embryo. Dev Biol 1993;156:552¨C556." R, a. {/ c7 x9 _

Moore T, Reik W. Genetic conflict in early development: Parental imprinting in normal and abnormal growth. Rev Reprod 1996;1:73¨C77.1 {9 P0 x: O- M) L$ D5 c2 i

Hassan KM, Norwood T, Gimelli G et al. Satellite 2 methylation patterns in normal and ICF syndrome cells and association of hypomethylation with advanced replication. Hum Genet 2001;109:452¨C462.( `: M9 M5 L+ }: j4 i$ N

Grohmann M, Spada F, Schermelleh L et al. Restricted mobility of Dnmt1 in preimplantation embryos: Implications for epigenetic reprogramming. BMC Dev Biol 2005;5:18.
+ w- v" N! ]2 w) x+ @3 Z
Doherty AS, Bartolomei MS, Schultz RM. Regulation of stage-specific nuclear translocation of Dnmt1o during preimplantation mouse development. Dev Biol 2002;242:255¨C266., n, |( H/ M$ z+ G4 H% Z

Santos F, Hendrich B, Reik W et al. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 2002;241:172¨C182.
7 q2 n+ [" V6 ~" P
Howell CY, Bestor TH, Ding F et al. Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 2001;104:829¨C838.

Feil R, Khosla S. Genomic imprinting in mammals: An interplay between chromatin and DNA methylation? Trends Genet 1999;15:431¨C435.

Schoenerr CJ, Levorse JM, Tilghman SM. CTCF maintains differential methylation at the Igf2/H19 locus. Nat Genet 2003;33:66¨C69.0 E2 A! p! d& L9 W+ J' o

Pant V, Mariano P, Kanduri C et al. The nucleotides responsible for direct physical contact between the chromatin insulator protein and the H19 imprinting control region manifest parent of origin specific long distance insulation and methylation free domains. Genes Dev 2003;17: 586¨C590.

Bowman AB, Levorse JM, Ingram RS et al. Functional characterisation of a testis specific DNA binding activity at the H19/Igf2 imprinting control region. Mol Cell Biol 2003;23:8345¨C8351.- L/ d6 v% X7 O$ [% C8 Y; a) \
2 }& p& s8 o0 }9 ~
Yang Y, Li T, Vu TH et al. The histone code regulating expression of the imprinted mouse Igf2r gene. Endocrinology 2003;144:5658¨C5670.8 `7 `0 e$ U" m8 n6 J

Kang YK, Park JS, Koo DB et al. Limited demethylation leaves mosaic-type methylation states in cloned bovine pre-implantation embryos. EMBO J 2002;21:1092¨C1100.

Kang YK, Koo DB, Park JS et al. Typical demethylation events in cloned pig embryos. Clues on species-specific differences in epigenetic reprogramming of a cloned donor genome. J Biol Chem 2001;276: 39980¨C39984.5 `$ K& z" `" c
+ a) _0 a) ]0 A9 f. g
Simerly C, Dominko T, Navara C et al. Molecular correlates of primate nuclear transfer failures. Science 2003;300:297.8 n6 C# x" Y" o  c
5 r) g" X" |; v4 H
Aoki F, Hara KT, Schultz RM. Acquisition of transcriptional competence in the 1-cell mouse embryo: Requirement for recruitment of maternal mRNAs. Mol Reprod Dev 2003;64:270¨C274.
8 M2 N1 g1 A( J+ i0 O6 D. e* H
Gao S, Chung YG, Williams JW et al. Somatic cell-like features of cloned mouse embryos prepared with cultured myoblast nuclei. Biol Reprod 2003;69:48¨C56.

Ng RK, Gurdon JB. Maintenance of epigenetic memory in cloned embryos. Cell Cycle 2005;4:760¨C763.8 y) I# ?5 m1 U

Sebastiano V, Gentile L, Garagna S et al. Cloned pre-implantation mouse embryos show correct timing but altered levels of gene expression. Mol Reprod Dev 2005;70:146¨C154.
' U; d: n) ^# f5 r$ K
Boiani M, Eckardt S, Scholer HR et al. Oct4 distribution and levels in mouse clones: Consequences for pluripotency. Genes Dev 2002;16: 1209¨C1219.2 `& t, F0 _! a/ I# s
/ N: e& `6 ~8 Z1 O6 E  b
Simonsson S, Gurdon J. DNA methylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nat Cell Biol 2004;6:984¨C990.

Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000;403:41¨C45.0 P. q2 C. d7 R- i' ~/ X  |
6 b$ L: P  m4 S7 d4 F
Brownell JE, Zhou J, Ranalli T et al. Tetrahymena histone acetyltransferase A: A homolg to yeast Gcn5p linking histone acetylation to gene activation. Cell 1996;84:843¨C851.
! c1 t8 b% y/ i) o! R" t) d; [
Allfrey VG, Faulkner R, Mirskey AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci U S A 1964;51:786¨C794.6 C( f% v/ [  @# V" v3 ^& u
: P6 U1 S7 m+ E) K  z+ `
Nowak SJ, Corces VG. Phosphorylation of histone H3: A balancing act between chromosome condensation and transcriptional activation. Trends in Genetics 2004;20:214¨C220.; \# m) B7 E0 r! r- W( c% v& P* h
$ e# l. d5 U& O" U! _. |
Belikov S, Karpov V. Localization of histone H1 binding sites within the nucleosome by UV-induced H1-DNA crosslinking in vivo. J Biomol Struct Dyn 1998;16:35¨C39.
' Y. N' m& d8 v- O7 }# S
Fuks F. DNA methylation and histone modifications: Teaming up to silence genes. Curr Opin Genet Dev 2005;15:490¨C495.
" B$ _+ D9 ]. n5 [, T0 ]! P7 v+ ?4 q
Hebbes TR, Clayton AL, Thorne AW et al. Core histone hyperacetylation co-maps with generalised DNaseI hypersensitivity in the chicken beta-globin chromosomal domain. EMBO J 1994;13:1823¨C1830.

Danam RP, Howell SR, Brent TP et al. Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins. Mol Cancer Ther 2005; 4:61¨C69.7 Z; P) W* [4 P3 `8 v

McGraw S, Robert C, Massicotte L et al. Quantification of histone acetyltransferase and histone deacteylase transcripts during bovine embryo development. Biol Reprod 2003;68:383¨C389.

Miao F, Natarajan R. Mapping global histone methylation patterns in the coding regions of human genes. Mol Cell Biol 2005;25:4650¨C4661.
( `3 ]6 O( b. Z: n- j
Czermin B, Melfi R, McCabe D et al. Drosophila enhancer of zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal polycomb sites. Cell 2002;111:185¨C196.* u& A/ F. g0 m. z; r7 F8 n( g
& l- r* P1 s) d5 f( }: \
Cao R, Wang H, Wang L et al. Role of Histone H3 Lysine 27 methylation in polycomb group silencing. Science 2002;298:1039¨C1043.3 l, V* x) Q$ D9 a4 a; B

Shi Y, Lan F, Matson C et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004;119:941¨C953.
( J6 l3 `" G  k, Y
Santos-Rosa H, Schneider R, Bannister AJ et al. Active genes are trimethylated at K4 of histone H3. Nature 2002;419:407¨C411.7 U6 V" o# k2 M( c, G; E
- n! W5 l% `# n  {+ l
Van der Heijden GW, Dieker JW, Derijck AA et al. Asymmetry in Histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote. Mech Dev 2005;122:1008¨C1022.

Liu H, Kim JM, Aoki F. Regulation of histone H3 lysine 9 methylation in oocytes and early pre-implantation embryos. Development 2004;131: 2269¨C2280.
4 A6 [% E7 U& {( s' w! S0 Y. g( V
Erhardt S, Su IH, Schneider R et al. Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development 2003;130:4235¨C4248.

Kikyo N, Wolfe AP. Reprogramming nuclei: Insights from cloning, nuclear transfer and heterokaryons. J Cell Sci 2000;113:11¨C20.2 @) M5 I) H; h: W/ v: u3 T
9 l3 n  w. k; _, ~' M2 M0 _, c
Kimura H, Tada M, Nakatsuji N et al. Histone Code Modifications on pluripotential nuclei of reprogrammed somatic cells. Mol Cell Biol 2004;24:5710¨C5720.

收藏0 分享0 顶0 踩0