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PubMed1999

Host defenses to parasitic sequences and the evolution of epigenetic control mechanisms.

The analysis of transgene silencing effects in plants and other eukaryotic organisms has revealed novel mechanisms of epigenetic regulation that are based on recognition of nucleic acid sequence homology. These homology-dependent gene silencing phenomena are characterized by an inverse relationship between copy number of a particular sequence and expression levels. Depending on whether promoter regions or transcribed sequences are repeated, silencing occurs at the transcriptional or post-transcriptional level, respectively. Different silencing effects involving DNA-DNA or RNA-DNA associations in the nucleus, and RNA-RNA interactions in the cytoplasm appear to reflect distinct host defense responses to parasitic sequences, including transposable elements (TEs), viroids and RNA viruses. Natural epigenetic phenomena that resemble transgene silencing effects often involve endogenous genes comprising recognizable TE sequences or rearrangements generated by TEs and can thus be interpreted in terms of host defense systems. A genome defense that inactivates TEs by methylation might have been recruited during evolution to regulate the transcription of plant and vertebrate genes that contain remnants of TE insertions in promoter regions.

DNA Methylation↗
PubMedDate not supplied

[Intranuclear ion fountains as regulators of genome work: fountain hypothesis of dominance and some epigenetic effects].

It is hypothesized that gene function is modulated through the action of the ion channels of the internal nuclear membrane, and that this underlies the phenomenon of dominance and some epigenetic effects. The topographic specificity essential to gene regulation by injecting portions of ions--ion fountains--is ensured by special fountain RNAs (fRNAs), which operate as double-stranded molecules, and fions, the fRNA-binding sites on the DNA. Every specific fion.fRNA complex then binds with the protein of an ion channel in the inner nuclear membrane, whereby this channel briefly opens to dispense, e.g., Ca2+, Zn2+, or K+ from the perinuclear cistern into the nucleus, as defined by the specificity of fRNA, fion, and the channel chosen by them. Fions may be situated both in introns of genes and at their flanks, even quite far from the target gene. Allelic fions, that is, fions located in homologous sites of homologous chromosomes but differing in the capacity of binding different fRNAs, will unequally influence the ionic surroundings of their structural genes. Ion channels can provide the dominant allele with an ionic atmosphere dissimilar from that of the recessive allele. Distinctions in the nature, number, and location of fions may be the main reason why the dominant and recessive alleles of a structural gene differ in activity even though their other properties are identical. Unequal changes occurring in the vicinity of the alleles may involve chromatin configuration, transcriptional activity of the gene, mRNA processing and lifespan. Isolation of structural genes in a chromosome by long intergene spacers, and large distances between chromosomes in the nucleus prevent undesirable interference of ion fountains. Fions may be key components of many enhancers and silencers. The performance of fions may be affected by pairing of homologous nucleotide sequences of chromosomes, which generates a number of epigenetic effects, such as transvection and gene position effect. Excessive approach of a structural gene to inadequate ion fountains may cause unscheduled chromatin compaction and gene suppression.

Cations↗
PubMed2001

Epigenetic patterns in the progression of esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) arises after normal squamous mucosa undergoes metaplasia to specialized columnar epithelium (intestinal metaplasia or Barrett's esophagus), which can then ultimately progress to dysplasia and subsequent malignancy. Epigenetic studies of this model have thus far been limited to the DNA methylation analysis of a few genes. In this study, we analyzed a panel of 20 genes using a quantitative, high-throughput methylation assay, METHYLIGHT: We used this broader approach to gain insight into concordant methylation behavior between genes and to generate epigenomic fingerprints for the different histological stages of EAC. Our study included a total of 104 tissue specimens from 51 patients with different stages of Barrett's esophagus and/or associated adenocarcinoma. We screened 84 of these samples with the full panel of 20 genes and found distinct classes of methylation patterns in the different types of tissue. The most informative genes were those with an intermediate frequency of significant hypermethylation [ranging from 15% (CDKN2A) to 60% (MGMT) of the samples]. This group could be further subdivided into three classes, according to the absence (CDKN2A, ESR1, and MYOD1) or presence (CALCA, MGMT, and TIMP3) of methylation in normal esophageal mucosa and stomach, or the infrequent methylation of normal esophageal mucosa accompanied by methylation in all normal stomach samples (APC). The other genes were less informative, because the frequency of hypermethylation was below 5% (ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THBS1), completely absent (CTNNB1, RB1, TGFBR2, and TYMS1), or ubiquitous (HIC1 and MTHFR), regardless of tissue type. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC, suggesting a step-wise loss of multiple protective barriers against CpG island hypermethylation. The aberrant hypermethylation occurs at many different loci in the same tissues, suggestive of an overall deregulation of methylation control in EAC tumorigenesis. However, we did not find evidence for a distinct group of tumors with a CpG island methylator phenotype. Finally, we found that normal and metaplastic tissues from patients with evidence of associated dysplasia or cancer had a significantly higher incidence of hypermethylation than similar tissues from patients with no further progression of their disease. The fact that the samples from these two groups of patients were histologically indistinguishable, yet molecularly distinct, suggests that the occurrence of such hypermethylation may provide a clinical tool to identify patients with premalignant Barrett's who are at risk for further progression.

Adenocarcinoma↗
PubMed2001

Epigenetic reprogramming of the genome--from the germ line to the embryo and back again.

Mammalian parental genomes are not functionally equivalent, and both a maternal and paternal contribution is required for normal development. The differences between the parental genomes are the result of genomic imprinting--a form of gene regulation that results in monoallelic expression of imprinted genes. Cis-regulatory elements at imprinted loci are responsible for directing allele-specific epigenetic marks required for correct gene expression. This cis information must be interpreted at various points in development, including in the germline where existing imprints are erased and reset. Imprints must also be maintained during preimplantation development, when the genome undergoes dramatic global epigenetic changes.

Animals↗
PubMed2001

Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma.

Methylation associated inactivation of RASSF1, a putative tumor suppressor identified at 3p21.3, has been frequently observed in several human malignancies, including lung and breast cancers. To explore the penetrance of RASSF1 in gastric carcinogenesis, we performed expression and mutation analyses of 3 isotypes of RASSF1 (A, B, and C) in 150 gastric specimens, including 15 carcinoma cell lines. RASSF1A and RASSF1B transcripts were not expressed in 60% (9 of 15) and 33% (5 of 15) of gastric carcinoma cell lines, respectively, whereas RASSF1C was detectable in all cell lines. Bisulfite DNA sequencing analysis revealed that the CpG island in the RASSF1A promoter is hypermethylated in all RASSF1A-nonexpressing cell lines. In addition, both RASSF1A and RASSF1B were re-expressed by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Among 90 primary gastric adenocarcinomas examined, 41 (46%) and 19 (21%) expressed no or abnormally low levels of RASSF1A and RASSF1B, respectively, and 12 (13%) tumors showed no expression of both isoforms. Loss or abnormal down-regulation of RASSF1A correlated with tumor stage and grade but not with histological types of tumors. Methylation-specific PCR analysis demonstrated that 95% (39 of 41) of RASSF1A-nonexpressing primary tumors are methylated at the CpG sites in the promoter, whereas none of the adjacent noncancerous or normal tissues are methylated. No somatic mutations were detected in RASSF1 transcripts expressed in unmethylated tumors. However, 10 methylated tumors, including 4 cell lines, showed low genomic levels of RASSF1 and expressed no RASSF1A transcripts, suggesting that RASSF1A inactivation might be caused by both epigenetic and genetic mechanisms in a subset of gastric adenocarcinomas. In conclusion, our data indicate that epigenetic transcriptional silencing of RASSF1, especially RASSF1A isoform, is a frequent event in gastric tumorigenesis and might play an important role in the malignant progression of gastric adenocarcinomas.

Adenocarcinoma↗
PubMed2001

Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays.

It is now clear that aberrant DNA methylation observed in cancer cells is not restricted to a few CpG islands, but affects multiple loci. When this epigenetic event occurs at the 5'-end of the regulatory region of genes, it is frequently associated with transcriptional silencing. To investigate further this widespread event in the tumor genome, we developed a novel microarray containing 7776 short GC-rich tags tethered to glass slide surfaces. This DNA chip was used to study 17 paired tissues of breast tumors and normal controls. Amplicons, representing differential pools of methylated DNA fragments between tumors and normal controls, were cohybridized to the microarray panel. Hypermethylation of multiple CpG island loci was then detected in a two-color fluorescence system. Approximately 1% (on average, 83 loci) of these CpG islands examined were hypermethylated in this patient group. Hierarchical clustering segregated these tumors based on their methylation profiles and identified a group of CpG island loci that corresponds to the hormone-receptor status of breast cancer. This observation was independently confirmed by examining a single locus, the promoter of the human glypican 3 gene, which was predominately hypermethylated in the hormone receptor-negative tumors. Our findings support the notion that hypermethylation of critical CpG island loci influences cancer development and produces distinct epigenetic signatures for particular tumor subtypes.

Breast Neoplasms↗
PubMed2002

Epigenetic inactivation of 14-3-3 sigma in oral carcinoma: association with p16(INK4a) silencing and human papillomavirus negativity.

In vitro studies have identified 14-3-3sigma as a regulator of senescence in human keratinocytes. To assess its contribution to squamous neoplasia, we have analyzed genetic and epigenetic changes in this gene in squamous cell carcinomas (SCCs) and dysplastic lesions of the oral cavity. No mutations were detected in the coding sequence of 14-3-3sigma in 20 oral carcinomas, and there was loss of heterozygosity in only 7 of 40 informative cases. In contrast to the absence of genetic change, aberrant methylation within 14-3-3sigma was detected in 32 of 92 squamous cell carcinomas and in 3 of 6 oral dysplasias and was associated with reduced or absent expression at both mRNA and protein levels. Methylation was not detected in matched, normal epithelial tissue controls. Carcinomas in which 14-3-3sigma was methylated were significantly more likely to lack DNA sequences from human papillomavirus and to have coincident methylation of p16(INK4a) than cases that expressed 14-3-3sigma. Methylation was detected in SCC, both wild-type and mutant for p53, but was more commonly detected in cancers with wild-type p53. These results implicate coincident epigenetic abrogation of function in both sigma and p16(INK4a) in a subset of SCCs of the oral cavity.

14-3-3 Proteins↗
PubMed2002

Endogenous reactivation of the RARbeta2 tumor suppressor gene epigenetically silenced in breast cancer.

Loss of expression of retinoic acid receptor beta2 (RARbeta2), a potent tumor suppressor gene, is commonly observed during breast carcinogenesis. RARbeta2 silencing can be traced to epigenetic chromatin changes affecting the RARbeta P2 promoter. Here we show that retinoic acid therapy fails to induce RARbeta2 in primary breast tumors, which carry a methylated RARbeta P2 promoter. DNA methylation leads to repressive chromatin deacetylation at RARbeta P2. By inducing an appropriate level of histone reacetylation at RARbeta P2 we could reactivate endogenous RARbeta2 transcription from unmethylated as well as methylated RARbeta P2 in breast cancer cell lines and xenograft tumors, and obtain significant growth inhibition both in vitro and in vivo. This study may have translational implications for breast cancer and other cancers carrying an epigenetically silenced RARbeta P2 promoter.

Acetylation↗
PubMed2002

Characterization of a defensin gene expressed in oil palm inflorescences: induction during tissue culture and possible association with epigenetic somaclonal variation events.

From differential display studies performed on oil palm (Elaeis guineensis Jacq.) tissue cultures bearing or lacking an epigenetic homeotic flowering abnormality, known as mantled, EGAD1, a gene coding for a putative plant defensin, has been identified and characterized. In whole plants, transcripts of the EGAD1 gene were detected only in inflorescences. The closest characterized relative of the oil palm EGAD1 gene is the Petunia PPT gene, which is expressed principally in the pistil of the flower. The 77 amino acid polypeptide encoded by the EGAD1 gene displays strong similarities with a number of plant defensin proteins, which are thought to play a protective role and which have been shown in some cases to possess antifungal properties. Oil palm tissue cultures exhibit a generally strong induction of accumulation of EGAD1 transcripts, which were detected to differing extents at all stages of the tissue culture regeneration process. The 5' flanking region of the EGAD1 gene was found to contain two different types of potential cis-acting DNA element previously identified in the promoters of plant defence-related genes, which may explain the observed expression in tissue cultures. At the callus stage of the in vitro regeneration procedure, a differential accumulation of EGAD1 transcripts was observed which correlated with the presence or absence of the mantled flowering abnormality. EGAD1 gene expression may therefore be a marker of epigenetic somaclonal variation events.

5' Flanking Region↗
PubMed1975

On possible genetic and epigenetic modes of diabetes transmission.

1 In 4058 diabetics, an inverse relation (negative semilogarithmic correlation) was found between the age of onset and the familial aggregation of diabetes mellitus (P less than 0.01). Hence, juvenile (especially infantile) diabetes appears to be predominantly caused by genetic defects (mutations), whereas adult onset diabetes appears to be essentially based on epigenetic factors. 2. In 3890 diabetics with an onset age of more than 10 years, a highly significant predominance of familial diabetes aggregation was observed on the maternal side as compared to the paternal side (P less than 0.001). This finding suggests the possibility of an epigenetic ("teratogenetic") mode of diabetes transmission mediated by the mother.

Adolescent↗
PubMed2003

[Epigenetic variability induced by nicotinic acid in Triticum aestivum L].

The effect of nicotinic acid (NA) on hereditary traits of spring common wheat cultivar Kazakhstanskaya 126 (K.126) were studied under the laboratory and field conditions. Treatment of seeds and vegetating plants with 0.01-0.1% NA (aqueous solution) induced heritable epigenetic changes in wheat. As a result, strong tall plants with the long productive spike, large seeds, and several quantitative and qualitative characters other than in the original cultivar were obtained in the second and further generations after treatment. Crosses of changed plants with each other did not result in segregation with respect to leaf downiness or anthocyan stem color in F2-F4, suggesting the same epigenetic state of genes responsible for changed characters. In crosses with the original cultivar, characters of the changed plants always dominated in F1. Basing on the current views, the changes were attributed to a transition of the hl1 and pc recessive marker genes into new, dominant epiallelic states Hl1 and Pc, which respectively determine downy leaves and the colored stem. The NA effect was specific, since only one type of the variation was observed. The changed characters were stable, and no reversion to the original phenotype was detected in 57 generations.

Genes, Plant↗
PubMed2003

The proline-rich acidic protein is epigenetically regulated and inhibits growth of cancer cell lines.

The proline-rich acidic protein (PRAP) gene was found previously to be expressed in the epithelial cells of the mouse and rat gastrointestinal tracts, and pregnant mouse uterus. This article describes the isolation, distribution, and functional characterization of the human homologue. PRAP was abundantly expressed in the epithelial cells of the human liver, kidney, gastrointestinal tract, and cervix. PRAP expression was significantly down-regulated in hepatocellular carcinoma and right colon adenocarcinoma compared with the respective adjacent normal tissues. Treatment of the cells with butyrate, trichostatin A, and 5'-aza-2' deoxycytidine caused increases in PRAP gene expression of up to 30-fold, suggesting that the gene is suppressed through epigenetic mechanisms involving histone deacetylation and methylation. To determine the significance of PRAP expression in cancer cells, we cloned PRAP and its two major splice variants from human colon and liver, and overexpressed it in HeLa, HT29, and HepG2 cells. PRAP caused cell growth inhibition in the cancer cell lines in transient transfection assays, colony formation assays, and in the growth rates of stable clones. The data suggest that PRAP and its variants may play an important role in maintaining normal growth homeostasis in epithelial cells. The epigenetic suppression of PRAP expression in cancer may cause growth dysregulation, a hallmark of the carcinogenic process.

Amino Acid Sequence↗
PubMed2003

Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers in the world. However, the underlying molecular mechanisms contributing to hepatocarcinogenesis are still unclear. A putative tumor suppressor gene, namely DLC-1 (frequently deleted in liver cancer) was identified and mapped at chromosome 8p21.3-22, a recurrently deleted region in human cancers. The gene exerts inhibitory effects on the cell proliferation of HCC cells. In this study, we investigated the biological function, and genetic and epigenetic status of this gene in human HCC. With in vitro GTPase activating proteins activity assay, we established that DLC-1 protein was a GTPase-activating protein specific for RhoA and Cdc42. Deletion of the DLC-1 gene was frequent in human HCC, as revealed by loss of heterozygosity analysis performed on 100 human HCC cases with markers mapped at the DLC-1 locus, and allelic losses ranging from 44% to 50% of the informative cases. However, somatic mutations of the DLC-1 gene were rare. Moreover, with real-time quantitative PCR, we found that DLC-1 mRNA was significantly underexpressed in HCCs when compared with the corresponding nontumorous livers (P < 0.0001). In addition, the CpG island 5' to the DLC-1 gene was methylated in 3 of 7 HCC cell lines and in 6 (24%) of 25 primary HCCs. These data suggest that transcriptional silencing by hypermethylation may contribute to the inactivation of the DLC-1 gene. Taken together, the results of our study suggest that both genetic and epigenetic alterations play an important role in inactivation of the DLC-1 gene in hepatocarcinogenesis.

Azacitidine↗
PubMed2003

Epigenetic regulation of coxsackie and adenovirus receptor (CAR) gene promoter in urogenital cancer cells.

Coxsackie and adenovirus receptor (CAR) is not only a high-affinity receptor for adenovirus, but also a tumor inhibitor in both prostate and bladder cancer lines. Decreased CAR gene expression is often detected in cancer specimens; however, the mechanism(s) is still unknown. In this study, we cloned the entire CAR gene and characterized the core promoter sequence of the CAR gene. The CAR gene promoter activity correlated with the differential expression of CAR mRNA levels from several urogenital cancer cell lines, indicating that the down-regulation of CAR gene expression is mediated by transcriptional regulation. It is known that epigenetic control, such as DNA methylation and histone acetylation of chromatin structure, dictates gene expression. Data from this study indicate that the activation of the CAR gene promoter is modulated by histone acetylation, but not by DNA methylation, in urogenital cancer cells. Also, a potent cancer chemotherapeutic agent (FR901228), a histone deacetylase inhibitor, was able to induce endogenous CAR gene expression in several urogenital cancer cells. Taken together, epigenetic control of CAR gene underlies the down-regulation of this gene in urogenital cancers.

Base Sequence↗
PubMed2004

Integument pattern formation involves genetic and epigenetic controls: feather arrays simulated by digital hormone models.

Pattern formation is a fundamental morphogenetic process. Models based on genetic and epigenetic control have been proposed but remain controversial. Here we use feather morphogenesis for further evaluation. Adhesion molecules and/or signaling molecules were first expressed homogenously in feather tracts (restrictive mode, appear earlier) or directly in bud or inter-bud regions ( de novo mode, appear later). They either activate or inhibit bud formation, but paradoxically colocalize in the bud. Using feather bud reconstitution, we showed that completely dissociated cells can reform periodic patterns without reference to previous positional codes. The patterning process has the characteristics of being self-organizing, dynamic and plastic. The final pattern is an equilibrium state reached by competition, and the number and size of buds can be altered based on cell number and activator/inhibitor ratio, respectively. We developed a Digital Hormone Model which consists of (1) competent cells without identity that move randomly in a space, (2) extracellular signaling hormones which diffuse by a reaction-diffusion mechanism and activate or inhibit cell adhesion, and (3) cells which respond with topological stochastic actions manifested as changes in cell adhesion. Based on probability, the results are cell clusters arranged in dots or stripes. Thus genetic control provides combinational molecular information which defines the properties of the cells but not the final pattern. Epigenetic control governs interactions among cells and their environment based on physical-chemical rules (such as those described in the Digital Hormone Model). Complex integument patterning is the sum of these two components of control and that is why integument patterns are usually similar but non-identical. These principles may be shared by other pattern formation processes such as barb ridge formation, fingerprints, pigmentation patterning, etc. The Digital Hormone Model can also be applied to swarming robot navigation, reaching intelligent automata and representing a self-re-configurable type of control rather than a follow-the-instruction type of control.

Animals↗
PubMed2004

Genetics and epigenetics in flower pigmentation associated with transposable elements in morning glories.

Among the genus Ipomoea, three morning glories, I. nil the Japanese morning glory), I. purpurea (the common morning glory), and I. tricolor, were domesticated well for floricultural plants, and many spontaneous mutants displaying various flower pigmentation patterns were isolated. Most of these spontaneous mutations were found to be caused by the insertion of DNA transposable elements in the genes for the anthocyanin pigmentation in flowers, and many of them exhibited variegated flowers, such as white flowers with pigmented spots and sectors. Here, we describe the historical background of the mutants displaying variegated flowers and review the genetic and epigenetic regulation in flower pigmentation associated with transposable elements of these morning glories. The flecked, speckled, r-1, and purple mutations in I. nil were caused by insertions of Tpnl and its relatives in the En/Spm superfamily, Tpn2, Tpn3, and Tpn4, into the genes for anthocyanin coloration in flowers,i.e., DFR-B, CHI, CHS-D, and InNHXI, respectively. Similarly, the flaked and pink mutants of I. purpurea have distantly related elements, Tip100 and Tip201, in the Ac/Ds superfamily inserted into the CHS-D and F3'H genes, respectively. The flower variegation patterns can be determined by the frequency and timing of the excision of these transposons, and their stable insertions produce plain color flowers without generating pigmented spots or sectors; furthermore, both genetic and epigenetic regulation appeared to play important roles in determining the frequency and timing of the excision of the transposons. However, flower variegation is not always associated with the excision of an integrated DNA transposon from one of the genes for anthocyanin pigmentation. The mutant Flying Saucers of I. tricolor displaying variegated flowers was found to have the transposon ItMULE inserted into the DFR-B promoter region, but no excision of ITMULEL from the DFR-B could be detected in the variegated flower lines. The instable pearly-vrg allele in cv. Flying Saucers is likely to be an epiallele because the DNA methylation in the DFR-B promoter appeared to be associated with flower pigmentation.

Journal Article↗
PubMed2004

Genetics and epigenetics in flower pigmentation associated with transposable elements in morning glories.

Among the genus Ipomoea, three morning glories, I. nil (the Japanese morning glory), I. purpurea (the common morning glory), and I. tricolor, were domesticated well for floricultural plants, and many spontaneous mutants displaying various flower pigmentation patterns were isolated. Most of these spontaneous mutations were found to be caused by the insertion of DNA transposable elements in the genes for the anthocyanin pigmentation in flowers, and many of them exhibited variegated flowers, such as white flowers with pigmented spots and sectors. Here, we describe the historical background of the mutants displaying variegated flowers and review the genetic and epigenetic regulation in flower pigmentation associated with transposable elements of these morning glories. The flecked, speckled, r-1, and purple mutations in I. nil were caused by insertions of Tpn1 and its relatives in the En/Spm superfamily, Tpn2, Tpn3, and Tpn4, into the genes for anthocyanin coloration in flowers, i.e., DFR-B, CHI, CHS-D, and InNHX1, respectively. Similarly, the flaked and pink mutants of I. purpurea have distantly related elements, Tip100 and Tip201, in the Ac/Ds superfamily inserted into the CHS-D and F3'H genes, respectively. The flower variegation patterns can be determined by the frequency and timing of the excision of these transposons, and their stable insertions produce plain color flowers without generating pigmented spots or sectors; furthermore, both genetic and epigenetic regulation appeared to play important roles in determining the frequency and timing of the excision of the transposons. However, flower variegation is not always associated with the excision of an integrated DNA transposon from one of the genes for anthocyanin pigmentation. The mutant Flying Saucers of I. tricolor displaying variegated flowers was found to have the transposon ItMULE1 inserted into the DFR-B promoter region, but no excision of ItMULE1 from the DFR-B could be detected in the variegated flower lines. The instable pearly-vrg allele in cv. Flying Saucers is likely to be an epiallele because the DNA methylation in the DFR-B promoter appeared to be associated with flower pigmentation.

Alleles↗
PubMed2004

[Evolution of mammalian sex chromosomes: cooperation of genetic and epigenetic factors].

The X and Y chromosomes of mammals, which significantly differ in structure and genetic composition, are thought to originate from a pair of autosomes. During evolution of sex chromosomes in placental mammals, the degradation of the Y chromosome and inactivation spreading along the X chromosome occurred gradually and in concert. Thus, at the molecular level, the genetic and epigenetic factors interacted toward greater differentiation of the X/Y pair. In this review, in context of a comparison permitting to trace this evolutionary pathway, we consider the structural features of mammalian sex chromosomes focusing on the X-chromosomal genes and the unique epigenetic mechanism of their regulation. Possible causes and consequences of the genes skipping inactivation and aspects of molecular mechanism of X-chromosome inactivation are discussed. A number of hypotheses are considered on evolutionary relationships of X-chromosome inactivation and other molecular processes in mammals.

Animals↗