Chromosomal Histone Research Articles

Aging-associated reduction of chromosomal histones in mammalian oocytes.

Mammalian oocytes undergo a long-term meiotic arrest that can last for almost the entire reproductive lifespan. This arrest occurs after DNA replication and is prolonged with age, which poses a challenge to oocytes in maintaining replication-dependent chromosomal proteins required for the completion of meiosis. In this study, we show that chromosomal histones are reduced with age in mouse oocytes. Both types of histone H3 variants, replication-dependent H3.1/H3.2 and replication-independent H3.3, decrease with age. Aging-associated histone reduction is associated with transcriptomic features that are caused by genetic depletion of histone H3.3. Neither the genetic reduction of chromosomal H3.1/H3.2 nor H3.3 accelerates the aging-associated increase in premature chromosome separation that causes meiotic segregation errors. We suggest that aging-associated reduction of chromosomal histones is linked to several transcriptomic abnormalities but does not significantly contribute to errors in meiotic chromosome segregation during the reproductive lifespan of mice.

Suppression of LPS-activated inflammatory responses and chromosomal histone modifications in macrophages by micropattern-induced nuclear deformation.

Macrophages are important immune effector cells which participate various physiological and pathological conditions. Numerous studies have demonstrated the regulation of macrophage phenotype by micropatterns. It is well accepted that micropatterns affect cellular behaviors through changing cell shape and modulating the associated mechanical sensors on the plasma membrane and cytoskeleton. However, the role of nucleus, which serves as a critical physical sensing device, is often ignored. Herein, we found the nuclear deformation and the subsequently increased chromosomal histone methylation (H3K36me2) may contribute to the micropattern-induced suppression of macrophage inflammatory responses. Specifically, macrophages on micropatterned surfaces expressed lower levels of key inflammatory genes, compared with those on flat surfaces. Further investigation on macrophage nuclei showed that micropatterned surfaces cause shrinkage of nucleus volume and compaction of chromatin. Moreover, micropatterned surfaces elevated the methylation level of H3K36me2 in macrophages, while decreased the methylation level of H3K4me3. Our study provides new mechanistic insight into how micropatterns affect macrophage phenotype and highlights the importance of nuclear shape and chromatin histone modification in mediating micropattern-induced change in cell behaviors.

Global histone H2B degradation regulates insulin/IGF signaling-mediated nutrient stress.

Eukaryotic organisms adapt to environmental fluctuations by altering their epigenomic landscapes and transcriptional programs. Nucleosomal histones carry vital epigenetic information and regulate gene expression, yet the mechanisms underlying chromatin-bound histone exchange remain elusive. Here, we found that histone H2Bs are globally degraded in Caenorhabditis elegans during starvation. Our genetic screens identified mutations in ubiquitin and ubiquitin-related enzymes that block H2B degradation in starved animals, identifying lysine 31 as the crucial residue for chromatin-bound H2B ubiquitination and elimination. Retention of aberrant nucleosomal H2B increased the association of the FOXO transcription factor DAF-16 with chromatin, generating an ectopic gene expression profile detrimental to animal viability when insulin/IGF signaling was reduced in well-fed animals. Furthermore, we show that the ubiquitin-proteasome system regulates chromosomal histone turnover in human cells. During larval development, C. elegans epidermal cells undergo H2B turnover after fusing with the epithelial syncytium. Thus, histone degradation may be a widespread mechanism governing dynamic changes of the epigenome.

The Histone Demethylase KDM5D Drives Sex Differences in Colorectal Cancer.

The Y chromosome histone demethylase gene, KDM5D, drives sex differences in colorectal cancer (CRC).

Micronucleus and FTIR spectroscopy analysis as screening tests for HPV vírus detection

Human Papillomavirus (HPV) infection is the main precursor of cervical cancer. Pap Smear is the main diagnostic method of this neoplasm by cytological analysis, however presents a high rate of false-negative cases. This study aimed to verify if micronucleus (MN) frequency test and the Fourier Transform Infrared (FTIR) Spectroscopy analysis may be alternative useful techniques to detect HPV in cervical fluid. Fifty samples with normal cytology obtained from patients after cytopathological examination were divided into two groups based on the presence or absence of HPV by previous analysis of molecular biology. Of the fifty samples analyzed, 46% showed the presence of MN in the cells. The frequency of MN observed was higher in the samples with HPV positive and was related with age, use of oral contraceptives and use of alcoholic beverages (p <0.001). FTIR analysis spectra showed high peak DNA and proteins in samples with a high frequency of MN (1170cm-1; 1516cm-1; 1404cm-1; 1473cm-1) compared with samples with absence of MN, probably due to chromosomal histones and MN constituents. However, no statistically significant difference was observed between these groups considering that the FTIR is a screening test and not specific. Thus, by the FTIR technique it was not possible to classify the samples by the spectral differences presented. The MN test can be considered a screening test for the detection of HPV, being possible to use it in clinical practice because it is a practical, simple, low-cost and non-invasive method. However, it is important to carry out studies in larger sample groups to investigate the application of the MN test and FTIR spectroscopy in the diagnosis of this infection and in the application in the prevention of cervical cancer.

Allele-Specific Chemical Rescue of Histone Demethylases Using Abiotic Cofactors.

Closely related protein families evolved from common ancestral genes present a significant hurdle in developing member- and isoform-specific chemical probes, owing to their similarity in fold and function. In this piece of work, we explore an allele-specific chemical rescue strategy to activate a "dead" variant of a wildtype protein using synthetic cofactors and demonstrate its successful application to the members of the alpha-ketoglutarate (αKG)-dependent histone demethylase 4 (KDM4) family. We show that a mutation at a specific residue in the catalytic site renders the variant inactive toward the natural cosubstrate. In contrast, αKG derivatives bearing appropriate stereoelectronic features endowed the mutant with native-like demethylase activity while remaining refractory to a set of wild type dioxygenases. The orthogonal enzyme-cofactor pairs demonstrated site- and degree-specific lysine demethylation on a full-length chromosomal histone in the cellular milieu. Our work offers a strategy to modulate a specific histone demethylase by identifying and engineering a conserved phenylalanine residue, which acts as a gatekeeper in the KDM4 subfamily, to sensitize the enzyme toward a novel set of αKG derivatives. The orthogonal pairs developed herein will serve as probes to study the role of degree-specific lysine demethylation in mammalian gene expression. Furthermore, this approach to overcome active site degeneracy is expected to have general application among all human αKG-dependent dioxygenases.

A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin.

Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies.

Dark response genes: a group of endogenous pendulum/timing players in maize?

Maize has a set of dark response genes, expression of which is influenced by multiple factor and varies with maize inbred lines but without germplasm specificity. The response to photoperiod is a common biological issue across the species kingdoms. Dark is as important as light in photoperiod. However, further in-depth understanding of responses of maize (Zea mays) to light and dark transition under photoperiod is hindered due to the lack of understanding of dark response genes. With multiple public "-omic" datasets of temperate and tropical/subtropical maize, 16 maize dark response genes, ZmDRGs, were found and had rhythmic expression under dark and light-dark cycle. ZmDRGs 6-8 were tandemly duplicated. ZmDRGs 2, 13, and 14 had a chromosomal collinearity with other maize genes. ZmDRGs 1-11 and 13-16 had copy-number variations. ZmDRGs 2, 9, and 16 showed 5'-end sequence deletion mutations. Some ZmDRGs had chromatin interactions and underwent DNA methylation and/or m6A mRNA methylation. Chromosomal histones associated with 15 ZmDRGs were methylated and acetylated. ZmDRGs 1, 2, 4, 9, and 13 involved photoperiodic phenotypes. ZmDRG16 was within flowering-related QTLs. ZmDRGs 1, 3, and 6-11 were present in cis-acting expression QTLs (eQTLs). ZmDRGs 1, 4, 6-9, 11, 12, and 14-16 showed co-expression with other maize genes. Some of ZmDRG-encodedZmDRGs showed obvious differences in abundance and phosphorylation. Sixteen ZmDRGs 1-16 are associated with the dark response of maize. In the process of post-domestication and/or breeding, the ZmDRGs undergo the changes without germplasm specificity, including epigenetic modifications, gene copy numbers, chromatin interactions, and deletion mutations. In addition to effects by these factors, ZmDRG expression is influenced by promoter elements, cis-acting eQTLs, and co-expression networks.

Epigenetics. Mechanism and significance in gene regulation

Epigenetics deals with the study of structural modifications in the regions of the genome, by methylation of DNA or chromosomal histones, or other mechanisms that affect the expression of genes without altering the base composition of DNA. Cell differentiation, which is established in embryonic development from blastocyst status, is the consequence of differential cell reprogramming, based on programmed epigenetic modifications, which establish differences in the epigenome of cells and tissues. Maternal and paternal genomes of the gametes have genomic imprinting differences due to DNA methylation or other epigenetic modifications established in the germinal cells during gametogenesis. Maternal and paternal parental genomes present differences of genomic imprinting, which are established by DNA methylation or other epigenetic modifications during embryonic development, in the primordial germ cells. Unscheduled epigenetic modifications may also occur under the influence of uncontrolled environmental factors, which can lead to health disturbances. However, all epigenetic modifications are erased after fertilization and those affecting the germ line of the embryo or fetus during their development are not inherited beyond the second generation, - F2 -. Epigenetics should not be considered a new type of inheritance with transgenerational consequences, but as a set of mechanisms related to genetic regulation.

Ezh2-dependent H3K27me3 modification dynamically regulates vitamin D3-dependent epigenetic control of CYP24A1 gene expression in osteoblastic cells.

Epigenetic control is critical for the regulation of gene transcription in mammalian cells. Among the most important epigenetic mechanisms are those associated with posttranslational modifications of chromosomal histone proteins, which modulate chromatin structure and increased accessibility of promoter regulatory elements for competency to support transcription. A critical histone mark is trimethylation of histone H3 at lysine residue 27 (H3K27me3), which ismediated by Ezh2, the catalytic subunit of the polycomb group complex PRC2 to repress transcription. Treatment of cells with the active vitamin D metabolite 1,25(OH)2 D3 , results in transcriptional activation of the CYP24A1 gene, which encodes a 24-hydroxylase enzyme, that is, essential for physiological control of vitamin D3 levels. We report that the Ezh2-mediated deposition of H3K27me3 at the CYP24A1 gene promoter is a requisite regulatory component during transcriptional silencing of this gene in osteoblastic cells in the absence of 1,25(OH)2 D3 . 1,25(OH)2 D3 dependent transcriptional activation of the CYP24A1 gene is accompanied by a rapid release of Ezh2 from the promoter, together with the binding of the H3K27me3-specific demethylase Utx/Kdm6a and thereby subsequent erasing of the H3K27me3 mark. Importantly, we find that these changes in H3K27me3 enrichment at the CYP24A1 gene promoter are highly dynamic, as this modification is rapidly reacquired following the withdrawal of 1,25(OH)2 D3 .

The origin of chromosomal histones in a 30S ribosomal protein

Histones are genes that regulate chromatin structure. They are present in both eukaryotes and archaea, and form nucleosomes with DNA, but their exact evolutionary origins have hitherto remained a mystery. A longstanding hypothesis is that they have precursors in ribosomal proteins with whom they share much in common in terms of size and chemistry. By examining the proteome of the Asgard archaeon, Lokiarchaeum, the most conserved of all the histones, H4, is found to plausibly be homologous with one of its 30S ribosomal proteins, RPS6. This is based on both sequence identity and statistical analysis. The N-terminal tail, containing key sites involved in post-translational modifications, is notably present in the precursor gene. Although other archaeal groups possess similar homologs, these are not as close to H4 as the one found in Lokiarchaeum. The other core histones, H2A, H2B and H3, appear to have also evolved from the same ribosomal protein. Parts of H4 are also similar to another ribosomal protein, namely RPS15, suggesting that the ancestral precursor could have resembled both. Eukaryotic histones, in addition, appear to have an independent origin to that of their archaeal counterparts that evolved from similar, but still different, 30S subunit proteins, some of which are much more like histones in terms of their physical structure. The nucleosome may, therefore, be not only of archaeal but also of ribosomal origin.

Promoter conservation in HDACs points to functional implications

BackgroundHistone deacetylases (HDACs) are the proteins responsible for removing the acetyl group from lysine residues of core histones in chromosomes, a crucial component of gene regulation. Eleven known HDACs exist in humans and most other vertebrates. While the basic function of HDACs has been well characterized and new discoveries are still being made, the transcriptional regulation of their corresponding genes is still poorly understood.ResultsHere, we conducted a computational analysis of the eleven HDAC promoter sequences in 25 vertebrate species to determine whether transcription factor binding sites (TFBSs) are conserved in HDAC evolution, and if so, whether they provide useful information about HDAC expression and function. Furthermore, we used tissue-specific information of transcription factors to investigate the potential expression patterns of HDACs in different human tissues based on their transcription factor binding sites. We found that the TFBS profiles of most of the HDACs were well conserved in closely related species for all HDAC promoters except HDAC7 and HDAC10. HDAC5 had particularly strong conservation across over half of the species studied, with nearly identical profiles in the primate species. Our comparisons of TFBSs with the tissue specific gene expression profiles of their corresponding TFs showed that most HDACs had the ability to be ubiquitously expressed. A few HDAC promoters exhibited the potential for preferential expression in certain tissues, most notably HDAC11 in gall bladder, while HDAC9 seemed to have less propensity for expression in the nervous system.ConclusionsIn general, we found evolutionary conservation in HDAC promoters that seems to be more prominent for the ubiquitously expressed HDACs. In turn, when conservation did not follow usual phylogeny, human TFBS patterns indicated possible functional relevance. While we found that HDACs appear to uniformly expressed, we confirm that the functional differences in HDACs may be less a matter of location of activity than a question of which proteins and which acetyl groups they may be acting on.

Depletion of ATP-Citrate Lyase (ATPCL) Affects Chromosome Integrity Without Altering Histone Acetylation in Drosophila Mitotic Cells.

The Citrate Lyase (ACL) is the main cytosolic enzyme that converts the citrate exported from mitochondria by the SLC25A1 carrier in Acetyl Coenzyme A (acetyl-CoA) and oxaloacetate. Acetyl-CoA is a high-energy intermediate common to a large number of metabolic processes including protein acetylation reactions. This renders ACL a key regulator of histone acetylation levels and gene expression in diverse organisms including humans. We have found that depletion of ATPCL, the Drosophila ortholog of human ACL, reduced levels of Acetyl CoA but, unlike its human counterpart, does not affect global histone acetylation and gene expression. Nevertheless, reduced ATPCL levels caused evident, although moderate, mitotic chromosome breakage suggesting that this enzyme plays a partial role in chromosome stability. These defects did not increase upon X-ray irradiation, indicating that they are not dependent on an impairment of DNA repair. Interestingly, depletion of ATPCL drastically increased the frequency of chromosome breaks (CBs) associated to mutations in scheggia, which encodes the ortholog of the mitochondrial citrate carrier SLC25A1 that is also required for chromosome integrity and histone acetylation. Our results indicate that ATPCL has a dispensable role in histone acetylation and prevents massive chromosome fragmentation when citrate efflux is altered.

DNA double-strand break repair: a tale of pathway choices.

Deoxyribonucleic aciddouble-strand breaks (DSBs) are cytotoxic lesions that must be repaired either through homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways. DSB repair is critical for genome integrity, cellular homeostasis and also constitutes the biological foundation for radiotherapy and the majority of chemotherapy. The choice between HR and NHEJ is a complex yet not completely understood process that will entail more future efforts. Herein we review our current understandings about how the choice is made over an antagonizing balance between p53-binding protein 1 and breast cancer 1in the context of cell cycle stages, downstream effects, and distinct chromosomal histone marks. These exciting areas of research will surely bring more mechanistic insights about DSB repair and be utilized in the clinical settings.

Suppression of Antimicrobial Peptide Expression by Ureaplasma Species

Ureaplasma species commonly colonize the adult urogenital tract and are implicated in invasive diseases of adults and neonates. Factors that permit the organisms to cause chronic colonization or infection are poorly understood. We sought to investigate whether host innate immune responses, specifically, antimicrobial peptides (AMPs), are involved in determining the outcome of Ureaplasma infections. THP-1 cells, a human monocytoid tumor line, were cocultured with Ureaplasma parvum and U. urealyticum. Gene expression levels of a variety of host defense genes were quantified by real-time PCR. In vitro antimicrobial activities of synthetic AMPs against Ureaplasma spp. were determined using a flow cytometry-based assay. Chromosomal histone modifications in host defense gene promoters were tested by chromatin immunoprecipitation (ChIP). DNA methylation status in the AMP promoter regions was also investigated. After stimulation with U. parvum and U. urealyticum, the expression of cell defense genes, including the AMP genes (DEFB1, DEFA5, DEFA6, and CAMP), was significantly downregulated compared to that of TNFA and IL-8, which were upregulated. In vitro flow cytometry-based antimicrobial assay revealed that synthetic peptides LL-37, hBD-3, and hBD-1 had activity against Ureaplasma spp. Downregulation of the AMP genes was associated with chromatin modification alterations, including the significantly decreased histone H3K9 acetylation with U. parvum infection. No DNA methylation status changes were detected upon Ureaplasma infection. In conclusion, AMPs have in vitro activity against Ureaplasma spp., and suppression of AMP expression might be important for the organisms to avoid this aspect of the host innate immune response and to establish chronic infection and colonization.

Abstract 4192: Genome-wide microRNA and functional genomics analysis during differentiation of acute promyelocytic leukemia to granulocytes.

Abstract MicroRNA (miRNAs) are short noncoding RNAs that play important roles in human diseases, including cancer, and function to regulate gene expression of critical processes, such as apoptosis, cell proliferation and differentiation, by either translational inhibition or mRNA degradation. However, little is known about the role of miRNAs in granulopoiesis and acute myeloid leukemia (AML). We performed genome-wide miRNAs and functional genomics analysis in the acute promyelocytic leukemia (APL) human cell line HL-60 during its differentiation towards granulocytes, by using miRNA microarrays Exiqon platform, quantitative real time polymerase chain reaction (qRT-PCR) and Ingenuity Pathways Analysis(IPA). Among 1279 human miRNAs analyzed, we identified a unique signature of 86 differentially expressed miRNAs between control and DMSO-treated cells (at p<0.05), 51 of them were up-regulated and 35 of were down-regulated, which have not previously identified as regulators of hematopoietic differentiation. Our data showed that miRNA expression profiling revealed distinctive miRNA signatures that correlated with morphological changes in the cell and nucleus, granule formation, and chromatin condensation, all these processes being consistent with neutrophil maturation. Transmission electron microscopy (TEM) showed large mitochondria and revealed the presence of multiple autophagosome-like vacuoles with double-membrane structures in neutrophil-like differentiated cells. Specific miRNAs, such as miR-125a-5p and miR-483-3p, appeared to be associated with chromatin remodeling and nuclear protein expression, such as chromosome condensation (CHC1L) and histone family member X (H1FX), during HL-60 cell differentiation towards granulocytes. We found by gain-of-function experiments that miRNA-125a-5p and miR483-3p promoted granulocytic differentiation of HL-60 leukemic cells as confirmed by nitroblue tetrazolium (NBT) staining and mature myeloid cell marker expression, while miR-17-92 cluster attenuated granulocytic differentiation. Therefore miRNA-125a-5p, miRNA-483-3p up-regulation and miRNA-17-92 cluster down-regulation provide new insight into the mechanism of granulopoiesis. Molecular network analysis of miRNA targetome during APL differentiation showed a regulation by individual miRNAs that constitute a biological network of functionally-associated molecules in human cells, closely linked to pathological events involved in cancer, p53 signaling, gene expression, cellular growth and differentiation. These findings provide unique molecular insights into how APL malignant cells can be differentiated towards terminal neutrophil-like cells, which might lead to the identification of novel molecular targets in leukemia differentiation therapy. Citation Format: El Habib Dakir, Jun-ichi Satoh, Faustino Mollinedo. Genome-wide microRNA and functional genomics analysis during differentiation of acute promyelocytic leukemia to granulocytes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4192. doi:10.1158/1538-7445.AM2013-4192

Wavefronts and Mechanical Signaling in Early Drosophila Embryos

Many developmental processes use signaling for synchronization. One possible and well-known method is for each component to measure the local concentration of some diffusing biochemical species, and if that concentration exceeds a certain threshold, to release more of the same biochemical, giving rise to wavefront propagation in the chemically excitable medium. There are however more ways in which a medium can be excited and wavefronts can be formed. We suggest a new kind of signaling based not on diffusion of a chemical species, but on the propagation of mechanical stress. We construct a theoretical approach to describe mechanical signaling in an overdamped system as a nonlinear wavefront propagation problem. We apply the theory to mitosis in the early syncytial Drosophila embryo, which is highly correlated in space and time, as manifested in mitotic wavefronts that propagate across the embryo. We compare our results to data taken on Drosophila embryos in which histones in the nuclear chromosomes are labeled with GFP. By analyzing confocal microscopy videos of the mitotic wavefront, we find that the wavefront can be resolved into two distinct wavefronts in each cycle, corresponding to the onset of metaphase and of anaphase, respectively. The two wavefronts have the same speed and are separated by a time interval that is independent of cycle, indicating that they are two different markers for the same process. We find that the dependence of wavefront speed on cell cycle number is most naturally explained by mechanical signaling via stress diffusion, and that the entire process suggests a scenario in which biochemical and mechanical signaling are coupled.

Структура комплексов ДНК с хромосомным белком HMGB1 и гистоном Н1 в присутствии ионов марганца. II. Спектроскопия кругового дихроизма в ИК области

Complexes of DNA with nonhistone chromosomal protein HMGB1 and histone H1 in the presence of manganese ions were studied using absorption and circular dichroism spectroscopy in infrared region. It was shown that the approach provides good results for solutions containing large particles, which cause light scattering in UV region. It was also shown that the manganese ions are able to coordinate to the chemical groups of DNA as well as to the carboxylic amino acid residues of the protein HMGB1. The latter stimulates DNA condensation and slightly weakens DNA-protein interactions in the complex.

Packaging the fly genome: domains and dynamics

Two independent genomic approaches have recently converged to provide insight into the domain organization of the Drosophila genome. Genome-wide mapping of chromosomal proteins and histone modifications has generated detailed maps of the Drosophila chromatin landscape and has led to the identification of a number of different chromatin states and their distribution in domains across the genome. A remarkably similar domain organization is derived from whole genome mapping of chromatin interactions that reveals the segmentation of the genome into structural domains. This review focuses on our current understanding of this domain architecture which provides a foundation for our understanding of the link between chromatin organization and the dynamic activity of the genome.

Evolutionary origin of chromatin remodeling for dosage compensation: Lessons from epigenetic modifications of X chromosomes in germ cells of Drosophila, C.elegans and Mammals

Epigenetic modifications of entire X chromosome(s) are adapted in many animals to keep balance of gene dose difference between sexes possessing different number of sex chromosomes required for sex determination. Different animals have adapted different mechanisms for epigenetic regulation of X chromosomal expression depending on ‘demasculinization’ of the X chromosome. The epigenetic programming for dosage compensation in Drosophila is to hyperactivate the male X chromosome by histone H4 modification. In Caenorhabditis elegans, both X chromosomal histones of hermaphrodite are methylated for down regulation of X linked gene expression. Mammals have developed a system of epigenetic modification for both upregulation and repression of X chromosomal genes for dosage compensation. In recent years, epigenetic modifications that occur during male meiosis are characterized with special attention on events that define meiotic sex chromosome inactivation. As data accumulate, noval features of dosage compensation processes of different animals are also gaining attention. This review highlights the crucial roles of germline X chromosomal organization, that are potentially relevant to epigenetic modulation of somatic dosage compensation in the three animals.