Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes.

Many processes can cause the same nucleotide change in a genome, making the identification of the mechanisms causing mutations a difficult challenge. Here, we show that clustered mutations provide a more precise fingerprint of mutagenic processes. Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking. An additional signature matches the spectrum of translesion DNA polymerase eta (POLH). In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation. In solid tumors, however, they are associated with UV exposure and alcohol consumption and target the H3K36me3 chromatin of active genes in a mismatch repair (MMR)-dependent manner. These regions normally have a low mutation rate because error-free MMR also targets H3K36me3 chromatin. Carcinogens and error-prone repair therefore redistribute mutations to the more important regions of the genome, contributing a substantial mutation load in many tumors, including driver mutations.

Epigenetic marks or not? The discovery of novel DNA modifications in eukaryotes.

DNA modifications add another layer of complexity to the eukaryotic genome to regulate gene expression, playing critical roles as epigenetic marks. In eukaryotes, the study of DNA epigenetic modifications has been confined to 5mC and its derivatives for decades. However, rapid developing approaches have witnessed the expansion of DNA modification reservoirs during the past several years, including the identification of 6mA, 5gmC, 4mC, and 4acC in diverse organisms. However, whether these DNA modifications function as epigenetic marks requires careful consideration. In this review, we try to present a panorama of all the DNA epigenetic modifications in eukaryotes, emphasizing recent breakthroughs in the identification of novel DNA modifications. The characterization of their roles in transcriptional regulation as potential epigenetic marks is summarized. More importantly, the pathways for generating or eliminating these DNA modifications, as well as the proteins involved are comprehensively dissected. Furthermore, we briefly discuss the potential challenges and perspectives, which should be taken into account while investigating novel DNA modifications.

Emerging roles of plant transcriptional gene silencing under heat.

Plants continuously endure unpredictable environmental fluctuations that upset their physiology, with stressful conditions negatively impacting yield and survival. As a contemporary threat of rapid progression, global warming has become one of the most menacing ecological challenges. Thus, understanding how plants integrate and respond to elevated temperatures is crucial for ensuring future crop productivity and furthering our knowledge of historical environmental acclimation and adaptation. While the canonical heat-shock response and thermomorphogenesis have been extensively studied, evidence increasingly highlights the critical role of regulatory epigenetic mechanisms. Among these, the involvement under heat of heterochromatic suppression mediated by transcriptional gene silencing (TGS) remains the least understood. TGS refers to a multilayered metabolic machinery largely responsible for the epigenetic silencing of invasive parasitic nucleic acids and the maintenance of parental imprints. Its molecular effectors include DNA methylation, histone variants and their post-translational modifications, and chromatin packing and remodeling. This work focuses on both established and emerging insights into the contribution of TGS to the physiology of plants under stressful high temperatures. We summarized potential roles of constitutive and facultative heterochromatin as well as the most impactful regulatory genes, highlighting events where the loss of epigenetic suppression has not yet been associated with corresponding changes in epigenetic marks.

SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression.

The homeotic (Hox) genes are highly conserved in metazoans, where they are required for various processes in development, and misregulation of their expression is associated with human cancer. In the developing embryo, Hox genes are activated sequentially in time and space according to their genomic position within Hox gene clusters. Accumulating evidence implicates both enhancer elements and noncoding RNAs in controlling this spatiotemporal expression of Hox genes, but disentangling their relative contributions is challenging. Here, we identify two cis-regulatory elements (E1 and E2) functioning as shadow enhancers to regulate the early expression of the HoxA genes. Simultaneous deletion of these shadow enhancers in embryonic stem cells leads to impaired activation of HoxA genes upon differentiation, while knockdown of a long noncoding RNA overlapping E1 has no detectable effect on their expression. Although MLL/COMPASS (complex of proteins associated with Set1) family of histone methyltransferases is known to activate transcription of Hox genes in other contexts, we found that individual inactivation of the MLL1-4/COMPASS family members has little effect on early Hox gene activation. Instead, we demonstrate that SET1A/COMPASS is required for full transcriptional activation of multiple Hox genes but functions independently of the E1 and E2 cis-regulatory elements. Our results reveal multiple regulatory layers for Hox genes to fine-tune transcriptional programs essential for development.

Hop stunt viroid infection induces heterochromatin reorganization.

Viroids are pathogenic noncoding RNAs that completely rely on their host molecular machinery to accomplish their life cycle. Several interactions between viroids and their host molecular machinery have been identified, including interference with epigenetic mechanisms such as DNA methylation. Despite this, whether viroids influence changes in other epigenetic marks such as histone modifications remained unknown. Epigenetic regulation is particularly important during pathogenesis processes because it might be a key regulator of the dynamism of the defense response. Here we have analyzed the changes taking place in Cucumis sativus (cucumber) facultative and constitutive heterochromatin during hop stunt viroid (HSVd) infection using chromatin immunoprecipitation (ChIP) of the two main heterochromatic marks: H3K9me2 and H3K27me3. We find that HSVd infection is associated with changes in both H3K27me3 and H3K9me2, with a tendency to decrease the levels of repressive epigenetic marks through infection progression. These epigenetic changes are connected to the transcriptional regulation of their expected targets, genes, and transposable elements. Indeed, several genes related to the defense response are targets of both epigenetic marks. Our results highlight another host regulatory mechanism affected by viroid infection, providing further information about the complexity of the multiple layers of interactions between pathogens/viroids and hosts/plants.

Epigenetics.

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities.

Sperm histone modifications may predict success in human assisted reproduction: a pilot study.

PURPOSE: Currently, assisted reproduction clinics employ various sperm selection techniques to identify the best sperm for fertilization. However, these techniques may not assess crucial sperm traits that can substantially impact embryonic quality. To address this, we propose analyzing diverse histone modifications as potential markers of sperm functionality and success in assisted reproduction techniques. METHODS: Cross-sectional pilot study including infertile male patients attending an infertility clinic in CABA, Argentina between April and August 2019 was performed. We used immunofluorescence techniques to evaluate post-translational modifications of histones in sperm and established correlations with in vitro fertilization outcome and embryo quality. RESULTS: Our findings indicate a negative correlation between H3K4me3 and H3K4me2 marks and fertilization rate and showed a positive correlation of this parameter with H3K9me mark. In addition, there was a positive correlation between H3K27me3 and good embryo quality. CONCLUSIONS: This pilot study proposes a non-invasive strategy to predict embryo quality by analyzing spermatozoa prior to fertilization. The assessment of histone post-translational modifications in sperm samples could provide useful information for the recognition of epigenetic marks that could predict the health of the embryo of an assisted fertilization treatment.

DNA Glycosylases Define the Outcome of Endogenous Base Modifications.

Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell fate by regulating chromatin organisation and gene expression. Identical chemical modifications exerting different functions pose a challenge for the cell's DNA repair machinery, as it needs to accurately distinguish between epigenetic marks and DNA damage to ensure proper repair and maintenance of (epi)genomic integrity. The specificity and selectivity of the recognition of these modified bases relies on DNA glycosylases, which acts as DNA damage, or more correctly, as modified bases sensors for the base excision repair (BER) pathway. Here, we will illustrate this duality by summarizing the role of uracil-DNA glycosylases, with particular attention to SMUG1, in the regulation of the epigenetic landscape as active regulators of gene expression and chromatin remodelling. We will also describe how epigenetic marks, with a special focus on 5-hydroxymethyluracil, can affect the damage susceptibility of nucleic acids and conversely how DNA damage can induce changes in the epigenetic landscape by altering the pattern of DNA methylation and chromatin structure.

Differential expression of HNF1A and HNF1A-AS1 in colon cancer cells.

The human hepatocyte nuclear factor 1 homeobox A (HNF1A) gene loci express the protein-coding HNF1A transcript and a long non-coding RNA in the anti-sense (HNF1A-AS1) direction. HNF1A-AS1 is expressed in numerous types of cancers and poor clinical outcomes such as higher mortality rates, greater metastatic capacity, and poor prognosis of the disease are the results of this expression. In this study, we determined the epigenetic features of the HNF1A gene loci, and expression and cellular localization of HNF1A-AS1 RNA, HNF1A RNA, and HNF1A protein in colorectal cancer (HT-29, HTC116, RKO, and SW480) and normal colon epithelial (CCD841) cells. The HT-29 HNF1A gene had active histone marks (H3K4me3, H3K27ac) and DNase 1 accessible sites at the promoter regions of the HNF1A and HNF1A-AS1 genes. These epigenetic marks were not observed in the other colorectal cancer cells or in the normal colon epithelial cells. Consistent with the active gene epigenetic signature of the HNF1A gene in HT-29 cells, HNF1A protein, and HNF1A/HNF1A-AS1 transcripts were detected in HT-29 cells but poorly, if at all observed, in the other cell types. In HT-29 cells, HNF1A-AS1 localized to the nucleus and was found to bind to the enhancer of zeste homolog 2 (EZH2, a member of PRC2 complex) and potentially form RNA-DNA triplexes with DNase 1 accessible sites in the HT-29 genome. These activities of HNF1A-AS1 may contribute to the oncogenic properties of this long non-coding RNA.

Molecular basis of priming-induced acquired tolerance to multiple abiotic stresses in plants.

The growth, survival, and productivity of plants are constantly challenged by diverse abiotic stresses. When plants are exposed to stress for the first time, they can capture molecular information and store it as a form of memory, which enables them to competently and rapidly respond to subsequent stress(es). This process is referred to as a priming-induced or acquired stress response. In this review, we discuss how (i) the storage and retrieval of the information from stress memory modulates plant physiological, cellular, and molecular processes in response to subsequent stress(es), (ii) the intensity, recurrence, and duration of priming stimuli influences the outcomes of the stress response, and (iii) the varying responses at different plant developmental stages. We highlight current understanding of the distinct and common molecular processes manifested at the epigenetic, (post-)transcriptional, and post-translational levels mediated by stress-associated molecules and metabolites, including phytohormones. We conclude by emphasizing how unravelling the molecular circuitry underlying diverse priming-stimuli-induced stress responses could propel the use of priming as a management practice for crop plants. This practice, in combination with precision agriculture, could aid in increasing yield quantity and quality to meet the rapidly rising demand for food.

[Male infertility and urologic cancers: Advances in studies].

Male infertility is one of the most common diseases in andrology. Studies show that male infertility is significantly correlated with the incidence and mortality of tumors, especially malignant tumors in the genitourinary system, such as testis cancer and prostate cancer. The relationship of male infertility with genitourinary system tumors involves various aspects, mainly including changes in chromosome mutations, epigenetic marks, hormonal imbalance, and congenital deformity. Besides, some chronic diseases are shown to be significantly associated with male infertility, and semen quality or fertility status may be biomarkers of the overall health of males. In-depth studies of the correlation between male infertility and these factors are very important for an insight into the pathogenesis and prevention of the related diseases.

Lsd1 interacts with cMyb to demethylate repressive histone marks and maintain inner ear progenitor identity.

During development, multipotent progenitor cells must maintain their identity while retaining the competence to respond to new signalling cues that drive cell fate decisions. This depends on both DNA-bound transcription factors and surrounding histone modifications. Here, we identify the histone demethylase Lsd1 as a crucial component of the molecular machinery that preserves progenitor identity in the developing ear prior to lineage commitment. Although Lsd1 is mainly associated with repressive complexes, we show that, in ear precursors, it is required to maintain active transcription of otic genes. We reveal a novel interaction between Lsd1 and the transcription factor cMyb, which in turn recruits Lsd1 to the promoters of key ear transcription factors. Here, Lsd1 prevents the accumulation of repressive H3K9me2, while allowing H3K9 acetylation. Loss of Lsd1 function causes rapid silencing of active promoters and loss of ear progenitor genes, and shuts down the entire ear developmental programme. Our data suggest that Lsd1-cMyb acts as a co-activator complex that maintains a regulatory module at the top of the inner ear gene network.

Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer's Disease.

Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through epigenetic modulators, mainly by the histone code. One of the main challenges for the cell is maintaining functionality and identity, despite the accumulation of DNA damage throughout the aging process. Replicative cells can remain in a senescent state or develop a malign cancer phenotype. In contrast, post-mitotic cells such as pyramidal neurons maintain extraordinary functionality despite advanced age, but they lose their identity. This review focuses on tau, a protein that protects DNA, organizes chromatin, and plays a crucial role in genomic stability. In contrast, tau cytosolic aggregates are considered hallmarks of Alzheimer´s disease (AD) and other neurodegenerative disorders called tauopathies. Here, we explain AD as a phenomenon of chromatin dysregulation directly involving the epigenetic histone code and a progressive destabilization of the tau-chromatin interaction, leading to the consequent dysregulation of gene expression. Although this destabilization could be lethal for post-mitotic neurons, tau protein mediates profound cellular transformations that allow for their temporal survival.

Direct and Base Excision Repair-Mediated Regulation of a GC-Rich cis-Element in Response to 5-Formylcytosine and 5-Carboxycytosine.

Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely explored. We analyzed the expression of reporter constructs containing either 2'-deoxy-(5-fC/5-caC) or their BER-resistant 2'-fluorinated analogs, asymmetrically incorporated into CG-dinucleotide of the GC box cis-element (5'-TGGGCGGAGC) upstream from the RNA polymerase II core promoter. In the absence of BER, 5-caC caused a strong inhibition of the promoter activity, whereas 5-fC had almost no effect, similar to 5-methylcytosine or 5-hydroxymethylcytosine. BER of 5-caC caused a transient but significant promoter reactivation, succeeded by silencing during the following hours. Both responses strictly required thymine DNA glycosylase (TDG); however, the silencing phase additionally demanded a 5'-endonuclease (likely APE1) activity and was also induced by 5-fC or an apurinic/apyrimidinic site. We propose that 5-caC may act as a repressory mark to prevent premature activation of promoters undergoing the final stages of DNA demethylation, when the symmetric CpG methylation has already been lost. Remarkably, the downstream promoter activation or repression responses are regulated by two separate BER steps, where TDG and APE1 act as potential switches.

Pairwise Proximity-Differentiated Visualization of Single-Cell DNA Epigenetic Marks.

Spatial positioning and proximity of relevant biomolecules such as DNA epigenetic marks are fundamental to a deeper understanding of life. However, it remains poorly explored and technically challenging. Here we report the pairwise proximity-differentiated visualization of single-cell 5-formylcytosine (5fC) and 5-hydroxymethylcytosine (5hmC). These two marks on chromatin in fixed cells are successively labeled and crosslinked with their DNA primer probes via click chemistry. Based on a pairwise proximity-differentiated mechanism, proximal 5fC/5hmC sites and residual 5fC or 5hmC sites are encoded with respective circularized barcodes. These barcodes are simultaneously amplified for multiplexed single-molecule imaging. We thus demonstrate the differentiated visualization of 5fC or 5hmC spatial positioning and their pairwise proximity in single cells. Such multi-level subcellular information may provide insights into regulation functions and mechanisms of chromatin modifications, and the spatial proximity can expose the potential crosstalk or interaction between their reader proteins.

Local DNA methylation helps to regulate muscle sirtuin 1 gene expression across seasons and advancing age in gilthead sea bream (Sparus aurata).

BACKGROUND: Sirtuins (SIRTs) are master regulators of metabolism, and their expression patterns in gilthead sea bream (GSB) reveal different tissue metabolic capabilities and changes in energy status. Since little is known about their transcriptional regulation, the aim of this work was to study for the first time in fish the effect of age and season on sirt gene expression, correlating expression patterns with local changes in DNA methylation in liver and white skeletal muscle (WSM). METHODS: Gene organization of the seven sirts was analyzed by BLAT searches in the IATS-CSIC genomic database (www.nutrigroup-iats.org/seabreamdb/). The presence of CpG islands (CGIs) was mapped by means of MethPrimer software. DNA methylation analyses were performed by bisulfite pyrosequencing. A PCR array was designed for the simultaneous gene expression profiling of sirts and related markers (cs, cpt1a, pgc1α, ucp1, and ucp3) in the liver and WSM of one- and three-year-old fish during winter and summer. RESULTS: The occurrence of CGIs was evidenced in the sirt1 and sirt3 promoters. This latter CGI remained hypomethylated regardless of tissue, age and season. Conversely, DNA methylation of sirt1 at certain CpG positions within the promoter varied with age and season in the WSM. Among them, changes at several SP1 binding sites were negatively correlated with the decrease in sirt1 expression in summer and in younger fish. Changes in sirt1 regulation match well with variations in feed intake and energy metabolism, as judged by the concurrent changes in the analyzed markers. This was supported by discriminant analyses, which identified sirt1 as a highly responsive element to age- and season-mediated changes in energy metabolism in WSM. CONCLUSIONS: The gene organization of SIRTs is highly conserved in vertebrates. GSB sirt family members have CGI- and non-CGI promoters, and the presence of CGIs at the sirt1 promoter agrees with its ubiquitous expression. Gene expression analyses support that sirts, especially sirt1, are reliable markers of age- and season-dependent changes in energy metabolism. Correlation analyses suggest the involvement of DNA methylation in the regulation of sirt1 expression, but the low methylation levels suggest the contribution of other putative mechanisms in the transcriptional regulation of sirt1.

Microspore embryogenesis: targeting the determinant factors of stress-induced cell reprogramming for crop improvement.

Under stress, isolated microspores are reprogrammed in vitro towards embryogenesis, producing doubled haploid plants that are useful biotechnological tools in plant breeding as a source of new genetic variability, fixed in homozygous plants in only one generation. Stress-induced cell death and low rates of cell reprogramming are major factors that reduce yield. Knowledge gained in recent years has revealed that initiation and progression of microspore embryogenesis involve a complex network of factors, whose roles are not yet well understood. Here, I review recent findings on the determinant factors underlying stress-induced microspore embryogenesis, focusing on the role of autophagy, cell death, auxin, chromatin modifications, and the cell wall. Autophagy and cell death proteases are crucial players in the response to stress, while cell reprogramming and acquisition of totipotency are regulated by hormonal and epigenetic mechanisms. Auxin biosynthesis, transport, and action are required for microspore embryogenesis. Initial stages involve DNA hypomethylation, H3K9 demethylation, and H3/H4 acetylation. Cell wall remodelling, with pectin de-methylesterification and arabinogalactan protein expression, is necessary for embryo development. Recent reports show that treatments with small modulators of autophagy, proteases, and epigenetic marks reduce cell death and enhance embryogenesis initiation in several crops, opening up new possibilities for improving in vitro embryo production in breeding programmes.

H3K9me3, H3K36me3, and H4K20me3 Expression Correlates with Patient Outcome in Esophageal Squamous Cell Carcinoma as Epigenetic Markers.

BACKGROUND: Histone methylation, as an essential pattern of posttranslational modifications, contributes to multiple cancer-related biological processes. Dysregulation of histone methylation is now considered a biomarker for cancer prognosis. AIMS: This study investigated and evaluated the potential role of four histone lysine trimethylation markers as biomarkers for esophageal squamous cell carcinoma (ESCC) prognosis. METHODS: Tissue arrays were made from 135 paraffin-embedded ESCC samples and examined for histone markers by immunohistochemistry, and 10 pairs of cancer and noncancerous mucosa tissues from ESCC patients were investigated with Western blot. Chi-squared test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard trend analyses were performed to assess the prognostic values of the markers. RESULTS: Histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 4 lysine 20 trimethylation (H4K20me3), but not histone 3 lysine 36 trimethylation (H3K36me3), showed stronger immunostaining signals in tumor tissues than in the corresponding adjacent non-neoplastic mucosa tissues. The expression patterns of H3K36me3, H3K9me3, and H4K20me3 correlated with tumor infiltrating depth, lymph node involvement, and pTNM stage. Low-scoring H3K9me3 and H4K20me3 predicted better prognosis, while H3K36me3 manifested the opposite trend. Poor prognosis occurred in ESCC patients with expression patterns of high levels of H3K9me3, high levels of H4K20me3, and low levels of H3K36me3 expression. CONCLUSIONS: H3K9me3, H4K20me3, and H3K36me3 showed a close relationship with clinical features and were considered independent risk factors for survival of ESCC patients. The combination of H3K9me3, H4K20me3, and H3K36me3 expression, rather than the expression of a single histone marker, is believed to further enhance evaluations of ESCC prognosis and management.

Methylation Patterns of Lys9 and Lys27 on Histone H3 Correlate with Patient Outcome in Gastric Cancer.

BACKGROUND: Histone methylation has been considered as one of the epigenetic mechanisms of carcinogenesis and progression. Researches on the correlation between histone lysine methylation and gastric cancer (GC) will help in finding novel epigenetic biomarkers for monitoring cancers. AIMS: The study detected the expression patterns of histone 3 lysine 9 dimethylation (H3K9me2), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3) in GC tissues and evaluated their clinical merit for GC patients. METHODS: One hundred thirty-three paraffin-embedded GC samples were examined by immunohistochemistry for the histone markers: H3K9me2, H3K9me3, and H3K27me3. The relationship and clinicopathological significance of the three lysine methylations on histone H3 with GC were assessed by Paired t test, Chi-square test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard analyses. RESULTS: Strong positive immunostaining of H3K9me2, H3K9me3, and H3K27me3 was observed in cancerous tissues than in their counterpart non-cancer tissues. Higher expression patterns of H3K9me2, H3K9me3, and H3K27me3 significantly related to differentiation degree, lymph nodes metastases, and pathological TNM staging in GC. The GC patients with low scoring of the three markers implied long survival period and best prognosis. In contrast, the patients' survival time was significantly shorter if their cancerous tissues presented high expression of the three markers. CONCLUSIONS: H3K9me2, H3K9me3, and H3K27me3 expression patterns closely relate to clinicopathological features and may be the independent risk factors for the survival of GC patients. The combined pattern of the three markers rather than an individual marker is considered to more accurately evaluate the outcome of GC patients.

Pharmaco-epigenomics: On the Road of Translation Medicine.

Epigenomics refers to the study of genome-wide changes in epigenetic mechanisms including DNA methylation, histone modifications and non-coding RNAs expression. The alterations in normal DNA methylation and histone acetylation/deacetylation patterns lead to deregulated transcription and chromatin organization resulting in altered gene expression profiles that facilitates tumor development and progression. In consequence, novel therapeutic strategies aimed at reversing aberrant epigenetic marks in cancer cells have been developed and used in recent molecular studies and clinical trials. Pharmaco-epigenomics is a research area, which refers to the study of epigenome changes in cancer development and how chemotherapeutic agents can reverse these aberrant epigenetic marks by targeting the epigenetic machinery. Besides, the effects of genome-wide polymorphisms in populations leading to variations in drug response are also study subject of pharmaco-epigenomics and are being studied extensively in cancer. Recent findings showed that drug response could be largely influenced by the presence of aberrant epigenetic marks of the whole genome. This implies that biological pathways and cellular processes are under the impact of epigenome status. However, data about the relationship between drug response and the epigenomic variations is still scarce mainly because the epigenome is highly variable between individuals. The present chapter reviewed the advances on the epigenetics changes mainly DNA methylation and histones modifications on cervical and breast human cancers. A special emphasis in how they could be used as targets for the development and use of novel drugs in cancer therapy is delineated.