Epi-miRNAs: Regulators of the Histone Modification Machinery in Human Cancer.
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ABSTRACT:
SUBMITTER: Mortazavi D
PROVIDER: S-EPMC8789461 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIncreasing evidence linking epigenetic mechanisms and different diseases, including cancer, has prompted in the last 15 years the investigation of histone post-translational modifications (PTMs) in clinical samples. Methods allowing the isolation of histones from patient samples followed by the accurate and comprehensive quantification of their PTMs by mass spectrometry (MS) have been developed. However, the applicability of these methods is limited by the requirement for substantial amounts of material.ResultsTo address this issue, in this study we streamlined the protein extraction procedure from low-amount clinical samples and tested and implemented different in-gel digestion strategies, obtaining a protocol that allows the MS-based analysis of the most common histone PTMs from laser microdissected tissue areas containing as low as 1000 cells, an amount approximately 500 times lower than what is required by available methods. We then applied this protocol to breast cancer patient laser microdissected tissues in two proof-of-concept experiments, identifying differences in histone marks in heterogeneous regions selected by either morphological evaluation or MALDI MS imaging.ConclusionsThese results demonstrate that analyzing histone PTMs from very small tissue areas and detecting differences from adjacent tumor regions is technically feasible. Our method opens the way for spatial epi-proteomics, namely the investigation of epigenetic features in the context of tissue and tumor heterogeneity, which will be instrumental for the identification of novel epigenetic biomarkers and aberrant epigenetic mechanisms.
| S-EPMC8317427 | biostudies-literature
Project description:Dysregulated epigenetic enzymes and resultant abnormal epigenetic modifications (EMs) have been suggested to be closely related to tumor occurrence and progression. Histone modifications (HMs) can assist in maintaining genome stability, DNA repair, transcription, and chromatin modulation within breast cancer (BC) cells. In addition, HMs are reversible, dynamic processes involving the associations of different enzymes with molecular compounds. Abnormal HMs (e.g. histone methylation and histone acetylation) have been identified to be tightly related to BC occurrence and development, even though their underlying mechanisms remain largely unclear. EMs are reversible, and as a result, epigenetic enzymes have aroused wide attention as anti-tumor therapeutic targets. At present, treatments to restore aberrant EMs within BC cells have entered preclinical or clinical trials. In addition, no existing studies have comprehensively analyzed aberrant HMs within BC cells; in addition, HM-targeting BC treatments remain to be further investigated. Histone and non-histone protein methylation is becoming an attractive anti-tumor epigenetic therapeutic target; such methylation-related enzyme inhibitors are under development at present. Consequently, the present work focuses on summarizing relevant studies on HMs related to BC and the possible mechanisms associated with abnormal HMs. Additionally, we also aim to analyze existing therapeutic agents together with those drugs approved and tested through pre-clinical and clinical trials, to assess their roles in HMs. Moreover, epi-drugs that target HMT inhibitors and HDAC inhibitors should be tested in preclinical and clinical studies for the treatment of BC. Epi-drugs that target histone methylation (HMT inhibitors) and histone acetylation (HDAC inhibitors) have now entered clinical trials or are approved by the US Food and Drug Administration (FDA). Therefore, the review covers the difficulties in applying HM-targeting treatments in clinics and proposes feasible approaches for overcoming such difficulties and promoting their use in treating BC cases.
| S-EPMC9522521 | biostudies-literature
Project description:BackgroundAn integral component of cancer biology is the understanding of molecular properties uniquely distinguishing one cancer type from another. One class of such properties is histone post-translational modifications (PTMs). Many histone PTMs are linked to the same diverse nuclear functions implicated in cancer development, including transcriptional activation and epigenetic regulation, which are often indirectly assayed with standard genomic technologies. Thus, there is a need for a comprehensive and quantitative profiling of cancer lines focused on their chromatin modification states.ResultsTo complement genomic expression profiles of cancer lines, we report the proteomic classification of 24 different lines, the majority of which are cancer cells, by quantifying the abundances of a large panel of single and combinatorial histone H3 and H4 PTMs, and histone variants. Concurrent to the proteomic analysis, we performed transcriptomic analysis on histone modifying enzyme abundances as a proxy for quantifying their activity levels. While the transcriptomic and proteomic results were generally consistent in terms of predicting histone PTM abundance from enzyme abundances, several PTMs were regulated independently of the modifying enzyme expression. In addition, combinatorial PTMs containing H3K27 methylation were especially enriched in breast cell lines. Knockdown of the predominant H3K27 methyltransferase, enhancer of zeste 2 (EZH2), in a mouse mammary xenograft model significantly reduced tumor burden in these animals and demonstrated the predictive utility of proteomic techniques.ConclusionsOur proteomic and genomic characterizations of the histone modification states provide a resource for future investigations of the epigenetic and non-epigenetic determinants for classifying and analyzing cancer cells.
| S-EPMC3710262 | biostudies-literature
Project description:BackgroundHistone acetylation (HA) is an important and common epigenetic pathway, which could be hijacked by tumor cells during carcinogenesis and cancer progression. However, the important role of HA across human cancers remains elusive.MethodsIn this study, we performed a comprehensive analysis at multiple levels, aiming to systematically describe the molecular characteristics and clinical relevance of HA regulators in more than 10000 tumor samples representing 33 cancer types.ResultsWe found a highly heterogeneous genetic alteration landscape of HA regulators across different human cancer types. CNV alteration may be one of the major mechanisms leading to the expression perturbations in HA regulators. Furthermore, expression perturbations of HA regulators correlated with the activity of multiple hallmark oncogenic pathways. HA regulators were found to be potentially useful for the prognostic stratification of kidney renal clear cell carcinoma (KIRC). Additionally, we identified HDAC3 as a potential oncogene in lung adenocarcinoma (LUAD).ConclusionOverall, our results highlights the importance of HA regulators in cancer development, which may contribute to the development of clinical strategies for cancer treatment.
| S-EPMC10408135 | biostudies-literature
Project description:Recently, several non-classical functions of histone modification regulators (HMRs), independent of their known histone modification substrates and products, have been reported to be essential for specific cellular processes. However, there is no framework designed for identifying such functions systematically. Here, we develop ncHMR detector, the first computational framework to predict non-classical functions and cofactors of a given HMR, based on ChIP-seq data mining. We apply ncHMR detector in ChIP-seq data-rich cell types and predict non-classical functions of HMRs. Finally, we experimentally reveal that the predicted non-classical function of CBX7 is biologically significant for the maintenance of pluripotency.
| S-EPMC7038559 | biostudies-literature
Project description:Lysine methylation is one of the most prominent histone posttranslational modifications that regulate chromatin structure. Changes in histone lysine methylation status have been observed during cancer formation, which is thought to be a consequence of the dysregulation of histone lysine methyltransferases or the opposing demethylases. KDM4/JMJD2 proteins are demethylases that target histone H3 on lysines 9 and 36 and histone H1.4 on lysine 26. This protein family consists of three ~130-kDa proteins (KDM4A-C) and KDM4D/JMJD2D, which is half the size, lacks the double PHD and Tudor domains that are epigenome readers and present in the other KDM4 proteins, and has a different substrate specificity. Various studies have shown that KDM4A/JMJD2A, KDM4B/JMJD2B, and/or KDM4C/JMJD2C are overexpressed in breast, colorectal, lung, prostate, and other tumors and are required for efficient cancer cell growth. In part, this may be due to their ability to modulate transcription factors such as the androgen and estrogen receptor. Thus, KDM4 proteins present themselves as novel potential drug targets. Accordingly, multiple attempts are under way to develop KDM4 inhibitors, which could complement the existing arsenal of epigenetic drugs that are currently limited to DNA methyltransferases and histone deacetylases.
| S-EPMC3655154 | biostudies-literature
Project description:Histone methylation is an epigenetic modification regulated by histone methyltransferases, histone demethylases, and histone methylation reader proteins that play important roles in the pathogenic mechanism of cancers. However, the prognostic value of histone methylation in lung adenocarcinoma (LUAD) remains unknown. Here, we found that LUAD cases could be divided into 2 subtypes by the 144 histone methylation modification regulators (HMMRs), with a significant difference in OS time. Ninety-five of the HMMRs were identified as differentially expressed genes (DEGs) between normal and tumor samples, and 13 of them were further discovered to be survival-related genes (SRGs). By applying the least absolute shrinkage and selector operator (LASSO) Cox regression, we constructed an 8-gene-based risk signature according to the TCGA (training) cohort, and the risk score calculated by the signature was proven to be an independent factor in both the training and validation cohorts. We then discovered that the immune functions were generally impaired in the high-risk groups defined by the HMMR signature (especially for the DCs and immune check-point pathway). Functional analyses showed that the DEGs between the low- and high-risk groups were related to the cell cycle. The drug sensitivity analysis indicated that our risk model could predict the sensitivity of commonly used drugs. Moreover, according to the DEGs between the low- and high-risk groups, we discovered several new compounds that showed potential therapeutic value for high-risk LUAD patients. In conclusion, our study demonstrated that HMMRs were promising predictors for the prognoses and drug therapeutic effects for LUAD patients.
| S-EPMC9574078 | biostudies-literature
Project description:The 3'-end processing machinery for metazoan replication-dependent histone precursor messenger RNAs (pre-mRNAs) contains the U7 small nuclear ribonucleoprotein and shares the key cleavage module with the canonical cleavage and polyadenylation machinery. We reconstituted an active human histone pre-mRNA processing machinery using 13 recombinant proteins and two RNAs and determined its structure by cryo-electron microscopy. The overall structure is highly asymmetrical and resembles an amphora with one long handle. We captured the pre-mRNA in the active site of the endonuclease, the 73-kilodalton subunit of the cleavage and polyadenylation specificity factor, poised for cleavage. The endonuclease and the entire cleavage module undergo extensive rearrangements for activation, triggered through the recognition of the duplex between the authentic pre-mRNA and U7 small nuclear RNA (snRNA). Our study also has notable implications for understanding canonical and snRNA 3'-end processing.
| S-EPMC7008720 | biostudies-literature
Project description:X inactivation is associated with chromosome-wide establishment of inactive chromatin. Although this is classically regarded as facultative heterochromatin that is uniform in nature, the exact distribution of associated epigenetic marks is not well defined. Here we have analysed histone modifications in human somatic cells within two selected regions of the X chromosome. Intergenic, coding and promoter regions are segregated into differentially marked chromatin. H3K27me3 is most prominent in intergenic and silenced coding regions, but is associated with some active coding regions as well. Histone H3/H4 acetylation and H3K4me3 are locally enriched at promoter regions but do not necessarily mark continuing transcription. Remarkably, H3K9me3 is predominant in coding regions of active genes, a phenomenon that is not restricted to the X chromosome. These results argue against the exclusiveness of individual marks to heterochromatin or euchromatin, but rather suggest that composite patterns of interdependent or mutually exclusive modifications together signal the gene expression status.
| S-EPMC1479594 | biostudies-literature
Project description:PurposeAlternations to the paternal epigenome, specifically the components of sperm chromatin, can lead to infertility in humans and potentially transmit aberrant information to the embryo. One key component of sperm chromatin is the post-translational modification of histones (PTMs). We previously identified a comprehensive profile of histone PTMs in normozoospermic sperm; however, only specific histone PTMs have been identified in abnormal sperm by antibody-based approaches and comprehensive changes to histone PTM profiles remain unknown. Here, we investigate if sperm with abnormalities of total motility, progressive motility, and morphology have altered histone PTM profiles compared to normozoospermic sperm samples.MethodsDiscarded semen samples from 31 men with normal or abnormal semen parameters were analyzed for relative abundance of PTMs on histone H3 and H4 by "bottom-up" nano-liquid chromatography-tandem mass spectrometry.ResultsAsthenoteratozoospermic samples (abnormal motility, forward progression, and morphology, n = 6) displayed overall decreased H4 acetylation (p = 0.001) as well as alterations in H4K20 (p = 0.003) and H3K9 methylation (p < 0.04) when compared to normozoospermic samples (n = 8). Asthenozoospermic samples (abnormal motility and progression, n = 5) also demonstrated decreased H4 acetylation (p = 0.04) and altered H4K20 (p = 0.005) and H3K9 methylation (p < 0.04). Samples with isolated abnormal progression (n = 6) primarily demonstrated decreased acetylation on H4 (p < 0.02), and teratozoospermic samples (n = 6) appeared similar to normozoospermic samples (n = 8).ConclusionSperm samples with combined and isolated abnormalities of total motility, progressive motility, and morphology display distinct and altered histone PTM signatures compared to normozoospermic sperm. This provides evidence that alterations in histone PTMs may be important for normal sperm function and fertility.
| S-EPMC6420512 | biostudies-literature