Genome-Wide Investigation of Oxidosqualene Cyclase Genes Deciphers the Genetic Basis of Triterpene Biosynthesis in Tea Plants.

Triterpenoids from Camellia species comprise a diverse class of bioactive compounds with great therapeutic potential. However, triterpene biosynthesis in tea plants (Camellia sinensis) remains elusive. Here, we identified eight putative 2,3-oxidosqualene cyclase (OSC) genes (CsOSC1-8) from the tea genome and characterized the functions of five through heterologous expression in yeast and tobacco and transient overexpression in tea plants. CsOSC1 was found to be a ß-amyrin synthase, whereas CsOSC4, 5, and 6 exhibited multifunctional α-amyrin synthase activity. Molecular docking and site-directed mutagenesis showed that the CsOSC6M259T/W260L double mutant yielded >40% lupeol, while the CsOSC1 W259L single mutant alone was sufficient for lupeol production. The V732F mutation in CsOSC5 altered product formation from friedelin to taraxasterol and ψ-taraxasterol. The L254 M mutation in the cycloartenol synthase CsOSC8 enhanced the catalytic activity. Our findings shed light on the molecular basis governing triterpene diversity in tea plants and offer potential avenues for OSC engineering.

OXIDOSQUALENE CYCLASE 1 and 2 influence triterpene biosynthesis and defense in Nicotiana attenuata.

Triterpenes are a class of bioactive compounds with diverse biological functions, playing pivotal roles in plant defense against biotic stressors. Oxidosqualene cyclases (OSCs) serve as gatekeepers in the biosynthesis of triterpenes. In this study, we utilized a Nicotiana benthamiana heterologous expression system to characterize NaOSC1 from Nicotiana attenuata as a multifunctional enzyme capable of synthesizing lupeol, dammarenediol II, 3-alpha,20-lupanediol, and 7 other triterpene scaffolds. We also demonstrated that NaOSC2 is, in contrast, a selective enzyme, producing only the ß-amyrin scaffold. Through virus-induced gene silencing and in vitro toxicity assays, we elucidated the roles of NaOSC1 and NaOSC2 in the defense of N. attenuata against Manduca sexta larvae. Metabolomic and feature-based molecular network analyses of leaves with silenced NaOSC1 and NaOSC2 unveiled 3 potential triterpene glycoside metabolite clusters. Interestingly, features identified as triterpenes within these clusters displayed a significant negative correlation with larval mass. Our study highlights the pivotal roles of NaOSC1 and NaOSC2 from N. attenuata in the initial steps of triterpene biosynthesis, subsequently influencing defense against M. sexta through the modulation of downstream triterpene glycoside compounds.

Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair.

G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B12-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the complex assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood. Herein, we report the crystal structure of the human MMUT-MMAA nano-assembly, which reveals a dramatic 180° rotation of the B12 domain, exposing it to solvent. The complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation. The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the MMAA-MMUT interfaces we identify here.

The 2-methylpropene degradation pathway in Mycobacteriaceae family strains.

Mycolicibacterium gadium IBE100 and Mycobacterium paragordonae IBE200 are aerobic, chemoorganoheterotrophic bacteria isolated from activated sludge from a wastewater treatment plant. They use 2-methylpropene (isobutene, 2-MP) as the sole source of carbon and energy. Here, we postulate a degradation pathway of 2-methylpropene derived from whole genome sequencing, differential expression analysis and peptide-mass fingerprinting. Key genes identified are coding for a 4-component soluble diiron monooxygenase with epoxidase activity, an epoxide hydrolase, and a 2-hydroxyisobutyryl-CoA mutase. In both strains, involved genes are arranged in clusters of 61.0 and 58.5 kbp, respectively, which also contain the genes coding for parts of the aerobic pathway of adenosylcobalamin synthesis. This vitamin is essential for the carbon rearrangement reaction catalysed by the mutase. These findings provide data for the identification of potential 2-methylpropene degraders.

Aging-induced pseudouridine synthase 10 impairs hematopoietic stem cells.

Aged hematopoietic stem cells (HSC) exhibit compromised reconstitution capacity and differentiation-bias towards myeloid lineage, however, the molecular mechanism behind it remains not fully understood. In this study, we observed that the expression of pseudouridine (Ψ) synthase 10 is increased in aged hematopoietic stem and progenitor cells (HSPC) and enforced protein of Ψ synthase 10 (PUS10) recapitulates the phenotype of aged HSC, which is not achieved by its Ψ synthase activity. Consistently, we observed no difference of transcribed RNA pseudouridylation profile between young and aged HSPC. No significant alteration of hematopoietic homeostasis and HSC function is observed in young Pus10-/- mice, while aged Pus10-/- mice exhibit mild alteration of hematopoietic homeostasis and HSC function. Moreover, we observed that PUS10 is ubiquitinated by E3 ubiquitin ligase CRL4DCAF1 complex and the increase of PUS10 in aged HSPC is due to aging-declined CRL4DCAF1- mediated ubiquitination degradation signaling. Taken together, this study for the first time evaluated the role of PUS10 in HSC aging and function, and provided a novel insight into HSC rejuvenation and its clinical application.

The Identification of SQS/SQE/OSC Gene Families in Regulating the Biosynthesis of Triterpenes in Potentilla anserina.

The tuberous roots of Potentilla anserina (Pan) are an edible and medicinal resource in Qinghai-Tibetan Plateau, China. The triterpenoids from tuberous roots have shown promising anti-cancer, hepatoprotective, and anti-inflammatory properties. In this study, we carried out phylogenetic analysis of squalene synthases (SQSs), squalene epoxidases (SQEs), and oxidosqualene cyclases (OSCs) in the pathway of triterpenes. In total, 6, 26, and 20 genes of SQSs, SQEs, and OSCs were retrieved from the genome of Pan, respectively. Moreover, 6 SQSs and 25 SQEs genes expressed in two sub-genomes (A and B) of Pan. SQSs were not expanded after whole-genome duplication (WGD), and the duplicated genes were detected in SQEs. Twenty OSCs were divided into two clades of cycloartenol synthases (CASs) and ß-amyrin synthases (ß-ASs) by a phylogenetic tree, characterized with gene duplication and evolutionary divergence. We speculated that ß-ASs and CASs may participate in triterpenes synthesis. The data presented act as valuable references for future studies on the triterpene synthetic pathway of Pan.

PUS7 promotes the proliferation of colorectal cancer cells by directly stabilizing SIRT1 to activate the Wnt/ß-catenin pathway.

Pseudouridine synthase 7 (PUS7) may play key roles in cancer development. However, few studies have been conducted in this area. In the present study, we explored the function and potential mechanisms of PUS7 in colorectal cancer (CRC) progression. We found that PUS7 had higher expression in CRC tissues and cell lines. Clinically, high expression of PUS7 was associated with an unfavorable prognosis for CRC patients. Functionally, knockdown of PUS7 suppressed the proliferation of CRC cells in vitro and inhibited tumorigenicity in vivo. Mechanistically, RNA sequencing and coimmunoprecipitation (Co-IP) indicated that PUS7 exhibited oncogenic functions through the interaction of Sirtuin 1 (SIRT1) and activated the Wnt/ß-catenin signaling pathway. Thus, our findings suggest that PUS7 promotes the proliferation of CRC cells by directly stabilizing SIRT1 to activate the Wnt/ß-catenin pathway.

A conserved mechanism affecting hydride shifting and deprotonation in the synthesis of hopane triterpenes as compositions of wax in oat.

Triterpenoids are biologically active metabolites synthesized from a common linear precursor catalyzed by 2,3-oxidosqualene cyclases (OSCs) to form diverse triterpenoid skeletons. OSCs corresponding to many discovered triterpene alcohols in nature have not been functionally and mechanistically characterized due to the diversity of chemical structures and complexity of the cyclization mechanism. We carried out a genome-wide investigation of OSCs from Avena strigosa and discovered two triterpene synthases, namely, AsHS1 and AsHS2, using a Nicotiana benthamiana expression system. These synthases produce hopenol B and hop-17(21)-en-3ß-ol, which are components of surface wax in oat panicles and sheathes, respectively. We demonstrated that substitutions of two to three amino acid residues in AsHS1 with corresponding residues from AsHS2 allowed it to be completely converted into a hop-17(21)-en-3ß-ol synthase. AsHS2 mutants with a substitution at site 410 could synthesize hopenol B alone or mixed with a side product isomotiol. The combined quantum mechanics and molecular mechanics calculation demonstrated that the side chain size of the residue at site 410 regulated the relative orientations between the hopyl C22 cation and Phe257, leading to a difference in deprotonation positions through providing or not providing cation­π interaction between the aromatic ring of F257 and the carbocation intermediate. A similar mechanism could be applied to a hopenol B synthase from a dicotyledonous plant Aquilegia. This study provided mechanistic insight into triterpenoid synthesis and discovered key amino acid residues acting on hydride transfer and a deprotonation site to differentiate between hopane-type scaffolds in diverse plant species.

Metabolic stimulation-elicited transcriptional responses and biosynthesis of acylated triterpenoids precursors in the medicinal plant Helicteres angustifolia.

BACKGROUND: Helicteres angustifolia has long been used in Chinese traditional medicine. It has multiple pharmacological benefits, including anti-inflammatory, anti-viral and anti-tumor effects. Its main active chemicals include betulinic acid, oleanolic acid, helicteric acid, helicterilic acid, and other triterpenoid saponins. It is worth noting that some acylated triterpenoids, such as helicteric acid and helicterilic acid, are characteristic components of Helicteres and are relatively rare among other plants. However, reliance on natural plants as the only sources of these is not enough to meet the market requirement. Therefore, the engineering of its metabolic pathway is of high research value for enhancing the production of secondary metabolites. Unfortunately, there are few studies on the biosynthetic pathways of triterpenoids in H. angustifolia, hindering its further investigation. RESULTS: Here, the RNAs of different groups treated by metabolic stimulation were sequenced with an Illumina high-throughput sequencing platform, resulting in 121 gigabases of data. A total of 424,824 unigenes were obtained after the trimming and assembly of the raw data, and 22,430 unigenes were determined to be differentially expressed. In addition, three oxidosqualene cyclases (OSCs) and four Cytochrome P450 (CYP450s) were screened, of which one OSC (HaOSC1) and one CYP450 (HaCYPi3) achieved functional verification, suggesting that they could catalyze the production of lupeol and oleanolic acid, respectively. CONCLUSION: In general, the transcriptomic data of H. angustifolia was first reported and analyzed to study functional genes. Three OSCs, four CYP450s and three acyltransferases were screened out as candidate genes to perform further functional verification, which demonstrated that HaOSC1 and HaCYPi3 encode for lupeol synthase and ß-amyrin oxidase, which produce corresponding products of lupeol and oleanolic acid, respectively. Their successful identification revealed pivotal steps in the biosynthesis of acylated triterpenoids precursors, which laid a foundation for further study on acylated triterpenoids. Overall, these results shed light on the regulation of acylated triterpenoids biosynthesis.

Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing.

Pseudouridine is a modified nucleotide that is prevalent in human mRNAs and is dynamically regulated. Here, we investigate when in their life cycle mRNAs become pseudouridylated to illuminate the potential regulatory functions of endogenous mRNA pseudouridylation. Using single-nucleotide resolution pseudouridine profiling on chromatin-associated RNA from human cells, we identified pseudouridines in nascent pre-mRNA at locations associated with alternatively spliced regions, enriched near splice sites, and overlapping hundreds of binding sites for RNA-binding proteins. In vitro splicing assays establish a direct effect of individual endogenous pre-mRNA pseudouridines on splicing efficiency. We validate hundreds of pre-mRNA sites as direct targets of distinct pseudouridine synthases and show that PUS1, PUS7, and RPUSD4-three pre-mRNA-modifying pseudouridine synthases with tissue-specific expression-control widespread changes in alternative pre-mRNA splicing and 3' end processing. Our results establish a vast potential for cotranscriptional pre-mRNA pseudouridylation to regulate human gene expression via alternative pre-mRNA processing.

Expression Analysis of Lanosterol Synthase Gene in Dynamic Accumulation of Triterpenoids in Sanghuangporus baumii.

BACKGROUND: Sanghuangporus baumii is a traditional Chinese medicine with anti- cancer, anti-tumor, and anti-inflammatory effects. Triterpenoids are one of the main medicinal ingredients found in S. baumii. However, the dynamic changes of triterpenoids content and its molecular regulation mechanism are still unclear. OBJECTIVE: Some studies have shown that Lanosterol synthase ( LS) is a key enzyme involved in the mevalonate pathway (MVA pathway) to produce lanosterol, which is a precursor for synthesizing S. baumii triterpenoids. Therefore, the study of LS gene and expression characteristics can provide clues for the further study of triterpenoids synthesis. METHODS: The PCR, RACE PCR, RT-PCR, homologous recombination and prokaryotic expression technology were used to research the gene characteristic and dynamic changes of LS transcription level. RESULTS: The S. baumii LS sequence included a 5'-untranslated region (129 bp), a 3'-untranslated region (87 bp), and an open reading frame (2,229 bp) encoding 734 amino acids. The S. baumii LS protein was expressed in E. coli BL21 (DE3). The transcription start site of the S. baumii LS promoter sequence ranged from 1 740 bp to 1790 bp. The LS promoter contained 12 CAAT-boxes, 5 ABREs, 6 G-Boxes, 6 CGTCA-motifs, and so on. The LS transcription levels were the highest on day 11 in mycelia (1.6-fold), and the triterpenoids content also gradually increased. The transcription levels began to decrease on day 13, but the triterpenoids content still increased. CONCLUSION: The S. baumii LS was cloned and characterized to help to understand the mechanism of triterpenoids synthesis. In addition, we studied the relationship between LS transcription level and triterpenoid dynamic accumulation, and we found that they had a certain correlation.

Potential roles for pattern molecule of PAMP-triggered immunity in improving crop cold tolerance.

KEY MESSAGE: The application of flagellin 22 (flg22), the most widely studied PAMP, enhance crop cold tolerance. ICE1-CBF pathway and SA signaling is involved in the alleviation of cold injury by flg22 treatment. Pathogen infection cross-activates cold response and increase cold tolerance of host plants. However, it is not possible to use the infection to increase cold tolerance of field plants. Here flagellin 22 (flg22), the most widely studied PAMP (pathogen-associated molecular patterns), was used to mimic the pathogen infection to cross-activate cold response. Flg22 treatment alleviated the injury caused by freezing in Arabidopsis, oilseed and tobacco. In Arabidopsis, flg22 activated the expression of immunity and cold-related genes. Moreover, the flg22 induced alleviation of cold injury was lost in NahG transgenic line (SA-deficient), sid2-2 and npr1-1 mutant plants, and flg22-induced expression of cold tolerance-related genes, which indicating that salicylic acid signaling pathway is required for the alleviation of cold injury by flg22 treatment. In short flg22 application can be used to enhance cold tolerance in field via a salicylic acid-depended pathway.

PUS7: a targetable epitranscriptomic regulator of glioblastoma growth.

Pseudouridine is the most abundant yet unexplored RNA modification in glioblastoma. Cui and coworkers find that PUS7, a pseudouridine depositing enzyme, promotes tumor growth and can be targeted by small molecule inhibitors. Mechanistically, PUS7 modifies tRNAs, reduces TYK2 translation, and downregulates a proliferation-restricting interferon-STAT1 pathway in glioblastoma.

Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance.

Dyskerin and its homologs are ancient and conserved enzymes that catalyze the most common post-transcriptional modification found in cells, pseudouridylation. The resulting pseudouridines provide stability to RNA molecules and regulate ribosome biogenesis and splicing events. Dyskerin does not act independently-it is the core component of a protein heterotetramer, which associates with RNAs that contain the H/ACA motif. The variety of H/ACA RNAs that guide the function of this ribonucleoprotein (RNP) complex highlights the diversity of cellular processes in which dyskerin participates. When associated with small nucleolar (sno) RNAs, it regulates ribosomal (r) RNAs and ribosome biogenesis. By interacting with small Cajal body (sca) RNAs, it targets small nuclear (sn) RNAs to regulate pre-mRNA splicing. As a component of the telomerase holoenzyme, dyskerin binds to the telomerase RNA to modulate telomere maintenance. In a disease context, dyskerin malfunction can result in multiple detrimental phenotypes. Mutations in DKC1, the gene that encodes dyskerin, cause the premature aging syndrome X-linked dyskeratosis congenita (X-DC), a still incurable disorder that typically leads to bone marrow failure. In this review, we present the classical and most recent findings on this essential protein, discussing the evolutionary, structural, and functional aspects of dyskerin and the H/ACA RNP. The latest research underscores the role that dyskerin plays in the regulation of gene expression, translation efficiency, and telomere maintenance, along with the impacts that defective dyskerin has on aging, cell proliferation, haematopoietic potential, and cancer.

De Novo Biosynthesis of the Anticancer Compound Euphol in Saccharomyces cerevisiae.

Euphol is a euphane-type tetracyclic triterpene which is primarily found in the Euphorbia genus. Euphol has been renowned because of its great potential as a promising anticancer drug. Surprisingly, despite its diverse antitumor effects, the respective gene for euphol biosynthesis had not been identified until this study. In our experiments with Euphorbia tirucalli, euphol was detected predominantly in latex, the element that is often used for cancer treatments in Brazil. Two latex-specifically expressed oxidosqualene cyclases (OSCs) from E. tirucalli, designated as EtOSC5 and EtOSC6, were functionally characterized by expression in a lanosterol synthase knockout yeast strain GIL77. EtOSC5 produces euphol and its 20S-isomer tirucallol as two of the major products, while EtOSC6 produces taraxasterol and ß-amyrin as the major products. These four compounds were also detected as the major triterpenes in the E. tirucalli latex, suggesting that EtOSC5 and EtOSC6 are the primary catalysts for the formation of E. tirucalli latex triterpene alcohols. Based on a model structure of EtOSC5 followed with site-mutagenesis experiments, the mechanism for the EtOSC5 activity was proposed. By applying state-of-the-art engineering techniques, the expression of EtOSC5 together with three other known precursor genes were chromosomally integrated into Saccharomyces cerevisiae. The resulting engineered yeast strain YS5E-1 produced 1.84 ± 0.17 mg/L of euphol in shake flasks.

A novel circular RNA, circPUS7 promotes cadmium-induced transformation of human bronchial epithelial cells by regulating Kirsten rat sarcoma viral oncogene homolog expression via sponging miR-770.

Cadmium is a human carcinogen, which induces cancers by mechanisms that are not fully understood. Induction of oxidative stress, apoptosis resistance, genotoxic effects, and epigenetic modulations have been indicated to regulate cadmium-induced carcinogenesis. Circular RNAs are epigenetic regulators that have been recognized to play essential roles in carcinogenesis. Yet, the involvement of circular RNAs in cadmium carcinogenesis remains unclear. In this study, a novel circular RNA, circPUS7, was identified and described for the first time. CircPUS7 was significantly upregulated at week 12, 16, and 20 during the cadmium-induced transformation of human bronchial epithelial BEAS-2B cells. Knockdown of circPUS7 in cadmium-transformed BEAS-2B (T-BEAS-2B) cells significantly attenuated transformation markers including cell proliferation, migration, invasion, and anchorage-independent growth. Moreover, circPUS7 promoted malignant phenotypes by competitively binding with miR-770. Overexpression of miR-770 significantly inhibited the transformation properties of T-BEAS-2B cells while inhibition of miR-770 potently reversed the inhibitory effects of circPUS7 knockdown in proliferation, migration, invasion, and anchorage-independent growth of the T-BEAS-2B cells. Kirsten rat sarcoma viral oncogene homolog (KRAS), which was increased synchronically with circPUS7 during cadmium-induced cell transformation, was regulated by circPUS7 through sponging miR-770. In summary, our findings demonstrate that circPUS7 promotes cadmium-induced cell transformation through sponging miR-770 to regulate KRAS expression, providing a new perspective with the involvement of circular RNAs to further understand the mechanisms of cadmium carcinogenesis.

Novel mutations in Chinese hypotrichosis simplex patients associated with LSS gene.

Hypotrichosis simplex (HS) is a rare form of hereditary alopecia caused by a variety of genetic mutations. Currently, only four studies regarding LSS-related HS have been reported. In this study, we try to make a definite diagnosis in two unrelated Chinese families with three pediatric patients clinically suspected of HS. Whole-exome sequencing (WES) was performed for these two families to reveal the pathogenic mutation. WES revealed two different compound heterozygous mutations in LSS in two probands that confirmed the diagnosis, including three novel mutations. In this paper, we describe a new accompanying phenotype of teeth dysplasia in a HS patient. Moreover, we provide a review of all reported LSS mutation-related patients and infer some potential genotype-phenotype correlations for the first time.

The tRNA pseudouridine synthase TruB1 regulates the maturation of let-7 miRNA.

Let-7 is an evolutionary conserved microRNA that mediates post-transcriptional gene silencing to regulate a wide range of biological processes, including development, differentiation, and tumor suppression. Let-7 biogenesis is tightly regulated by several RNA-binding proteins, including Lin28A/B, which represses let-7 maturation. To identify new regulators of let-7, we devised a cell-based functional screen of RNA-binding proteins using a let-7 sensor luciferase reporter and identified the tRNA pseudouridine synthase, TruB1. TruB1 enhanced maturation specifically of let-7 family members. Rather than inducing pseudouridylation of the miRNAs, high-throughput sequencing crosslinking immunoprecipitation (HITS-CLIP) and biochemical analyses revealed direct binding between endogenous TruB1 and the stem-loop structure of pri-let-7, which also binds Lin28A/B. TruB1 selectively enhanced the interaction between pri-let-7 and the microprocessor DGCR8, which mediates miRNA maturation. Finally, TruB1 suppressed cell proliferation, which was mediated in part by let-7. Altogether, we reveal an unexpected function for TruB1 in promoting let-7 maturation.

Dual-Localized WHIRLY1 Affects Salicylic Acid Biosynthesis via Coordination of ISOCHORISMATE SYNTHASE1, PHENYLALANINE AMMONIA LYASE1, and S-ADENOSYL-L-METHIONINE-DEPENDENT METHYLTRANSFERASE1.

Salicylic acid (SA) influences developmental senescence and is spatiotemporally controlled by various mechanisms, including biosynthesis, transport, and conjugate formation. Altered localization of Arabidopsis WHIRLY1 (WHY1), a repressor of leaf natural senescence, in the nucleus or chloroplast causes a perturbation in SA homeostasis, resulting in adverse plant senescence phenotypes. WHY1 loss-of-function mutation resulted in SA peaking 5 d earlier compared to wild-type plants, which accumulated SA at 42 d after germination. SA accumulation coincided with an early leaf-senescence phenotype, which could be prevented by ectopic expression of the nuclear WHY1 isoform (nWHY1). However, expressing the plastid WHY1 isoform (pWHY1) greatly enhanced cellular SA levels. Transcriptome analysis in the WHY1 loss-of-function mutant background following expression of either pWHY1 or nWHY1 indicated that hormone metabolism-related genes were most significantly altered. The pWHY1 isoform predominantly affected stress-related gene expression, whereas nWHY1 primarily controlled developmental gene expression. Chromatin immunoprecipitation-quantitative PCR assays indicated that nWHY1 directly binds to the promoter region of isochorismate synthase1 (ICS1), thus activating its expression at later developmental stages, but that it indirectly activates S-adenosyl- l -Met-dependent methyltransferase1 (BSMT1) expression via ethylene response factor 109 (ERF109). Moreover, nWHY1 repressed expression of Phe ammonia lyase-encoding gene (PAL1) via R2R3-MYB member 15 (MYB15) during the early stages of development. Interestingly, rising SA levels exerted a feedback effect by inducing nWHY1 modification and pWHY1 accumulation. Thus, the alteration of WHY1 organelle isoforms and the feedback of SA are involved in a circularly integrated regulatory network during developmental or stress-induced senescence in Arabidopsis.

Epitranscriptomics in Normal and Malignant Hematopoiesis.

Epitranscriptomics analyze the biochemical modifications borne by RNA and their downstream influence. From this point of view, epitranscriptomics represent a new layer for the control of genetic information and can affect a variety of molecular processes including the cell cycle and the differentiation. In physiological conditions, hematopoiesis is a tightly regulated process that produces differentiated blood cells starting from hematopoietic stem cells. Alteration of this process can occur at different levels in the pathway that leads from the genetic information to the phenotypic manifestation producing malignant hematopoiesis. This review focuses on the role of epitranscriptomic events that are known to be implicated in normal and malignant hematopoiesis, opening a new pathophysiological and therapeutic scenario. Moreover, an evolutionary vision of this mechanism will be provided.