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| Open AccessMegakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels
Circulating cell-free DNA (cfDNA) has diagnostic potential, and clarifying its origins will aid in the minimally-invasive detection and monitoring of disease. Here, authors find that physiologically, megakaryocytes are major sources of cfDNA, while erythroblasts also release small amounts of cfDNA.
- Joshua Moss
- , Roni Ben-Ami
- & Yuval Dor
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Article
| Open AccessRelease of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation
Methyl-phos switches on histones have been shown to regulate reader protein displacement from chromatin. However, in this study the authors find that H3T3ph is not required to remove transcription factors from H3K4me3 in mitosis. This might help to preserve promoter properties during cell division.
- Rebecca J. Harris
- , Maninder Heer
- & Jonathan M. G. Higgins
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| Open AccessThe transcriptional legacy of developmental stochasticity
Minor perturbations or noise can significantly impact development but are difficult to assess. Here, the authors detail allelic expression imbalance across the development of nine-banded armadillos that indicate stochastic developmental canalization.
- Sara Ballouz
- , Risa Karakida Kawaguchi
- & Jesse Gillis
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Article
| Open AccessFunctional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells
RYBP and YAF2 are a pair of paralog subunits of variant PRC1. Here, authors show that RYBP decrease but YAF2 increase during mESC neural differentiation, and that they are not redundant but function differentially in regulating this differentiation.
- Yanjiang Liu
- , Gongcheng Hu
- & Hongjie Yao
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Article
| Open AccessHomodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
| Open AccessThe chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts
Epigenetic alterations are frequent in human malignancies and have been shown to threaten genome integrity. Here the authors show that a chromatin network prevents R-loops and transcription-replication conflicts from genomic instability and mutagenic signatures frequently associated with cancer.
- Aleix Bayona-Feliu
- , Emilia Herrera-Moyano
- & Andrés Aguilera
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Article
| Open AccessDNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
Epigenetic therapies are known to synergize with immunotherapies through the de-repression of endogenous retroviral element (ERV)-encoded promoters. Here the authors identify treatment-induced neoantigens and validate their ability to induce T cell response and anti-tumor effects in vitro and in patient samples.
- Ashish Goyal
- , Jens Bauer
- & Christoph Plass
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Article
| Open AccessPaternal DNA methylation is remodeled to maternal levels in rice zygote
Liu et al. show that zygotic remodelling of paternal DNA methylation is matched to maternal levels in hybrids and that parental-specific epigenomes are re-established during embryogenesis, highlighting genetic control of epigenetic inheritance.
- Qian Liu
- , Xuan Ma
- & Dao-Xiu Zhou
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Article
| Open AccessTET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression
TET2 and GATA2 are two frequently co-mutated genes in CEBPA double mutated acute myeloid leukemia (AML). Here the authors show that the underlying mechanism for this cooccurrence is for TET2 loss-of-function mutation to counteract the increase in GATA2 expression, which is disadvantageous to these type of AML cells.
- Elizabeth Heyes
- , Anna S. Wilhelmson
- & Bo T. Porse
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Article
| Open AccessReactivation of a somatic errantivirus and germline invasion in Drosophila ovaries
Yoth et al. report that some mobile retrovirus-like genetic elements, errantiviruses, pose a threat to genome integrity when reactivated in somatic gonadal tissue, showing that they can infect the oocyte and transpose into the germline genome.
- Marianne Yoth
- , Stéphanie Maupetit-Méhouas
- & Emilie Brasset
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Article
| Open AccessSMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
Here the authors reveal that a neomorphic mutation in chromatin protein SMCHD1 enhances SMCHD1-mediated gene silencing, including at the FSHD disease-relevant locus, while depleting SMCHD1-mediated chromatin interactions, suggesting these SMCHD1 functions are unlinked.
- Andres Tapia del Fierro
- , Bianca den Hamer
- & Marnie E. Blewitt
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Article
| Open AccessYAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis
Small cell lung cancers (SCLC) have often inactivating mutations in RB1. In this study, the authors demonstrate that RB1 loss mediates low expression of YAP1 in SCLC tumors ultimately promoting metastasis and they propose to use benzamide family HDAC inhibitors to induce YAP1 expression for prevention of metastases.
- Zhengming Wu
- , Junhui Su
- & Kun-Liang Guan
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Article
| Open AccessDNA methylation profiling to determine the primary sites of metastatic cancers using formalin-fixed paraffin-embedded tissues
Molecular tests that can determine the tissue of origin of cancers of unknown primary (CUP) are still needed. Here, the authors develop a DNA methylation profiling assay and a machine learning classifier to predict the origin of metastatic tumours in CUP patients using formalin-fixed, paraffin embedded samples.
- Shirong Zhang
- , Shutao He
- & Hongcang Gu
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Article
| Open AccessGerminal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells
Loss-of-function mutations in the chromatin remodelling protein HELLS result in humoral immune deficiency. Authors here show in a conditional knockout mouse model that HELLS controls the kinetics of a typical germinal center response by DNA methylation, its absence leading to either the appearance of memory-B cell markers or a metabolic state change typical of plasma cells.
- Clara Cousu
- , Eléonore Mulot
- & Sébastien Storck
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| Open AccessEpigenome-wide association analysis of infant bronchiolitis severity: a multicenter prospective cohort study
DNA methylation patterns that are associated with disease can reveal genes involved in disease etiology. Here, the authors identify blood DNA methylation signatures that are associated with bronchiolitis severity and play important roles in tissues, cells, and pathways.
- Zhaozhong Zhu
- , Yijun Li
- & Kohei Hasegawa
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Article
| Open AccessA super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer
The epigenetic mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) are not fully elucidated. Here, the authors reveal a druggable super-enhancer-mediated RNA-binding protein cascade that supports PDAC growth through enhanced mRNA translation.
- Corina E. Antal
- , Tae Gyu Oh
- & Ronald M. Evans
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| Open AccessEpigenetic inheritance is unfaithful at intermediately methylated CpG sites
Here the authors question the prevalent view of DNA methylation as a stably inherited epigenetic mark, revealing that the existing model does not apply when considering genomic loci that are intermediately methylated.
- Amir D. Hay
- , Noah J. Kessler
- & Anne C. Ferguson-Smith
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Article
| Open AccessDownregulation of transposable elements extends lifespan in Caenorhabditis elegans
Transposable elements in somatic cells become increasingly mobile during ageing. Here, the authors show that in the nematode Caenorhabditis elegans, downregulation of transposable elements extends lifespan, and that their increases with age are coupled with progressively growing N6-adenine methylation in these genetic loci.
- Ádám Sturm
- , Éva Saskői
- & Tibor Vellai
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| Open AccessExtrachromosomal circular DNA and structural variants highlight genome instability in Arabidopsis epigenetic mutants
Epigenetic control of extrachromosomal circular DNA (eccDNA) compartment and the relationships between eccDNA and plant genome stability remain unclear. Here, the authors investigate eccDNA and structural variations in Arabidopsis epigenetic mutants to reveal the eccDNA repertoire and its impact on genome stability.
- Panpan Zhang
- , Assane Mbodj
- & Marie Mirouze
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| Open AccessDNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood
Here the authors identify an association between methylation of the suppressor of cytokine signaling 3 (SOCS3) and height in children from India, Gambia and the UK.
- Prachand Issarapu
- , Manisha Arumalla
- & Stephen Owens
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Article
| Open AccessMLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.
- Nicholas T. Crump
- , Alastair L. Smith
- & Thomas A. Milne
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| Open AccessCircadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons
Injured peripheral neurons activate pro-growth gene programs, yet the mechanisms remain unclear. Here, the authors show that disruption of circadian clock factor Bmal1 accelerates axon regeneration through augmented epigenetic responses after injury.
- Dalia Halawani
- , Yiqun Wang
- & Hongyan Zou
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Article
| Open AccessA qPCR technology for direct quantification of methylation in untreated DNA
Analysis of DNA methylation usually requires a chemical or an enzymatic pretreatment step. Here, the authors report a PCR-based technology for the detection of DNA methylation in untreated DNA, and present analytical and clinical results from methylation analysis of the MGMT promoter.
- Kamilla Kolding Bendixen
- , Maria Mindegaard
- & Rasmus Koefoed Petersen
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| Open AccessBile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides
Wang et al. clarify the regional heterogeneity of intestinal AMPs and identify that chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs.
- Yue Wang
- , Yanbo Yu
- & Yanqing Li
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Article
| Open AccessDemethylase-independent roles of LSD1 in regulating enhancers and cell fate transition
Here the authors describe the catalytic-independent role of LSD1 in regulating gene expression and cellular differentiation and a mechanism by which the LSD1-P300 axis contributes to the regulation of enhancers and cell fate.
- Cheng Zeng
- , Jiwei Chen
- & Kaixiang Cao
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| Open AccessMolecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome
The mechanism by which the chromatinized HBV genome is transcribed remains poorly understood. In this study, Liu et al. demonstrate how HBx exploits Spindlin1, a histone methylation reader, to overcome heterochromatin barriers and enhance HBV transcription from the cccDNA minichromosome.
- Wei Liu
- , Qiyan Yao
- & Haitao Li
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| Open AccessThe MOM1 complex recruits the RdDM machinery via MORC6 to establish de novo DNA methylation
It has generally been considered that MOM1, a transcriptional silencing factor in plants, mediated silencing is independent or downstream of DNA methylation. Here, the authors show that MOM1 complex recruits the RdDM machinery through MORC6 to establish de novo DNA methylation in Arabidopsis.
- Zheng Li
- , Ming Wang
- & Steven E. Jacobsen
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Article
| Open AccessHistone H1 facilitates restoration of H3K27me3 during DNA replication by chromatin compaction
Liu et al. investigated the dynamic re-establishment of H3K27me3 on nascent DNA during DNA replication. They found H1-mediated chromatin compaction facilitates the propagation and restoration of H3K27me3 after DNA replication.
- Cuifang Liu
- , Juan Yu
- & Guohong Li
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Article
| Open AccessTET2 and TET3 loss disrupts small intestine differentiation and homeostasis
DNA demethylation is known to be critical for the development and function of many tissues. Here the authors show that it is also required for intestinal lineage differentiation, and that mice lacking DNA demethylases have altered microbiomes and a predisposition to inflammation.
- Ihab Ansari
- , Llorenç Solé-Boldo
- & Yehudit Bergman
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| Open AccessIn vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting
The entry receptor for SARS-CoV-2, ACE2, translocates to the nucleus following infection with this virus. Here, the authors demonstrate that a peptide targeting the ACE2 nuclear localization signal promotes its methylation and abrogates viral replication of SARS-CoV-2 in Syrian hamsters.
- Wen Juan Tu
- , Michelle Melino
- & Sudha Rao
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Article
| Open AccessSingle-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis
The bone marrow is a common site of metastasis for neuroblastoma patients. Here, the authors perform single cell RNA-seq and ATAC-seq of bone marrow aspirates from 16 subjects and show conservation of tumor cell plasticity in metastases and identify tumor-to-bone marrow cell signals that trigger tumor promoting monocytes.
- Irfete S. Fetahu
- , Wolfgang Esser-Skala
- & Sabine Taschner-Mandl
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Article
| Open AccessSignaling mechanisms in renal compensatory hypertrophy revealed by multi-omics
The authors used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.
- Hiroaki Kikuchi
- , Chung-Lin Chou
- & Mark A. Knepper
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Article
| Open AccessImpaired histone inheritance promotes tumor progression
Here the authors show disturbing parental histone inheritance in cancer cells drives tumor progression by reprogramming the epigenetic profile and conferring fitness advantages to some of the newly emerged subclones.
- Congcong Tian
- , Jiaqi Zhou
- & Haiyun Gan
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Article
| Open AccessHistone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
The molecular mechanisms underlying androgen production in prostate cancer remain to be explored. Here, the authors reveal an epigenetic mark, K130Ac on H2A, following dual-phosphorylation on SREBP1 promoting de novo androgen synthesis to overcome the pharmacological inhibition of androgen synthesis.
- Thanh Nguyen
- , Dhivya Sridaran
- & Nupam P. Mahajan
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| Open AccessA multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest
The authors discovered a far distant genomic region containing multiple clusters of regulatory elements that drive coordinated Hoxa expression across chromatin topologically associating domains in cranial neural crest, and are required for patterning of facial structures.
- Sandra Kessler
- , Maryline Minoux
- & Filippo M. Rijli
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| Open AccessLong-read direct RNA sequencing reveals epigenetic regulation of chimeric gene-transposon transcripts in Arabidopsis thaliana
Transposons can be co-transcribed with genes in plant genomes. Here, the authors show the global production of chimeric transposon-gene transcripts and their epigenetic regulation in Arabidopsis thaliana.
- Jérémy Berthelier
- , Leonardo Furci
- & Hidetoshi Saze
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| Open AccessCFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis
Progesterone (P4) signalling is involved in physiological control of the endometrium and contributes to the pathogenesis of endometrial diseases such as endometriosis. Here the authors report that CFP1, a regulator of histone methylation, controls endometrial responses to P4 and lack of endometrial CFP1 leads to failure of embryo implantation and exacerbated experimental endometriosis in mice.
- Seung Chel Yang
- , Mira Park
- & Haengseok Song
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Article
| Open AccessBalanced SET levels favor the correct enhancer repertoire during cell fate acquisition
The usage of specific distal regulatory regions within the genome is critical for fate specification and cell maturation. Here, the authors show that the accumulation of the oncoprotein SET, as occurring in the rare Schinzel-Giedion syndrome, and associated histone hypo-acetylation interfere with normal enhancer repertoire employed during brain development.
- Mattia Zaghi
- , Federica Banfi
- & Alessandro Sessa
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| Open AccessA cryo-EM structure of KTF1-bound polymerase V transcription elongation complex
Here the authors report the cryo-EM structure of transcription elongation complex comprising eukaryotic RNA polymerase V and its elongation factor KTF1. This work provides structural understanding for the unique function of the fifth member of eukaryotic RNA polymerases.
- Hong-Wei Zhang
- , Kun Huang
- & Yu Zhang
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Article
| Open AccessNeural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction
Cleft lip and palate is a common birth defect thought to involve both genetic and environmental components in its etiology. Here they identify a mechanism involving inflammation and E-cadherin mutations that reduces neural crest migration, leading to craniofacial defects.
- Lucas Alvizi
- , Diogo Nani
- & Roberto Mayor
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Article
| Open AccessBase editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation
The role of DNA methylation in early embryo development has been difficult to determine due to the functional redundancy of DNA methyltransferases. Here they develop an efficient base editing system that enables one-step generation of Dnmt-null embryos and show that DNA methylation-related miRNA suppression may be involved in gastrulation.
- Qing Li
- , Jiansen Lu
- & Jinsong Li
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Article
| Open AccessSmall-sample learning reveals propionylation in determining global protein homeostasis
The development of a new smallsample learning framework, KprFunc, leads to the discovery of an important role for lysine propionylation in determining global protein homeostasis, mediated by a critical propionylation site on histone H2B, H2BK17pr.
- Ke Shui
- , Chenwei Wang
- & Yu Xue
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Article
| Open AccessmeQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans
Here, the authors performed a large-scale in-depth cis-meQTL mapping study in 961 African Americans from the GENOA study, investigating the co-regulation of methylation and gene expression in African Americans.
- Lulu Shang
- , Wei Zhao
- & Xiang Zhou
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Article
| Open AccessRoles of adenine methylation in the physiology of Lacticaseibacillus paracasei
The bacterium Lacticaseibacillus paracasei is used in the food industry and as a probiotic. Here, the authors use multi-omics and high-throughput chromosome conformation capture analyses to investigate the roles of a type of DNA methylation (N6-methyladenine modification) in this organism.
- Jie Zhao
- , Meng Zhang
- & Wenyi Zhang
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Article
| Open AccessThe Fgf/Erf/NCoR1/2 repressive axis controls trophoblast cell fate
Repression of gene expression contributes to lineage-specific transcriptional signatures. Here Lackner et al. demonstrate that the Erf-NCoR1/2 complex controls trophoblast differentiation by linking signalling with transcriptional repression
- Andreas Lackner
- , Michael Müller
- & Paulina A. Latos
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Article
| Open AccessReversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma
Noradrenergic and mesenchymal cell states have been proposed in neuroblastoma, but their contributions to the tumour are not clearly understood. Here, the authors used in vitro and in vivo models, as well as single-cell RNA-seq, to characterise noradrenergic and mesenchymal cells and their phenotypic plasticity in neuroblastoma.
- Cécile Thirant
- , Agathe Peltier
- & Isabelle Janoueix-Lerosey
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Article
| Open AccessDependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis
Transcriptional dysregulation contributes to tumor progression. Here the authors show that transcriptional complex NELF interacts with SLUG, and co-opts KAT2B, to promote the expression of epithelial-mesenchymal transition (EMT) and stemness-associated genes in breast cancer.
- Jieqiong Zhang
- , Zhenhua Hu
- & Wee-Wei Tee
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Article
| Open AccessThe AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner
rAAV vectors vary in their effectiveness between species, making it difficult to predict clinical outcomes. Here authors show that AAV capsid proteins influence the vector epigenomic state in cells, and that a single amino acid change in the vector can alter the vector epigenome and hence transgene expression levels between species.
- Adriana Gonzalez-Sandoval
- , Katja Pekrun
- & Mark A. Kay
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Article
| Open AccessMulti-omic underpinnings of epigenetic aging and human longevity
Here, the authors integrate genomic, bulk and single-cell transcriptomic, and metabolomic data sets to compare the biological underpinning of four epigenetic clocks and human longevity, offering novel insights into aging biology.
- Lucas A. Mavromatis
- , Daniel B. Rosoff
- & Falk W. Lohoff