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Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells
DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.
- Kosuke Yamaguchi
- , Xiaoying Chen
- & Pierre-Antoine Defossez
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| Open Access
KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma
There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.
- Yong Yean Kim
- , Berkley E. Gryder
- & Javed Khan
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| Open Access
Tissue-location-specific transcription programs drive tumor dependencies in colon cancer
Cancers of the same tissue type are characterized with different molecular features depending on anatomical location. Here, the authors show that proximal and distal colon stem cells have distinct transcriptional programs mediated by the transcription factor CDX2, with differential roles in colon cancers based on anatomical location.
- Lijing Yang
- , Lei Tu
- & Hariharan Easwaran
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Integrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types
Here the authors identify gene targets and causal cell types affected by genetic risk loci in uterine fibroids by combining meta-analysis on existing fibroid genome-wide association studies and integrated the identified risk loci and potentially causal single nucleotide polymorphisms with epigenomics, transcriptomics, 3D chromatin organization from diverse cell types as well as primary uterine fibroids patient’s samples.
- Kadir Buyukcelebi
- , Alexander J. Duval
- & Mazhar Adli
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| Open Access
Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance
The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.
- Harish N. Vasudevan
- , Emily Payne
- & David R. Raleigh
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Epigenetic reprogramming shapes the cellular landscape of schwannoma
Schwannomas are regularly treated with radiotherapy, but the molecular effects on these tumours and their microenvironment remain unclear. Here, the authors show that radiotherapy can induce epigenetic reprogramming and immune infiltration in schwannomas, and develop the snARC-seq approach to analyse the epigenomic evolution at the single-cell level.
- S. John Liu
- , Tim Casey-Clyde
- & David R. Raleigh
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Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q
The genetic and epigenetic predisposition of bilateral Wilms tumour remains to be investigated. Here, the authors perform multiomics analysis and identify the predominant genetic and epigenetic events associated with bilateral Wilms tumour predisposition.
- Andrew J. Murphy
- , Changde Cheng
- & Xiang Chen
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Article
| Open Access
Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort
Renal cell carcinoma (RCC) subtypes are associated with different molecular alterations and clinical outcomes, but they need to be characterised in diverse cohorts. Here, the authors perform genomic, transcriptomic, and epigenomic profiling in a large cohort of Japanese RCC cases, and identify epi-subtypes associated with a particular immune environment.
- Akihiko Fukagawa
- , Natsuko Hama
- & Tatsuhiro Shibata
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| Open Access
Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma
Current sequencing technologies can shed light on the stepwise progression of lung adenocarcinoma. Here, the authors characterize tumor progression in lung adenocarcinomas from an early stage using short and long read whole-genome sequencing, bulk and spatial transcriptomics, and epigenomics.
- Yasuhiko Haga
- , Yoshitaka Sakamoto
- & Ayako Suzuki
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Article
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SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors
The regulatory landscape of malignant rhabdoid tumor (MRT) due to SMARCB1 loss remains to be explored. Here, the authors perform multi-omics analysis using patient-derived MRT organoids and characterise the epigenetic reprogramming events underlying SMARCB1 loss.
- Ning Qing Liu
- , Irene Paassen
- & Jarno Drost
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Article
| Open Access
HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis
The drivers of melanoma brain metastases (MBM) remain poorly understood. Here, the authors identify stress-induced HDAC8 activity as the driver of a neural crest-stem cell like transcriptional state that leads to MBM, and explore the molecular mechanism that drives this transition.
- Michael F. Emmons
- , Richard L. Bennett
- & Keiran S. M. Smalley
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Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens
The role of HOXA9 in binding to noncoding regulatory sequences and regulates the downstream genes in MLL gene rearrangements (MLL-r) leukemia. Here, the use of CRISPR-mediated loss-of-function screen against HOXA9-bound peaks and integrative approaches reveal the noncoding regulation mechanism of HOXA9.
- Shaela Wright
- , Xujie Zhao
- & Chunliang Li
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Article
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The 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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CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes
N6-methyladenosine (m6A) modification has important implications in different cancer subtypes. Here, the authors perform transcriptomic m6A profiling to identify two subtypes of pancreatic ductal adenocarcinoma with differential m6A modifications and different clinical outcomes, which is driven by m6A regulator CSTF2.
- Yanfen Zheng
- , Xingyang Li
- & Zhixiang Zuo
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Article
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Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
Here, the authors apply the Activity-by-Contact (ABC) model to infer enhancer-gene regulation and the effect of associated variants across multiple cancer types, integrating genetic and multi-omics data. Then, they explore the mechanisms associated with ABC regulatory variants in colorectal cancer.
- Pingting Ying
- , Can Chen
- & Xiaoping Miao
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Article
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A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus
Here, the authors functionally characterize a complex genetic variant relevant in prostate cancer that regulates IRX4 expression through epigenetic activation. This work highlights the significance of non-single nucleotide polymorphism causal variants in explaining disease risk.
- Sandor Spisak
- , Viktoria Tisza
- & Matthew L. Freedman
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Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
Co-dependency mapping assays have revealed genetic dependencies in cancer and could shed light on chromatin crosstalk mechanisms. Here, the authors establish a pipeline to integrate co-dependency mapping screens with molecular information in pan-cancer cell lines in order to reveal chromatin complexes and potential drug targets.
- Xiao Chen
- , Yinglu Li
- & Chao Lu
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Article
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Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization
There are currently a lack of genetic models to study the biology of Uterine fibroids (UFs) tumours. Here the authors precisely engineer cells with mutant MED12 Gly-44 and generate myometrial smooth muscle cells (SMCs) that recapitulate major UFs-like cellular, transcriptional, and metabolic alterations.
- Kadir Buyukcelebi
- , Xintong Chen
- & Mazhar Adli
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| Open Access
Impaired 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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Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy
It remains critical to understand the genomic events in response to treatment of oesophageal adenocarcinoma (OAC). Here, the authors perform a multi-omics analysis of OAC patients from the DOCTOR phase II clinical trial, finding genomic features and immune clusters associated with survival.
- Marjan M. Naeini
- , Felicity Newell
- & Nicola Waddell
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| Open Access
Molecular patterns identify distinct subclasses of myeloid neoplasia
Myeloid neoplasias can show complex mutation patterns and molecular features. Here, the authors apply machine learning to classify risk groups of myeloid neoplasia which may correlate with differential response to treatment.
- Tariq Kewan
- , Arda Durmaz
- & Jaroslaw P. Maciejewski
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Article
| Open Access
SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance
The molecular mechanisms involved in the development of SMARCB1-deficient renal medullary carcinomas (RMCs) remain to be characterised. Here, the authors integrated RMC omics data to show that ferroptosis resistance contributes to transformation of renal thick ascending limb cells into several RMC cell states.
- Bujamin H. Vokshi
- , Guillaume Davidson
- & Gabriel G. Malouf
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Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance
Alternative lengthening of telomeres (ALT) provides cancer cells a mechanism to sustain replicative immortality. Here, the authors identify KDM2A as a molecular vulnerability in ALT-dependent cancer cells and demonstrate its role in the resolution of ALT-specific telomere clusters via recruitment of SENP6.
- Fei Li
- , Yizhe Wang
- & Hongwu Zheng
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Genomic characterization of DICER1-associated neoplasms uncovers molecular classes
DICER1 syndrome is associated with a predisposition to multiple tumor types. Here, the authors identify and characterize 3 molecular subgroups of mesenchymal tumors with DICER1 mutations.
- Felix K. F. Kommoss
- , Anne-Sophie Chong
- & William D. Foulkes
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Article
| Open Access
SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry
The development of neuroblastoma (NB) is regulated by multiple core transcription factors. Here, SOX11 is identified as a potential epigenetic master regulator upstream of the core regulatory circuitry in adrenergic high-risk neuroblastoma.
- Bieke Decaesteker
- , Amber Louwagie
- & Frank Speleman
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Article
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Sequence terminus dependent PCR for site-specific mutation and modification detection
Rapid and facile detection of specific nucleic acid modifications could have numerous applications. Here the authors present Specific Terminal Mediated Polymerase Chain Reaction (STEM-PCR) as a generic and accessible approach, and demonstrate proof-of-principle cancer biomarker detection.
- Gaolian Xu
- , Hao Yang
- & Hongchen Gu
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A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells
Mutations of ATRX are frequent in cancers that immortalize through the ALT (Alternative lengthening of telomeres) pathway. Here the authors show that ALT features are repressed in embryonic stem cells that lack ATRX but induced by continuous telomere instability triggered upon cell differentiation.
- Timothy K. Turkalo
- , Antonio Maffia
- & Dirk Hockemeyer
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Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing
It is essential to understand heterogeneity and evolution at different omics levels in oesophageal squamous cell carcinoma (ESCC). Here, the authors use multi-omics to analyse heterogeneity and evolution in ESCC patient samples, and characterise the levels of immune infiltration as well as selective pressure from the tumour microenvironment.
- Sijia Cui
- , Nicholas McGranahan
- & Shixiu Wu
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| Open Access
Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma
Clinical management of pancreatic cancer remains challenging. Here, the authors suggest SMARCD3 as a potential epigenetic dependency establishing the metabolic landscape in aggressive pancreatic cancer cells and as a potential therapeutic target in pancreatic cancer.
- L. Paige Ferguson
- , Jovylyn Gatchalian
- & Tannishtha Reya
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Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG
The role of risk loci identified from genome-wide association studies in prostate cancer (PCa) progression remains poorly characterised. Here, the authors report enrichment of transcription factor genes within PCa risk-associated regions and germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations.
- Nikolaos Giannareas
- , Qin Zhang
- & Gong-Hong Wei
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Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability
The ETV6-RUNX1 chimeric- and native RUNX1-responsive regulomes in paediatric B-acute lymphoblastic leukemia (B-ALL) remain to be characterized. Here, the authors reveal functional antagonism between the two transcription factors predominantly for the regulation of cell cycle-associated pathways and dependency on native RUNX1 for tumorigenesis which can be targeted pharmacologically.
- Jason P. Wray
- , Elitza M. Deltcheva
- & Tariq Enver
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Article
| Open Access
Replication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells
Suppression of transcription in S-phase is crucial to prevent genome instability. Zhang et al demonstrate that increase of H4K20me1 due to loss of Kmt5b cause genome instability in muscle stem cells, resulting in stem cell senescence but rhabdomyosarcoma formation when p53 is inactivated.
- Ting Zhang
- , Carsten Künne
- & Thomas Braun
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MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia
The links between DNA methylation and gene expression are poorly understood on large-scale. Here the authors show that MIR retrotransposons within introns can play this role in acute myeloid leukemia harbouring mutations in epigenetic modifiers.
- Aristeidis G. Telonis
- , Qin Yang
- & Maria E. Figueroa
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Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure
While cutaneous melanoma is linked to UV radiation, acral melanoma is not. Epigenetic mechanisms function as sensors to exposures and determinants of cell identity. Here, the authors use DNA methylation data to identify dysregulated pathways associated with UV radiation and pathobiology in cutaneous and acral melanomas.
- Anna Luiza Silva Almeida Vicente
- , Alexei Novoloaca
- & Akram Ghantous
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| Open Access
ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription
Here the authors show mutation of the BAF chromatin remodeler subunit ARID1A results in an ARID1B-dependent upregulation of HERVH, an ERV required for the pluripotency regulatory network. These HERVH RNAs can partition into BRD4 foci, affecting BRD4-dependent transcription. Suppression of HERVH in colorectal cancer cells and patient-derived organoids impairs tumor growth.
- Chunhong Yu
- , Xiaoyun Lei
- & Kai Yuan
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Article
| Open Access
Phasing analysis of lung cancer genomes using a long read sequencer
Long-read sequencing technologies are useful for the multifaceted task of characterising somatic mutations, including structural variants, in cancers. Here, the authors combine short and long read sequencing for the phasing analysis, which enables them to resolve the chromosomal backgrounds of somatic mutations in Japanese non-small cell lung cancers.
- Yoshitaka Sakamoto
- , Shuhei Miyake
- & Ayako Suzuki
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Article
| Open Access
The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma
Androgen receptor can promote tumour progression in desmoplastic small round cell tumour (DSRCT), an aggressive paediatric malignancy that predominantly affects young males. Here, the authors show that DSRCT is an AR-driven malignancy and sensitive to androgen deprivation therapy
- Salah-Eddine Lamhamedi-Cherradi
- , Mayinuer Maitituoheti
- & Joseph A. Ludwig
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Article
| Open Access
Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity
The chromatin accessibility landscape and gene regulatory network of pancreatic cancer has not been fully characterised. Here, the authors perform multi-omics analysis of 84 pancreatic cancer organoid lines and reveal gene regulatory networks and distinct molecular subtypes.
- Xiaohan Shi
- , Yunguang Li
- & Dong Gao
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Article
| Open Access
Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes
Astroblastoma (AB) is an uncommon brain tumour and its origin remains unknown. Here, the authors perform integrative molecular analysis of 35 AB-like tumours and provide evidence that these arise in the context of epigenetic and genetic changes in neural progenitors occurring during brain development.
- Norman L. Lehman
- , Nathalie Spassky
- & Akshitkumar M. Mistry
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Article
| Open Access
ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation
Mutations of ESR1, the gene encoding the estrogen receptor alpha, are associated with acquired resistance to therapy in luminalbreast cancer. Here the authors show that ESR1 mutant tumors gain basal-like features with increased expression of basal cytokeratines and immune activation.
- Zheqi Li
- , Olivia McGinn
- & Steffi Oesterreich
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Article
| Open Access
EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1
Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1.
- Jie Wang
- , Junshang Ge
- & Zhaoyang Zeng
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Article
| Open Access
The DNA methylome of cervical cells can predict the presence of ovarian cancer
Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer.
- James E. Barrett
- , Allison Jones
- & Martin Widschwendter
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Article
| Open Access
Functional dissection of inherited non-coding variation influencing multiple myeloma risk
The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.
- Ram Ajore
- , Abhishek Niroula
- & Björn Nilsson
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Article
| Open Access
Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers
Active enhancers are still understudied in colorectal cancers (CRC). Here the authors analyse active enhancers in CRC patients using genomics, transcriptomics, and epigenomics, identifying and validating variant super-enhancer loci as well as KLF3 as a relevant transcription factor.
- Qing-Lan Li
- , Xiang Lin
- & Min Wu
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Article
| Open Access
Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation
Identifying how genetic alterations cooperate in cancer is challenging. Here the authors analyze leukemia mouse models with both oncogenic NRAS and EZH2 mutations using single-cell RNA-sequencing, evaluate oncogenic cooperation, and identify GEM as a regulator of leukemia-initiating cells.
- Yuxuan Liu
- , Zhimin Gu
- & Jian Xu
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Article
| Open Access
Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility
The identification of transcription factors (TFs) whose binding sites are affected by risk genetic variants remains crucial. Here, the authors develop a statistical framework to analyse ChIP-seq and GWAS data, identify 22 breast cancer risk-associated TFs and a core TF-transcriptional network for FOXA1 and co-factors.
- Wanqing Wen
- , Zhishan Chen
- & Xingyi Guo
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Article
| Open Access
SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria
SMARCA4/2 loss in ovarian and lung cancers is associated with chemotherapy resistance. Here, the authors show that SMARCA4/2 deficiency in cancer cells reduces the expression of the ER-Ca2+ channel IP3R3 and subsequently calcium transfer to the mitochondria, which inhibits apoptotic cell death.
- Yibo Xue
- , Jordan L. Morris
- & Sidong Huang
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Article
| Open Access
RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage
The BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex is well known to play a fundamental role in DNA repair, but how the complex recruitment is regulated is still a matter of interest. Here the authors reveal mechanistic insights into RNF168 activity being responsible for PALB2 recruitment, through BARD1-BRCA1 during homologous recombination repair.
- John J. Krais
- , Yifan Wang
- & Neil Johnson
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Article
| Open Access
Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis
The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.
- Bo Ye
- , Dandan Fan
- & Yunbo Qiao
Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma