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| Open Access5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression
The mechanism by which DNA methylation regulates female reproduction in insects is largely unknown. Here Zhao et al. demonstrate that the 5mC modification orchestrates timely choriogenesis and proper fertilization by preventing prolonged ftz-f1 expression in the German cockroach.
- Zheng Zhao
- , Liang Li
- & Chonghua Ren
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Article
| Open AccessGenes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.
- Tina Rönn
- , Jones K. Ofori
- & Charlotte Ling
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Article
| Open AccessAn allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome
Nuclear organization impacts allelic exclusion. Here, the authors describe a self-limiting protein bridge that connects two chromosomes, and two transcription and splicing compartments, to maintain monogenic VSG expression in the African trypanosome.
- Joana R. C. Faria
- , Michele Tinti
- & David Horn
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Article
| Open AccessLoss of cohesin regulator PDS5A reveals repressive role of Polycomb loops
Through a genetic screen, the authors find that the cohesin regulator PDS5A is required for Polycomb target gene silencing. Derepression upon cohesin dysregulation is linked to loss of Polycomb loops without change in repressive chromatin domains.
- Daniel Bsteh
- , Hagar F. Moussa
- & Oliver Bell
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Article
| Open AccessNitric oxide controls shoot meristem activity via regulation of DNA methylation
The authors show that gaseous Nitric Oxide (NO) promotes transit amplifying cell fate in the Arabidopsis shoot meristem. NO acts by modifying AGO4-WUSCHEL protein interactions in stem cells, directly linking NO signaling with DNA methylation.
- Jian Zeng
- , Xin’Ai Zhao
- & Jan U. Lohmann
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Article
| Open AccessSMARCB1 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 AccessDominance in self-compatibility between subgenomes of allopolyploid Arabidopsis kamchatica shown by transgenic restoration of self-incompatibility
Self-incompatibility in diploid Arabidopsis relatives is determined by a dominance relationship that is epigenetically regulated. Using transgenic methods, this study demonstrates that the dominance relationship between subgenomes of the allopolyploid species Arabidopsis kamchatica underlies it’s self-compatibility.
- Chow-Lih Yew
- , Takashi Tsuchimatsu
- & Kentaro K. Shimizu
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Article
| Open AccessHDAC8-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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Article
| Open AccessOVOL2 sustains postnatal thymic epithelial cell identity
The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.
- Xue Zhong
- , Nagesh Peddada
- & Bruce Beutler
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Article
| Open AccessThe rate of epigenetic drift scales with maximum lifespan across mammals
Epigenetic drift has been hypothesized to contribute to epigenetic clock signals and variation in lifespan across species. Here, the authors show that an empirical measure of epigenetic drift scales with maximum lifespan across four mammal species and accumulates in non-random genomic locations.
- Emily M. Bertucci-Richter
- & Benjamin B. Parrott
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Article
| Open AccessLHP1-mediated epigenetic buffering of subgenome diversity and defense responses confers genome plasticity and adaptability in allopolyploid wheat
The regulation of genetic diversity resulting from polyploidization and its impact on environmental adaptability remain unclear. Here, the authors show that LHP1-mediated epigenetic buffering of subgenome diversity and defense responses confers genome plasticity and adaptability in allopolyploid wheat.
- Zijuan Li
- , Yuyun Zhang
- & Yijing Zhang
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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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