Epigenetics

  • Article
    | Open Access

    Polycomb Repressive Complex 2, an important regulator of embryonic development, exists in two configurations, PRC2.1 and PRC2.2. Here the authors dissect the functional contributions of these two PRC2 subunits and observed complex-specific alterations in the cell state of pluripotent and early differentiating cells.

    • Chet H. Loh
    • , Siebe van Genesen
    •  & Gert Jan C. Veenstra
  • Article
    | Open Access

    The molecular origins of epialleles remain unknown. Here, the authors show that a positive feedback loop between H3K9me2 and CMT2/3 is a major contributing factor to the origins of spontaneous epialleles and that heterochromatin is a quantitative trait associated with spontaneous epiallele formation.

    • Yinwen Zhang
    • , Hosung Jang
    •  & Robert J. Schmitz
  • Article
    | Open Access

    Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage with an aggressive subtype caused by translocations involving PAX3- /PAX7-FOXO1 chimeric transcription factors. Here the authors show that the BRG1-containing BAF complex is overexpressed and acts largely independently of the PAX3-FOXO1 chimera on chromatin to result in a myogenic differentiation blockade in this malignancy.

    • Dominik Laubscher
    • , Berkley E. Gryder
    •  & Javed Khan
  • Article
    | Open Access

    Dynamic changes in chromatin landscape affect CD8+ T cell phenotype and function in chronic infections and cancer. Here the authors show that targeting the histone demethylase LSD1 increases the persistence of progenitor exhausted CD8+ T cells, improving response to immune checkpoint blockade in preclinical cancer models.

    • Yi Liu
    • , Brian Debo
    •  & Yang Shi
  • Article
    | Open Access

    An upregulation of NSD2, a histone H3 lysine 36 (H3K36) methyltransferase is linked to multiple myeloma and other types of cancer. Here, the authors provide insights into the regulatory mechanism of NSD2 by determining the 2.8 Å cryo-EM structure of the NSD2 bound nucleosome complex, and based on MD simulations they discuss how two oncogenic mutations enhance NSD2 activity.

    • Ko Sato
    • , Amarjeet Kumar
    •  & Toru Sengoku
  • Article
    | Open Access

    The mammalian SWI/SNF nucleosome remodeler is required for spermatogenesis. Here, the authors show that PBAF is essential for meiotic cell division in males and required to activate the expression of critical genes involved in spindle assembly and nuclear division in spermatocytes.

    • Debashish U. Menon
    • , Oleksandr Kirsanov
    •  & Terry Magnuson
  • Article
    | Open Access

    Stochastic autosomal allele expression bias has been widely documented, yet the mechanisms behind this consequential phenomenon remain poorly understood. Here the authors show that the presence of introns greatly restricts monoallelic expression in a C. elegans model.

    • Bryan Sands
    • , Soo Yun
    •  & Alexander R. Mendenhall
  • Article
    | Open Access

    Muco-obstructive lung diseases are characterised by airway macrophage (AM) populations which may have epigenetic changes. Here using a mouse model the authors show epigenetic alteration of AMs with changes in LPS response, phagocytosis and efferocytosis similar to culture with mucus in vitro.

    • Joschka Hey
    • , Michelle Paulsen
    •  & Marcus A. Mall
  • Article
    | Open Access

    The effect of ATP-dependent chromatin remodelers on 3D genome organization has not been well studied. Here the authors employ in situ Hi-C with an auxin-inducible degron system to degrade chromatin remodelers in yeast to find that the 3D structure of chromatin collapses in their absence. The chromatin remodeling can modulate 3D architecture depending on chromosomal context and cell cycle stage.

    • Hyelim Jo
    • , Taemook Kim
    •  & Daeyoup Lee
  • Article
    | Open Access

    While a correlation between epigenetic modifications and mutation rates has been observed, experimental evidence of causality is limited. Here the authors measure the mutation rate in fungal mutants lacking histone modifications and confirm experimentally a causal effect of epigenetic modifications on mutation rates.

    • Michael Habig
    • , Cecile Lorrain
    •  & Eva H. Stukenbrock
  • Article
    | Open Access

    Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.

    • Paloma Cejas
    • , Yingtian Xie
    •  & Henry W. Long
  • Article
    | Open Access

    The molecular mechanism underlying the DNA hypermethylation phenotype observed in the SPOP-mutant prostate cancers is unclear. Here, the authors show that mutant SPOP induces global aberrant DNA methylation patterns through GLP/G9a and renders prostate cancer cells susceptible to DNA demethylating agents.

    • Jianong Zhang
    • , Kun Gao
    •  & Haojie Huang
  • Article
    | Open Access

    The causal relationship between DNA demethylation and gene expression regulation has not yet been fully resolved. Here the authors develop a nuclease-dead Cas9 (dCas9) and gRNA site-specific targeting approach to physically block DNA methylation at specific promoters to cause DNA demethylation in cells and tackle this question.

    • Daniel M. Sapozhnikov
    •  & Moshe Szyf
  • Article
    | Open Access

    CHARGE syndrome that affects cerebellar development can be caused by haploinsufficiency of the chromatin remodeling enzyme CHD7; however the precise role of CHD7 remains unknown. Here the authors show CHD7 promotes chromatin accessibility and enhancer activity in granule cell precursors and regulates morphogenesis of the cerebellar cortex, where loss of CHD7 triggers cerebellar polymicrogyria.

    • Naveen C. Reddy
    • , Shahriyar P. Majidi
    •  & Harrison W. Gabel
  • Article
    | Open Access

    The mechanisms underlying how monozygotic (or identical) twins arise are yet to be determined. Here, the authors investigate this in an epigenome-wide association study, showing that monozygotic twinning has a characteristic DNA methylation signature in adult somatic tissues.

    • Jenny van Dongen
    • , Scott D. Gordon
    •  & Dorret I. Boomsma
  • Article
    | Open Access

    A strategy to control HIV-1 infection is to stably repress HIV-1 and induce “deep latency”. Here the authors show that a recombinant anti-HIV-1-1 protein can be packaged as mRNA into exosomes and delivered systemically to repress HIV-1-1 within the context of virus infected mice and achieve long term silencing of HIV-1-1 expression.

    • Surya Shrivastava
    • , Roslyn M. Ray
    •  & Kevin V. Morris
  • Article
    | Open Access

    Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.

    • Vrutant V. Shah
    • , Aundrietta D. Duncan
    •  & Michelle Craig Barton
  • Article
    | Open Access

    Polycomb repressive complexes (PRC1 and PRC2) repress genes that are crucial for development via epigenetic modifications; however, their role in differentiation is not well known. Here the authors reveal that a PCGF1-containing PRC1 variant facilitates exit from pluripotency by downregulating target genes and recruiting PRC2.

    • Hiroki Sugishita
    • , Takashi Kondo
    •  & Haruhiko Koseki
  • Article
    | Open Access

    Some autosomal genes are expressed in a random monoallelic manner, but its extent and mechanisms have remained unclear. Here the authors show robust monoallelic expression in cell lines and mice, where the silent allele can be reexpressed using epidrugs. Further, they find these genes display various modalities of allelic expression with different degrees of allelic imbalance.

    • Lucile Marion-Poll
    • , Benjamin Forêt
    •  & Edith Heard
  • Article
    | Open Access

    The global pattern of the mammalian methylome is formed by changes in methylation and demethylation. Here the authors describe a metric methylation concurrence that measures the ratio of unmethylated CpGs inside the partially methylated reads and show that methylation concurrence is associated with epigenetically regulated tumour suppressor genes.

    • Jiejun Shi
    • , Jianfeng Xu
    •  & Wei Li
  • Article
    | Open Access

    The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.

    • Kira A. Perzel Mandell
    • , Nicholas J. Eagles
    •  & Andrew E. Jaffe
  • Article
    | Open Access

    Maternal smoking during pregnancy contributes to poor birth outcomes. Here the authors perform a meta-analysis of the associations between maternal smoking during pregnancy and placental DNA methylation and identify links between these and poor birth outcomes, which may better inform the mechanisms through which smoking impacts placental function and fetal growth.

    • Todd M. Everson
    • , Marta Vives-Usano
    •  & Mariona Bustamante
  • Article
    | Open Access

    The histone acetyltransferase p300 mostly localizes to active chromatin; however, some repressed genes marked with H3K27me3 are also bound by p300. Here the authors show p300 is capable of phase separation, which relies on its catalytic core, and that p300 catalytic activity is decreased in phase-separated droplets that co-localize with H3K27me3-marked chromatin.

    • Yi Zhang
    • , Kyle Brown
    •  & Tatiana G. Kutateladze
  • Article
    | Open Access

    The polycomb repressive complex 2 (PRC2) is a histone methyltransferase regulating cell differentiation and identity. Here, the authors show that the vertebrate-specific PRC2 accessory subunit PALI1 facilitates substrate binding by the complex and elucidate the allosteric mechanism of PALI1- mediated PRC2 activation.

    • Qi Zhang
    • , Samuel C. Agius
    •  & Chen Davidovich
  • Article
    | Open Access

    Germline mutations in the DNMT3A gene can cause an overgrowth syndrome associated with behavioural and hematopoietic phenotypes. Here the authors describe a mouse model of this syndrome that recapitulates many of these features, including conserved alterations in DNA methylation in the blood cells of both species.

    • Amanda M. Smith
    • , Taylor A. LaValle
    •  & Timothy J. Ley
  • Article
    | Open Access

    Whether thyroid hormones affect gene expression via DNA methylation is not well known. Here the authors show that type 2 deiodinase (D2) converts T4 to produce T3, which prevents DNA methylation of discrete areas in the neonatal liver. In the absence of D2, DNA methylation occurs and is associated with reduced chromatin accessibility in promoters and enhancers and affects gene expression.

    • Tatiana L. Fonseca
    • , Tzintzuni Garcia
    •  & Antonio C. Bianco
  • Article
    | Open Access

    Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.

    • Andrew J. King
    • , Duantida Songdej
    •  & Christian Babbs
  • Article
    | Open Access

    Histone H3K9 methylation (H3K9me) states define repressed chromatin in eukaryotic cells. Here the authors reveal complete loss of all H3K9me in mammalian cells through successive deletion of H3K9 methyltransferase genes that results in the dissolution of heterochromatin and the derepression of nearly all repeat families.

    • Thomas Montavon
    • , Nicholas Shukeir
    •  & Thomas Jenuwein
  • Article
    | Open Access

    A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.

    • Xing Jian
    •  & Gary Felsenfeld
  • Article
    | Open Access

    MORC ATPases are required for transposable element silencing and heterochromatin condensation in plants and animals. Here the authors show that Arabidopsis MORCs colocalize with sites of RNA-directed DNA methylation and provide evidence that they act as molecular tethers to efficiently establish DNA methylation.

    • Yan Xue
    • , Zhenhui Zhong
    •  & Steven E. Jacobsen
  • Article
    | Open Access

    The virulence of some infectious diseases seems to depend on the sex of the host the infection came from, as well as that of the current host. Here, McLeod et al. develop an epidemiological model to investigate the evolution of virulence when pathogens can retain epigenetic memories of their previous host.

    • David V. McLeod
    • , Geoff Wild
    •  & Francisco Úbeda
  • Article
    | Open Access

    Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues and found 5hmC shows tissue-specific patterns.

    • Bo He
    • , Chao Zhang
    •  & Chengqi Yi
  • Article
    | Open Access

    Stable epigenetic changes are relatively rare. Here the authors report that mating induces stable silencing of a single-copy transgene in C. elegans. Components of small RNA silencing are required for this stable silencing.

    • Sindhuja Devanapally
    • , Pravrutha Raman
    •  & Antony M. Jose
  • Article
    | Open Access

    Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.

    • Chi Zhang
    • , Filippo Macchi
    •  & Kirsten C. Sadler
  • Article
    | Open Access

    α-ketoglutarate (αKG) is an intermediate in the tricarboxylic acid cycle that is required in the nucleus for genomic DNA demethylation by Tet3. Here, the authors show that the enzyme glutamate dehydrogenase, which converts glutamate to αKG, is redirected from the mitochondria to the nucleus.

    • Franziska R. Traube
    • , Dilara Özdemir
    •  & Thomas Carell
  • Article
    | Open Access

    Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.

    • Min-A Jhun
    • , Michael Mendelson
    •  & Themistocles L. Assimes
  • Article
    | Open Access

    The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.

    • Benxia Hu
    • , Hyejung Won
    •  & Daniel H. Geschwind
  • Article
    | Open Access

    In most mammals, imprinted genes contain epigenetic marks that differ in each parental genome and control their parent-of-origin-specific expression. Here, the authors map imprinted genes in mouse preimplantation embryos and find that imprinted gene expression in blastocysts is mainly dependent on Polycomb-mediated H3K27me3-associated gene silencing.

    • Laura Santini
    • , Florian Halbritter
    •  & Martin Leeb