Major Epigenetics Discoveries from 2014

As 2014 comes to a close we reflect on some of the most interesting epigenetics discoveries of the year.  Epigenetics has emerged as a highly important field in the discovery of new medicines and the understanding of human biology. Here, you will find 9 papers that connect epigenetics and diseases affecting young (Ependymoma) and old (Alzheimer’s disease) and other diseases in between.  You will also find some very exciting discoveries that greatly increase our mechanistic understanding of human biology and therefore the potential for eventual new treatments of disease.

Did we miss any of your top epigenetics discoveries from 2014? Send us an email and we’ll feature your choices in the New Year!

In chronological order:

1. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. 
   Mack et al. Nature 506(7489):445-50. February 27 2014
   Ependymomas are common childhood brain tumours, most common in the paediatric hindbrain, that unusually have no significant recurrent single nucleotide variants. Mack et al. find that poor-prognosis hindbrain ependymomas show a CpG island methylator phenotype and respond to clinical drugs that target either DNA or H3K27 methylation in vitro and in vivo. This study represents the first rational strategy for therapy of these ependymomas and, importantly, shows that epigenetic modifications may be interesting and successful targets in the treatments of diseases devoid of hallmark genetic mutations or SNVs.
    
2. Molecular basis underlying histone H3 lysine-arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1. 
   Su et al. Genes Dev 28(6):622-36. March 15 2014 
   Spindlin1 consists of triple Spin/Ssty repeats and localizes to cell nuclei. This paper demonstrates that Spin readers are Tudor-like methyl-lysine/arginine reader domains that integrate a histone-binding activity with multiple cellular pathways including the Wnt signalling pathway. These new insights into Spindlin1 molecular function may allow for future progress in therapeutic applications related to Spindlin.
    
3. A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. 
   Alpatov et al. Cell 157(4):869-81. May 8 2014 
   Fragile X syndrome is caused by loss of the fragile X mental retardation protein FMRP. This study by Apatov et al. identifies FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). This suggests a novel, important role in the nucleus for a protein previously thought to only regulate translation in the cytoplasm and Apatov et al. show that this unanticipated role in the DDR at the chromatin interface is independent from the role of FMRP in translational regulation.
    
4. Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain. 
   Coppieters et al. Neurobiol Aging 35(6):1334-44. June 2014 
   Recent studies have begun to point toward the epigenome in the search for causes of Alzheimer’s disease. Coppieters et al. demonstrate in this study the involvement of two epigenetic markers, methylation and hydroxymethylation, in Alzheimer’s disease. Levels of methylation and hydroxymethylation were shown to be significantly and dramatically increased in Alzheimer’s disease patients’ middle frontal gyrus and middle temporal gyrus. These levels were positively correlated with each other and with the well-known markers of Alzheimer’s disease: amyloid beta, tau, and ubiquitin loads. This study introduces the question of whether methylation and hydroxymethylation control may be a potential therapeutic avenue in the treatment of Alzheimer’s disease.
    
5. AF9 YEATS Domain Links Histone Acetylation to DOT1L-Mediated H3K79 Methylation. 
   Li et al. Cell 159(3):558-71. October 23 2014
   Whereas few protein modules that recognize histone acetylation were previously known, Li et al. describe a novel family of histone acetylation readers: the YEATS domains. This study demonstrates that the YEATS domains of AF9 from diverse species all bind to H3K9ac and other acetylated H3 histones. Li et al. also outline the importance of the YEATS domains in connecting histone acetylation to diverse processes during development – indicating that YEATS domains may be important therapeutic targets for the treatment of human cancers.
    
6. Crystal structure of the PRC1 ubiquitylation module bound to the nucleosome. 
   McGinty et al. Nature 514(7524):591-6. October 30 2014 
   McGinty et al. describe the first crystal structure of a histone-modifying enzyme-nucleosome complex. This is also the first crystal structure of a ubiquitin E2-E3-substrate complex. Interestingly, the structure for the first time reveals how a histone-modifying enzyme recognizes its nucleosomal substrate. PRC1 uses several non-active site surfaces for nucleosomal recognition and specificity determination. This principle may be shared by many chromatin enzymes that function as part of large multi-component complexes.
    
7. The contribution of de novo coding mutations to autism spectrum disorder. 
   Iossifov et al. Nature 515(7526):216-21. November 13 2014 
   Iossifov et al. report whole exome sequencing of over 2500 families with a child with an autistic spectrum disorder (ASD).  This unprecedented evaluation of genetic vulnerability to ASD revealed several interesting de novo likely gene-disrupting (LGD) targets enriched in individuals with ASD including the strongest evidence yet for genes encoding chromatin modifiers as key players. The authors of this paper optimistically posit that the long-term prognosis for treating ASD is positive and that mechanism-based treatments for ASD might work for different diseases that share targets with ASD such as schizophrenia and intellectual disability.
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8. Synaptic, transcriptional and chromatin genes disrupted in autism. 
   De Rubeis et al. Nature 515(7526):209-15. November 13 2014
   In a massive whole exome sequencing study, strong evidence is provided for histone modifier genes and readers, especially those involved in lysine methylation, in sporadic ASD. De Rubeis et al. suggest that disruption of relevant genes in individuals with ASD induces alterations in chromatin dynamics and transcription which leads to impaired synaptic function. Essential for neural physiology, De Rubeis et al. suggest that the integrity of synaptic function and its perturbation may represent the intersection between diverse neuropsychiatric disorders.
    
9. A global assessment of cancer genomic alterations in epigenetic mechanisms. 
   Shah et al. Epigenetics Chromatin 7(1):29. December 4 2014 
   ​Shah et al. analyze mutational and transcriptional profiles across a collection of 441 chromatin factors and histones in this global assessment study. Their unbiased approach confirms previously published oncogenic aberrations, but also uncovers novel alterations targeting epigenetic mechanisms in specific cancer types. This study provides novel insight into the cancer epigenome and leads the way for future systematic analyses to investigate epigenetic transformations underlying distinct types and stages of cancer.