Epigenetic modifications and human disease

Journal name:
Nature Biotechnology
Year published:
Published online


Epigenetics is one of the most rapidly expanding fields in biology. The recent characterization of a human DNA methylome at single nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. Increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. These allow the mapping of epigenetic marks, such as DNA methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding RNA expression. In turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. Thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research.

At a glance


  1. DNA methylation patterns.
    Figure 1: DNA methylation patterns.

    DNA methylation can occur in different regions of the genome. The alteration of these patterns leads to disease in the cells. The normal scenario is depicted in the left column and alterations of this pattern are shown on the right. (a) CpG islands at promoters of genes are normally unmethylated, allowing transcription. Aberrant hypermethylation leads to transcriptional inactivation. (b) The same pattern is observed when studying island shores, which are located up to 2 kb upstream of the CpG island. (c) However, when methylation occurs at the gene body, it facilitates transcription, preventing spurious transcription initiations. In disease, the gene body tends to demethylate, allowing transcription to be initiated at several incorrect sites. (d) Finally, repetitive sequences appear to be hypermethylated, preventing chromosomal instability, translocations and gene disruption through the reactivation of endoparasitic sequences. This pattern is also altered in disease.

  2. Epigenetic machinery and interplay among epigenetic factors.
    Figure 2: Epigenetic machinery and interplay among epigenetic factors.

    Epigenetic marks are catalyzed by different epigenetic complexes, whose principal families are illustrated here. (a–c) Epigenetic regulation depends on the interplay among the different players: DNA methylation (a), histone marks (b) and nucleosome positioning (c). The interaction among the different factors brings about the final outcome. This figure illustrates selected examples of the possible interrelations among the various epigenetic players.

  3. Histone modifications.
    Figure 3: Histone modifications.

    All histones are subject to post-transcriptional modifications, which mainly occur in histone tails. The main post-transcriptional modifications are depicted in this figure: acetylation (blue), methylation (red), phosphorylation (yellow) and ubiquitination (green). The number in gray under each amino acid represents its position in the sequence.

  4. Nucleosome positioning patterns.
    Figure 4: Nucleosome positioning patterns.

    Nucleosome positioning plays an important role in transcriptional regulation. Transcriptionally active gene promoters possess a nucleosome-free region at the 5′ and 3′ untranslated region, providing space for the assembly and disassembly of the transcription machinery. The loss of a nucleosome directly upstream of the TSS is also necessary for gene activation, whereas the occlusion of this position leads to transcription repression. DNA methylation regulates transcription, and thus interferes with nucleosome positioning. Methylated DNA seems to be associated with 'closed' chromatin domains, where DNA is condensed into strictly positioned nucleosomes, thereby impeding transcription. Conversely, unmethylated DNA is associated with 'opened' chromatin domains, which allow transcription.


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  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.

    • Anna Portela &
    • Manel Esteller
  2. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.

    • Manel Esteller

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