All tags epigenetics Epigenetics articles of the month: April 2016

Epigenetics articles of the month: April 2016

Keep up with the latest epigenetics research. Read our summaries of research papers from the past month.

Methylome-wide analysis of chronic HIV infection reveals five-year increase in biological age and epigenetic targeting of HLA

The epigenetic consequences of chronic HIV infection

Individuals infected with HIV are live for many decades, thanks to the advances made to anti-retroviral drugs. However, chronic HIV infection has been linked to early-onset neurodegeneration, cancer and telomere shortening – potential signs of premature aging.

Aging is associated with epigenetic changes, and previous research has used CpG DNA methylation patterns to predict the age of individuals. To test the hypothesis that HIV-positive patients experience advanced or accelerated aging, a team led by Trey Ideker from the University of California, San Diego performed a global DNA methylation analysis of HIV-positive individuals. They found the following:

  • HIV-positive individuals show a DNA methylation age that is on average 4.9 years higher than their chronological age.
  • More recently infected HIV patients did not have a significant difference in age advancement compared with chronically infected individuals, suggesting that biological age enhancement occurs early in the course of the infection.
  • HIV infection results in hypomethylation in the region encoding the human leukocyte antigen locus (HLA), which is linked to lower CD4/CD8 T cell ratio.

The results presented in this paper show that HIV infection results in epigenetic changes that mirror age-related DNA methylation and influence regulation of HLA.

Read the full paper in Molecular Cell, April 2016.


Genetic and environmental influences interact with age and sex in shaping the human methylome

DNA methylation variation is affected by genetic and environmental factors

DNA methylation contributes to long-term gene expression regulation. Changes to DNA methylation occur in response to environmental and genetic stimuli, but these factors may affect the methylome differently depending on age and sex.

To estimate between-individual variation in DNA methylation, a team led by Dorret Boomsma from Vrije Universiteit in Amsterdam analyzed DNA methylation data from a large cohort of twins and family members. They found the following:

  • The genome-wide average heritability of methylation level was 19%.
  • Environmental or stochastic influences are a more important determinant of sex-specific and age-specific variation in methylation than genetic differences.
  • The importance of the environment in changing DNA methylation patterns increases with age at many sites.

This is the most comprehensive study to date to look at the importance of genetic and environmental factors on DNA methylation variation. The authors have cataloged genetic and environmental influences on DNA methylation across the genome.

Read the full paper in Nature Communications, April 2016.


Transcriptional regulators compete with nucleosomes post-replication

A new technique to study post-replication chromatin assembly

DNA replication involves disruption of the nucleosomes to allow DNA replication machinery to pass. Chromatin state is re-established by chromatin regulators; however, the sequence of events that re-establishes chromatin state after the replication fork passes is not known. Research on this topic has been limited by current methods to map newly replicated DNA, which provide data at kilobase resolution.

To map the newly replicated epigenome at base-pair resolution, a team led by Steven Henikoff from the Fred Hutchinson Cancer Research Center and Howard Hughes Medical Institute in Seattle developed a technique called mapping in vivo nascent chromatin with EdU and sequencing (MINCE-seq).

In this technique, newly replicated DNA is labeled with EdU, which is coupled with biotin for highly specific purification of newly replicated DNA. DNA fragments, nucleosomes and DNA-binding proteins are recovered, and chromatin mapped. Using this technique, the team were able to characterize the chromosome landscape in Drosophila melanogaster cells:

  • After replication, nucleosomes assemble at promoters, displacing DNA-binding proteins.
  • Nucleosome gain at promoters after replication is dependent on the replication-coupled nucleosome assembly pathway, and occurs more in highly active promoters.
  • After replication, loss of nucleosomes after the initial gain is driven by competition from transcription factors.

The authors have shown that MINCE-seq is capable of mapping newly replicated chromatin. Using this technique, they were able to identify changes in chromatin post replication.

Read the full paper in Cell, April 2016.


Histone H3 globular domain acetylation identifies a new class of enhancers 

A complex picture of enhancer histone acetylation

Acetylation and methylation of globular histone domains can alter chromatin structure, and assembly, and affect genome stability. However, many previous studies have focused on aceylation of histone tails rather than globular domains.

To gain a better understanding of histone acetylation, a team led by Wendy Bickmore from the University of Edinburgh looked at histone acetylation in the globular domain of histone H3. Here is what they found:

  • Lysine 64 and 122 residues in the globular domains of histone H3 are acetylated in active gene promoters and enhancers.
  • ​A class of highly active enhancers is marked by H3K122ac, but not H3K27ac – which is usually a predictor of active enhancers.
  • ​Recruitment of the Sid4x repressor to the enhancers resulted in a significant repression of their target genes.

This paper paints a complex picture of histone acetylation at enhancers. The authors have demonstrated that identification of enhancers requires a more comprehensive analysis of histone acetylation than previously thought.

Read the full paper in Nature Genetics, April 2016.


Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression

α-synuclein is regulated by a non-coding distal enhancer

The vast majority of Parkinson's disease cases result from complex interactions between genetic and environmental risk factors. Mutations and duplications in the α-synuclein (SNCA) gene has been implicated in both familial and sporadic cases of Parkinson's disease, with just small increases in gene expression thought to be sufficient to contribute to disease development.

​To analyze small changes in SNCA gene expression, a team led by Rudolf Jaenisch at the Whitehead Institute in Cambridge, Massachusetts combined genome-wide epigenetic information with CRISPR/Cas9 genome editing to quantify the consequences of targeted genetic modification. They found the following:

  • A common risk variant in a non-coding distal enhancer element regulates SNCA expression.
  • Transcriptional deregulation of SNCA is associated with binding of transcription factors EMX2 and NKX6-1.

In this paper, the authors have identified a Parkinson's disease risk variant in a non-coding distal enhancer element that regulates expression of α-synuclein.

Read the full paper in Nature, April 2016.


A long non-coding RNA associated with susceptibility to celiac disease

Lnc13 regulates inflammatory genes associated with celiac disease

Celiac disease is a chronic, immune-mediated intestinal disorder that develops in genetically-susceptible individuals. Previously, 14 intergenic SNPs associated with celiac disease were identified. One of these SNPs is in a region that encodes lnc13 in mice.

A team led by Sankar Ghosh from the University of Somewhere sought to characterize the role of lnc13 in celiac disease in humans. They found the following:

  • Intestinal biopsies from celiac patients have significantly reduced lnc13.
  • Dcp2, a RNA decapping protein, recognizes lnc13 and causes its degradation in inflamed tissue.
  • Lnc13 regulates expression of a subset of inflammatory genes.
  • hnRNPD, a member of the heterogeneous nuclear  ribonucleoprotein family, binds to chromatin as a complex with lnc13 and Hdac1, but binding is abolished with lnc13 degradation
  • The lnc disease-associated variant binds hnRNPD less efficiently than wild-type.

The results in the paper suggest that lnc13 down-regulation may contribute to the inflammation seen in celiac disease, and that this protein regulates inflammatory genes by linking hnRNPD, Hdac1 and chromatin.

Read the full paper in Science, April 2016.


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