For those of you with a keen eye, you’ll have already noticed the mass of Epigenomic Roadmap Studies published in Nature in February. In order to help you navigate this mountain of results we’ve highlighted some of our favorite findings from this collection of papers.
Here’s our Top Five Findings:
Enhancer-like Elements Take Center Stage in Autoimmune Disease
In order to better understand the genetic and epigenetic landscape of autoimmune disease the labs of David A. Hafler and Bradley E. Bernstein joined forces to develop a robust and precise integrated algorithm which they used to identify and maps the genetic and epigenetic causal variants loci associated with 21 different autoimmune diseases.
Key highlights about this important piece of work include:
- 90% of causal variants are non-coding.
- 60% of the causal variants map to enhancer-like elements associated with increased histone acetylation and non-coding RNA transcription.
- Causal SNPs are mostly enriched near binding sites for immune-related transcription factors.
The joint effort of these two labs provides a rich resource for autoimmune research, identifying context-specific immune enhancers in automimmune diseases, and offering an epigenetic mechanism of action for non-coding causal variants. This important work, which streamlined the causal variant loci identification process, is a great leap forward from conventional complicated genome-wide association study (GWAS)-based identification of genetic loci linked to disease susceptibility.
Read the full paper over in Nature, February 2015.
An Epigenetic Affair to Remember: Immune Response and Alzheimer’s Disease
If it is true that we are what we remember of ourselves, then Alzheimer’s disease (AD) destroys your identity. We all know AD is a devastating neurodegenerative disorder and probably the most onerous threat to health in old age. However, the fundamental cause(s) of Alzheimer’s disease remain unknown.
Interestingly, two independent studies published recently in Nature Neuroscience demonstrate an epigenetic link to AD, consistent with the idea of AD been influenced by environmental and experiential factors.
In a new and exciting twist to the story, researchers led by Manolis Kellis demonstrate that epigenetic marks present in the human and mouse brains can be linked to immune response and neuronal plasticity, two factors for which association with AD is well documented. Their observations are consistent with a model where epigenetic alterations in brain cells may provide a link between immune susceptibility to environmental factors and cognitive decline.
Highlights of their study include:
- Using ChiP-seq of a mouse model of AD and human samples from AD patients they found epigenetic matches for 90% of promoter regions, 84% of enhancer regions, 74% of polycomb-repressed regions and 33% of heterochromatin regions between human and mouse orthologues.
- Following up on the promoter regions, they found these regions were consistently enriched in immune functions and synapse and learning-associated functions.
- Interestingly, in adult brain tissues the enrichment in immune functions was weaker, suggesting a bias towards neuronal plasticity (dys)function with age.
Read more in the full article in Nature, February 2015.
Trailblazing Transcription Factors: First on the Scene for Transcriptional Competence
Understanding the steps underlying differentiation is a challenge that has caught the eye of many researchers, including the epigenetic changes associated with neuronal differentiation. For researchers in the lab of Alexander Meissner the interest lay in uncovering the changes of transcription factor dynamics during differentiation.
The team used micrococcal nuclease (MNase)-based ChIP-seq (MN ChIP-seq) to assess changes in the binding characteristics for over 30 different transcription factors (TFs) during the differentiation of human embryonic stem cells (hESCs) to cells representative of the early stages of endoderm (dEN), mesoderm (dME) and ectoderm (dEC). This represents an important data reference and its worth is further amplified by its association with similar ChIP-based studies assessing epigenetic changes, both within the same study and covered in another Epigenome Roadmap study.
Highlights of this current study include:
- The loss of DNA methylation upon binding of lineage-specific TF’s in their appropriate germ layer, suggesting a possible role of such TFs as “pioneer factors” which may act as the first step towards transcriptional competence of said regulatory region.
- The role for lineage-specific combinations of TF binding at super-enhancer regulatory elements marked by H3K27Ac.
Read the full story over at Nature, February 2015.
The Benefits of Being Open: Lower Mutations in Accessible Chromatin
Somatic mutations in cancer cells are not uniformly distributed along the human genome and are instead highly cell-type specific, much like epigenetic organization. Researchers led by Shamil R. Sunyaev compared the genomic distribution of mutations in eight types of cancer with 424 epigenetic features analyzed in cell types corresponding to the established or likely origin of the cancers studied.
Key findings included:
- Epigenomic features associated with active chromatin were associated with low mutation density, whereas repressive chromatin features were associated with regions of high mutation density.
- Together with replication timing, chromatin accessibility and modifications could explain a whopping 86% of the variation in mutation rates along cancer genomes.
- A predictive score based on mutations correctly identified 88% of cancers tested, including 94% of liver cancers and 100% of colorectal cancers and glioblastomas.
So, DNA sequence alone should be able to pinpoint the origin of a particular tumor. For the whole story, head over to Nature, February 2015.
Dynamic Chromatin Dance During Differentiation
Researchers in the Lab of epigenetic giant Bing Ren wanted to understand the relationship between higher order chromatin structure and gene expression during development.
Previously the Bing laboratory and others discovered that interphase chromosomes are divided into megabase and smaller sub domains called TAD (topologically associated domains). These TADs are the basis of the higher order chromatin structures called A and B compartment, which are associated with active and repressive chromatin, respectively.
The authors looked in five cells types, including ES cells and derived lineages, and took data on Chip-seq, mRNAseq, methylC-seq, and DHS data available from the consortium, and their own Hi-C data before analysis with HaploSeq.
From this they found:
- A and B compartments appear very dynamic upon ES differentiation and they switch conformation together with their respective TAD.
- The B compartment increases during differentiation.
- Despite these organizational changes, gene expression in the A and B compartments does not show high variation suggesting that the compartments are not a determinant for fate decision.
- At a higher level, within the TADs, the authors observe changes in chromatin structure correlating especially with active marks.
- The enhancer mark H3K4me1 was found to be the most important predictor of changes in chromatin structures.
- Chromatin compartments (A, B and TADs) between haplotypes appear very similar.
- Allelic imbalances do not reflect on/off states, but instead various shades of expression that correlate with allelic imbalances in histone acetylation, histone methylation, CTCF binding, DHS and DNA methylation status at promoters.
- Curiously the authors identify allelic enhancers that are connected through looping or transient interactions to genes that show allelic bias.
In this spaghetti like chromatin something seems to get out of the loop and determine development. Untangle the full story in Nature, February 2015.
This article only touches on a few of the papers that have come out of the epic Epigenetic Roadmap study, to access them all head over to the Nature Epigenomic Roadmap Page.