22 months ago by
UT Southwestern Medical Center
I'll also give a bit of information. I work with enhancers quite a lot, and looks like these little suckers will be the focal point of my PhD work as well.
It's pretty common knowledge by now that enhancers do not always regulate their most nearby gene, and it's also pretty established that not ALL enhancers activate via enhancer-promoter loops. A more trans-cis model has been adopted where some enhancers activate in trans, while others activate via cis-looping, for any number of misunderstood and unknown reasons.
Enhancers are also known to activate or at least interact with multiple genes, and this has been seen in quite a few studies. If you knock out a single enhancer, the expression of two or more genes that are known to interact with that enhancer are reduced. There's actually some really interesting ideas on why this occurs, and my main thought is that enhancers act more like liquid-droplets than solid binary structures.
So yes, assigning the enhancer to it's nearest gene isn't always correct. And the answer is, that this is still highly debated on the best way to identify accurate enhancer-promoter predictions. I don't know of a simple enhancer-promoter prediction tool that does this efficiently, but I know of several labs who are working on this (Lander lab at Broads, and McVicker at UCSD). Their approach is to systematically identify enhancers and their gene partners via wet lab techniques (CRISPR-Cas9 on one end, and another similar approach in the latter) and then build predictive models using a variety of sequencing datasets and hope something clicks.
I've built a small predictive model that uses Hi-C, GRO-seq, ChIP-seq of a couple of different TF's and histone modifications, and DNase-seq to predict enhancer-promoter interactions. Unfortunately, I'm not allowed to do much wet work at my current job, so it's hard to verify, but you may need to do something similar to this if you're really striving for semi-accurate annotation.
EDIT: Definitely not pointless to annotate enhancers to their nearest genes, pathway analysis is broad enough, and enhancers tend to interact with their most nearest gene frequently enough that you'll still be able to gain some useful information. Anything you do should be verified experimentally.
modified 22 months ago
22 months ago by
Sinji • 2.8k