enhancers in cell-type-specific signatures

Question

I was reading an article in nature : Epigenomics: Roadmap for regulation and was confused by the definition or/and interpretation of enhancers.

Enhancers are activated through interactions with transcription factors, which recognize and bind to specific DNA sequences within the enhancer region. Bound transcription factors recruit co-regulators, many of which deposit or remove modifications on histones. […] Enhancers that are active in cell-type-specific epigenomic signatures are typically highly enriched in DNA sequences to which lineage-determining and signal-dependent transcription factors bind.

As far as I know enhancers are the DNA sequences to which TFs bind, and then everything including co-activators complexes bind to basal TFs on the promoter.

I am confused by the last line:

Enhancers that are active in cell-type-specific epigenomic signatures are typically highly enriched in DNA sequences to which lineage-determining and signal-dependent transcription factors bind.

They state, that in DNA sequences to which TFs bind the active enhancers are highly enriched. For me it sounds strange because the definition of enhancers says that these are the DNA sequences to which TFs bind. And of course enhancers are enriched there because otherwise they would not be called enhancers. As for me they are trying to say that active enhancers (by definition TFs bind to them) are highly enriched in enhancers region to which TFs bind.

Does it make sense or not?

Answer 1

You nailed down what enhancers are (canadianer give a good explanation too, while not answering the question in my opinion).

For understanding the authors statement you first need to know that:

• Lineage-specific and signal-dependent transcription factors are specific classes of transcription factors. Those are TFs that require external signals for activation.

• All enhancers are not always accessible. This depends on the epigenetic marks, and subsequently histones binding, around those regions. If, for example, an enhancer is in a region of tightly packed DNA (i.e. heterochromatin) it will not bind any TFs and is therefore not active.

What the authors where trying to convey is, in my opinion, that active enhancers are highly enriched in DNA sequences specific for signal-dependent TFs. In other terms, the cell's identity is given by a combination of 1) epigenetic regulation of gene expression via a) a certain pattern of active enhancers and b) chromatin state of genes in conjunction with 2) signal-dependent transcription factors.

In summary this means that the cell identity is not only described by signal-dependent TFs but also by the active enhancer pattern. And this therefore implies that one might be able to predict TFs necessary to determine a specific cell's identity as stated in their next sentence:

Therefore, the delineation of a particular cell's active enhancer repertoire provides a powerful means of predicting the transcription factors required for that cell's identity.

I hope this helps.

Answer 2

Enhancer is a just a term for a regulatory region distant from a gene that contains specific sites where transcription factors bind. As it happens, a single enhancer can contain DNA binding sites for multiple transcription factors.

For example, an enhancer called TESCO, which regulates a gene called SOX9 (involved in sex determination) has binding sites for many different proteins (confirmed or putative): SRY, SF1, SOX9, ESR1, FOXL2 and likely many more that I haven't heard of. This allows complex regulation of SOX9 through protein-protein interactions.