Short version: introns aren’t “junk,” they’re basically regulatory real estate, and variants in them can absolutely mess with transcription factor (TF) binding, especially when those introns host enhancer / super-enhancer–like elements that talk to the promoter.

You asked specifically about transcription factor interactions and superpromoters, so I’ll stick to mechanisms rather than generic “noncoding variants matter” handwaving.

1. Introns can

be

enhancers / super-enhancer components

A lot of enhancers are intronic. Some “super-enhancers” or “stretch promoters” actually span into the first intron or lie entirely within introns of the same gene or a neighbor.

An intronic variant there can:

• Create / destroy TF motifs
  • Single-base change → higher/lower affinity motif for a TF (e.g. ETS, AP-1, NF-κB, etc.)
  • Outcome: gain of a new TF hub, loss of a necessary TF, or TF switching (one factor loses, another gains).
• Change cooperative TF binding
  • TFs at super-enhancer modules often bind cooperatively.
  • Slight motif spacing/strength changes can:
    • Break cooperative binding “clusters”
    • Change which TFs co-occupy that mini-module
    • Alter recruitment of cofactors like Mediator, p300, BRD4

Result: altered enhancer “potency,” which then feeds into how strongly it drives the promoter.

2. Superpromoters / super-enhancers: 3D looping & contact probability

In many loci, intronic enhancers loop to the promoter via:

• Cohesin (SMC1/3)
• CTCF motifs
• Mediator complex
• BRD4 and other coactivators

Intronic variants can affect TF interactions at these sites by: