The binding of proteins to sequences both near to and distant from the promoter can also affect levels of gene expression.

Protein binding can activate transcription by facilitating either RNA polymerase binding or steps farther along in the initiation process, or it can repress transcription by blocking the activity of the polymerase.

In E. coli, one protein that activates transcription is the cAMP receptor protein (CRP), which increases the transcription of genes coding for enzymes that metabolize sugars other than glucose when cells are grown in the absence of glucose. Repressors are proteins that block the synthesis of RNA at specific genes.

In the case of the Lac repressor, transcription of the genes for the enzymes of lactose metabolism is blocked when lactose is unavailable.