enhancer

**Definition and features** - Enhancers are cis-acting DNA elements (~50-1500 bp) that bind specific activator transcription factors and boost the transcription rate of a gene on the same DNA molecule. - They can act at long distances (up to 1 Mb or more), upstream or downstream of the gene, or within introns. They work in either orientation. - They are a major source of tissue-specific and developmental stage-specific gene expression.

**Mechanism** - Activators bind the enhancer. They recruit coactivators such as histone acetyltransferases (e.g., p300/CBP), chromatin remodelers, and the Mediator complex. - DNA looping (often facilitated by cohesin and CTCF-defined topologically associating domains) brings the enhancer close to the promoter. This helps assemble the RNA polymerase II preinitiation complex (TFIID, TFIIB, TFIIH, etc.) at the core promoter (TATA box). - Active enhancers are marked by H3K27 acetylation and H3K4 monomethylation (H3K4me1). They usually lie in open (DNase-hypersensitive) chromatin.

**Comparison with related elements (high-yield)** - **Promoter:** Located immediately upstream of the gene (TATA ~-25, CAAT ~-75, GC box). It is position- and orientation-dependent and sets the basal transcription level and start site. - **Silencer:** A cis-acting element that binds repressors and decreases transcription. - **Insulator:** Blocks enhancer-promoter interaction or heterochromatin spread. It binds CTCF. - **Response elements:** Enhancer-like sequences that bind hormone-receptor or signal-activated transcription factors (e.g., glucocorticoid response element, cAMP response element/CREB). - **Trans-acting factors** (transcription factors) are proteins that bind cis elements. Cis elements are the DNA sequences themselves.

**Clinical correlations** - **Burkitt lymphoma, t(8;14):** The c-myc proto-oncogene is placed next to the immunoglobulin heavy chain enhancer, which causes overexpression of MYC. - **Preaxial polydactyly:** Point mutations in the ZRS enhancer of Sonic hedgehog (SHH), located in an intron of the LMBR1 gene about 1 Mb away, cause ectopic SHH expression in the limb bud. - **β-thalassemia/hereditary persistence of fetal hemoglobin:** Mutations or deletions in the locus control region (LCR, a strong enhancer cluster) or the BCL11A erythroid enhancer affect globin gene expression. Casgevy (exagamglogene autotemcel) is a CRISPR therapy that edits the BCL11A erythroid enhancer to reactivate HbF in sickle cell disease and β-thalassemia. - **Cancer:** Enhancer hijacking and mutated or amplified enhancers can activate oncogenes (e.g., GATA2/EVI1 in inv(3)/t(3;3) AML). - **GWAS:** Most disease-associated noncoding variants lie in enhancers. - **Viral enhancers:** SV40, CMV, and HBV have enhancers. They are used in expression vectors.

**Board pearls** - Enhancer = cis-acting DNA, distance- and orientation-independent, binds activators. - Promoter mutations usually reduce the basal transcription rate. Enhancer mutations often alter tissue-specific expression. - Eukaryotic-specific regulation. Prokaryotes mostly use operons with promoters and operators (the lac operon's CAP-cAMP site is analogous but not a classical enhancer).