hnRNPK condensates facilitate enhancer-promoter looping and RNA polymerase II recruitment.

hnRNPK forms cavity-containing condensates that encapsulate RNA polymerase II through its RPB3 subunit and promote enhancer-promoter looping; the Au-Kline syndrome variant c.953+1dupG shifts these condensates from a liquid-like to a gel-like state.

Enhancer RNAs interact with promoter-derived RNAs to dictate enhancer-promoter looping, but the RNA-binding protein mediating this process was unidentified. The authors identify hnRNPK as a general structural regulator that preferentially binds nascent RNAs transcribed from enhancer and promoter regions, promoting looping and transcriptional activation. hnRNPK forms phase-separated, cavity-containing condensates that encapsulate RNA polymerase II via its RPB3 subunit, facilitating chromatin looping and potentially enabling polymerase recruitment from enhancers to promoters through protein dimerization. The Au-Kline syndrome variant c.953+1dupG shifts condensates from a liquid-like to a gel-like state, causing developmental defects in knock-in mice; fibroblasts from these mutants show reduced enhancer-promoter looping and decreased polymerase recruitment at promoters of key developmental genes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The interest for the clinical geneticist is indirect but real: having a precise mechanism, the liquid-to-gel switch of condensates, provides a functional framework for arguing the pathogenicity of HNRNPK variants currently classed as uncertain, particularly splice variants that are hard to interpret. The work nevertheless rests on a single recurrent variant and a knock-in mouse model, with no patient series, so it does not yet provide a functional assay transferable to the diagnostic laboratory. Worth following as a mechanistic building block rather than an immediately usable interpretation tool.

Analysis by Dr Thibaut Benquey