Hnrnpk is essential for embryonic limb bud development as a transcription activator and a collaborator of insulator protein Ctcf

Proper development of the limb bud relies on the concordance of various signals, but its molecular mechanisms have not yet been fully illustrated. Here we report that heterogeneous nuclear ribonucleoprotein K (hnRNPK) is essential for limb bud development. Its ablation in the limb bud results in limbless forelimbs and severe deformities of the hindlimbs. In terms of mechanism, hnRNPK functions as a transcription activator for the vital genes involved in the three regulatory axes of limb bud development. Simultaneously, for the first time we elucidate that hnRNPK binds to and coordinates with the insulator protein CCCTC binding factor (CTCF) to maintain a three-dimensional chromatin architecture. Ablation of hnRNPK weakens the binding strength of CTCF to topologically associating domain (TAD) boundaries, then leading to the loose TADs, and decreased interactions between promoters and enhancers, and further decreased transcription of developmental genes. Our study establishes a fundamental and novel role of hnRNPK in regulating limb bud development.

Automated summary

This study reveals that hnRNPK is crucial for limb bud development. Its absence leads to limbless forelimbs and severe hindlimb deformities. Mechanistically, hnRNPK functions as a transcription activator for key genes involved in limb bud development and coordinates with CTCF to maintain chromatin architecture. The loss of hnRNPK weakens CTCF binding, resulting in loose topologically associating domains (TADs), decreased interactions between promoters and enhancers, and reduced transcription of developmental genes.