ELF5‐Mediated Enhancer–Promoter Interaction Regulates LALBA Expression in Ovine Mammary Gland

ABSTRACT Epigenetic mechanisms underlying lactation traits in sheep remain poorly understood. Here, we systematically characterized the transcriptomic dynamics, chromatin accessibility landscape, and histone modification profiles of mammary gland tissues from Yuansheng Aite dairy sheep with divergent lactation performance. The lactalbumin alpha ( LALBA ) locus harbors a super‐enhancer, and expression of LALBA was upregulated in sheep with low lactation performance. Enhancer E4 functions as the core active element within the LALBA super‐enhancer, and its repression reduced LALBA expression. Chromosome conformation capture‐polymerase chain reaction (3C‐PCR) confirmed a direct chromatin interaction between E4 and the LALBA promoter. The E74‐like ETS transcription factor 5 (ELF5) binds to both E4 and the LALBA promoter, consistent with the observation that E4 and the LALBA promoter region exhibit greater chromatin accessibility in the low lactation ewes. E4 promotes LALBA transcription via ELF5‐mediated chromatin looping, thereby inhibiting cell cycle progression and the proliferation of ovine mammary epithelial cells (OMECs). This study suggests a new target and provides a theoretical basis for the genetic improvement of lactation performance in sheep.