Plant transformation is important for gene functional study and crop breeding application. The success of transformation largely depends on the totipotency of explants used and the regeneration efficiency. Though genetic transformation is available in many plant species, the transformation efficiency in wheat is generally low with strong varieties preference, which greatly restricting the genetic manipulation in wheat. Here, we use multi-comic analysis strategy to understand core transcriptional regulatory network (TRN) driving wheat regeneration and identify key factors which could boost the transformation efficiency. RNA-seq, ATAC-seq and Cut & Tag were used to profile the transcription and chromatin dynamic during regeneration process from immature embryo of wheat variety Fielder. We found sequential expression of gene clusters during regeneration induced by hormone signaling, which is mainly coordinated by changes of chromatin accessibility and H3K27me3 status. Furthermore, a sequential TRN driving wheat regeneration was built-up and 446 key transcriptional factors occupied the core of network were identified. Among them, 40 TFs are the orthologs of regeneration factors in Arabidopsis. We further compared the regeneration process between wheat and Arabidopsis. Genes related to cell proliferation, such as BBM and members of E2F family, show similar pattern. By contrast, LBD and DOF show distinct patterns between monocotyledons and dicotyledons, suggesting their species specific function potentially. Indeed, we found that DOF, SCR can significantly improve the transformation efficiency of wheat. Thus, our data uncovers the core TRN driving wheat regeneration from immature embryo, and identified novel boosters for lifting the transformation efficiency in wheat.