Zinc finger protein WIZ (WIZ)

Zinc finger protein WIZ is a transcription factor characterized by its widely interspaced C2H2-type zinc finger motifs, which allow it to act as a critical scaffold and recruiter for the G9a (EHMT2) and GLP (EHMT1) histone methyltransferase complex [1][2]. This complex is primarily responsible for the dimethylation of histone H3 lysine 9 (H3K9me2), a modification associated with gene silencing and heterochromatin formation. In erythroid cells, WIZ plays a pivotal role in the developmental silencing of fetal hemoglobin (HbF) by recruiting the G9a/GLP complex to the gamma-globin promoter, thereby facilitating the switch from fetal to adult hemoglobin [3][4]. Due to its role as a master repressor of HbF, WIZ has emerged as a high-value therapeutic target for hemoglobinopathies such as sickle cell disease and beta-thalassemia. Therapeutic strategies currently focus on the use of molecular glues—small molecules that induce a proximity-based interaction between WIZ and an E3 ubiquitin ligase, such as Cereblon—to trigger the selective degradation of the WIZ protein [4][5]. The loss of WIZ leads to the reactivation of gamma-globin expression and a significant increase in HbF levels, which can functionally compensate for defective adult hemoglobin and reduce the clinical severity of these genetic blood disorders [5].

Other names

Widely interspaced zinc finger motifsZinc finger protein 803ZNF803

Targeted protein degradation (TPD) using molecular glues to recruit the Cereblon (CRBN) E3 ubiquitin ligase, leading to the ubiquitination and proteasomal degradation of WIZ, which derepresses the gamma-globin gene and induces fetal hemoglobin (HbF) production.