POGZ Is Required for Silencing Mouse Embryonic β-like Hemoglobin and Human Fetal Hemoglobin Expression

Abstract

Fetal globin genes are transcriptionally silenced during embryogenesis through hemoglobin switching. Strategies to derepress fetal globin expression in the adult could alleviate symptoms in sickle cell disease and β-thalassemia. We identified a zinc-finger protein, pogo transposable element with zinc-finger domain (POGZ), expressed in hematopoietic progenitor cells. Targeted deletion of Pogz in adult hematopoietic cells in vivo results in persistence of embryonic β-like globin expression without affecting erythroid development. POGZ binds to the Bcl11a promoter and erythroid-specific intragenic regulatory regions. Pogz mice show elevated embryonic β-like globin expression, suggesting that partial reduction of Pogz expression results in persistence of embryonic β-like globin expression. Knockdown of POGZ in primary human CD34 progenitor cell-derived erythroblasts reduces BCL11A expression, a known repressor of embryonic β-like globin expression, and increases fetal hemoglobin expression. These findings are significant, since new therapeutic targets and strategies are needed to treat β-globin disorders.

Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes

“…In particular, 78 out of 913 and 251 genes annotated to neurogenesis (GO: 0022008) in human and mouse, respectively, showed commonly differential expression between human and mouse (Supplementary Tables 4 and 5). Considering that POGZ represses gene transcription in hematopoietic cells 37,38 , we focused on the upregulated genes in NSCs derived from the patient and POGZ WT/Q1038R mice. We found that, among these differentially expressed genes involving neuronal development, a Notch ligand, Jagged canonical Notch ligand 2 (JAG2), was expressed approximately two-fold higher in NSCs derived from both the patient (fold change = 1.970) and POGZ WT/Q1038R mice (fold change = 2.175) compared to each corresponding control NSCs (Supplementary Tables 4 and 5).…”

“…The source data underlying figures e, g and i are provided as a Source Data file. transcription factor, heterochromatin protein 1 (HP1), and chromodomain helicase DNA-binding protein 4 (CHD4) [35][36][37] , which suggests that POGZ functions as a chromatin regulator; however, the role of POGZ in brain development and the biological significance of ASD-associated de novo POGZ mutations in the etiology of ASD are largely unknown.…”

POGZ de novo missense variants in neuropsychiatric disorders

“…POGZ encodes a domesticated DNA transposase containing a cluster of multiple C 2 H 2 ‐type ZNF domains, a HTH domain, and a DDE domain (Bartholomeeusen et al, ; Nozawa et al, ). The expression pattern of POGZ in fetal brain tissues suggests that POGZ may play an essential role in early embryonic development (Gudmundsdottir et al, ; Stessman et al, ). Previous studies have shown that POGZ is involved in neuronal proliferation, neurite outgrowth, chromatin remodeling, and gene transcription regulation (De Rubeis et al, ; Gudmundsdottir et al, ; Hashimoto et al, ; Nozawa et al, ).…”

“…The expression pattern of POGZ in fetal brain tissues suggests that POGZ may play an essential role in early embryonic development (Gudmundsdottir et al, ; Stessman et al, ). Previous studies have shown that POGZ is involved in neuronal proliferation, neurite outgrowth, chromatin remodeling, and gene transcription regulation (De Rubeis et al, ; Gudmundsdottir et al, ; Hashimoto et al, ; Nozawa et al, ). Genotype–phenotype correlation analysis has revealed that likely gene‐disrupting variants in POGZ define a potential ASD and ID syndrome (Stessman et al, ).…”

Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

“…We studied how Pogz dosage affect phenotypic outcome by generating heterozygote and homozygote knockout (KO) of Pogz. Since a complete KO of Pogz cause early embryonic lethality 25 , we crossed a conditional Pogz flox/flox (Pogz fl/fl ) mice with transgenic Nestin CRE (Nes Cre/+ ; Pogz fl/+ ) in order to produce heterozygous (Nes Cre/+ ; Pogz fl/+ ) and homozygous (Nes Cre/+ ; Pogz fl/fl ) mutation restricted to the brain (hereafter referred to as Pogz cKO +/and Pogz cKO -/-) ( Figure 1A).…”