FAM122A Inhibits Erythroid Differentiation through GATA1

Abstract

Summary FAM1 22A is a highly conserved housekeeping gene, but its physiological and pathophysiological roles remain greatly elusive. Based on the fact that FAM1 22A is highly expressed in human CD71 + early erythroid cells, herein we report that FAM122A is downregulated during erythroid differentiation, while its overexpression significantly inhibits erythrocytic differentiation in primary human hematopoietic progenitor cells and erythroleukemia cells. Mechanistically, FAM122A directly interacts with the C-terminal zinc finger domain of GATA1, a critical transcriptional factor for erythropoiesis, and reduces GATA1 chromatin occupancy on the promoters of its target genes, thus resulting in the decrease of GATA1 transcriptional activity. The public datasets show that FAM1 22A is abnormally upregulated in patients with β-thalassemia. Collectively, our results demonstrate that FAM122A plays an inhibitory role in the regulation of erythroid differentiation, and it would be a potentially therapeutic target for GATA1-related dyserythropoiesis or an important regulator for amplifying erythroid cells ex vivo .

Oxidative phosphorylation pathway disruption is an alternative pathological mechanism leading to Diamond-Blackfan anemia

“…Therefore, we comprehensively screened genes without changes in transcript expression, but showing a significant decrease in protein expression; thus, identifying inefficiently translated genes that may be sensitive to ribosomal defects in DBA cells (Figure 5E). FAM122A was the most significantly downregulated protein in DBA cells (Figure 5E) and it is also abnormally upregulated in patients with β-thalassemia [46]. Downregulation of FAM122A can lead to reduced GATA1 transcriptional activity by decreasing its association with target DNA in erythroid cells during terminal erythroid differentiation [46].…”

“…FAM122A was the most significantly downregulated protein in DBA cells (Figure 5E) and it is also abnormally upregulated in patients with β-thalassemia [46]. Downregulation of FAM122A can lead to reduced GATA1 transcriptional activity by decreasing its association with target DNA in erythroid cells during terminal erythroid differentiation [46]. We identified a subset of sensitive genes whose functions have not been associated with ribosome defects in erythropoiesis, except for HBG1 and FOXJ2 [47].…”

FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells

“…To address this question, scientists may apply ATAC-seq 62 to elucidate the effect of FAM122A modulation on chromatin architecture directly. Previously, we observed that FAM122A acts as a co-repressor of GATA-1 (an essential TF for erythroid differentiation) to suppress the terminal differentiation of erythroids 25 ; therefore, FAM122A possibly interacts with essential ME-related TFs to participate in the regulation of ME gene activation, which needs to be checked dynamically in different stages of differentiation with IP-MS.…”

“…FAM122A knockout (KO) suppresses the growth of hepatocellular carcinoma cells and acute myeloid leukemia cells in vitro and in vivo, with independence or dependence of PP2A inhibitory activity. 22 , 23 In addition, FAM122A is essential for maintaining the self-renewal capability of hematological stem cells 24 and required for the differentiation of erythroid cells; 25 FAM122A also contributes to the maintenance of DNA stability in malignant tumor cells. 26 These studies suggest that FAM122A has multifaceted functions under physiological or pathological circumstances.…”