The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis

Ke Yang; Tianqi Zhu; Jiaying Yin; Qiaoli Zhang; Jing Li; Hong Fan; Gaijing Han; Weiyin Xu; Nan Liu; Xiang Lv

doi:10.1016/j.jgg.2024.02.003

The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis

J Genet Genomics. 2024 Feb 24:S1673-8527(24)00032-8. doi: 10.1016/j.jgg.2024.02.003. Online ahead of print.

Authors

Ke Yang¹, Tianqi Zhu², Jiaying Yin³, Qiaoli Zhang², Jing Li³, Hong Fan³, Gaijing Han³, Weiyin Xu², Nan Liu⁴, Xiang Lv⁵

Affiliations

¹ Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang 311121, China; The State Key Laboratory for Complex, Severe, and Rare Diseases, Haihe Laboratory of Cell Ecosystem, Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Electronic address: yangk_92@163.com.
² Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang 311121, China.
³ The State Key Laboratory for Complex, Severe, and Rare Diseases, Haihe Laboratory of Cell Ecosystem, Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
⁴ Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang 311121, China. Electronic address: liun@zju.edu.cn.
⁵ The State Key Laboratory for Complex, Severe, and Rare Diseases, Haihe Laboratory of Cell Ecosystem, Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Medical Epigenetics Research Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Electronic address: lvxiang@pumc.edu.cn.

PMID: 38403115
DOI: 10.1016/j.jgg.2024.02.003

Abstract

The post-transcriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process can have detrimental effects on normal development and give rise to various diseases. The search for novel post-transcriptional regulators and the exploration of their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait genome-wide association studies (GWAS) and transcriptomes of erythropoiesis, we identified FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in the late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner. Furthermore, we identified transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C, which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis. In conclusion, our study unveils a novel role of FAM46C in positively regulating lysosome and mitochondria components, thereby promoting erythropoiesis.

Keywords: Erythroblasts; Erythroid-specific enhancer; FAM46C; Poly(A) polymerase; Post-transcriptional regulation; TENT5C.