KHSRP combines transcriptional and posttranscriptional mechanisms to regulate monocytic differentiation

Jiayue Xu; Dongsheng Wang; Hongliu Ma; Xueying Zhai; Yue Huo; Yue Ren; Weiqian Li; Le Chang; Dongxu Lu; Yuehong Guo; Yanmin Si; Yufeng Gao; Xiaoshuang Wang; Yanni Ma; Fang Wang; Jia Yu

doi:10.1097/BS9.0000000000000122

KHSRP combines transcriptional and posttranscriptional mechanisms to regulate monocytic differentiation

Blood Sci. 2022 Jul 1;4(3):103-115. doi: 10.1097/BS9.0000000000000122. eCollection 2022 Jul.

Authors

Jiayue Xu^{1

2}, Dongsheng Wang³, Hongliu Ma⁴, Xueying Zhai^{1

2}, Yue Huo^{1

2}, Yue Ren^{1

2}, Weiqian Li^{1

2}, Le Chang^{1

2}, Dongxu Lu^{1

2}, Yuehong Guo^{1

2}, Yanmin Si^{1

2}, Yufeng Gao^{1

2}, Xiaoshuang Wang^{1

2}, Yanni Ma^{1

2}, Fang Wang^{1

2}, Jia Yu^{1

2

5}

Affiliations

¹ State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
² Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing 100005, China.
³ Department of Clinical Laboratory, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
⁴ Department of Gynecology, Dian Jiang People's Hospital of Chong Qing, Chongqing 408300, China.
⁵ Medical Epigenetic Research Center, Chinese Academy of Medical Sciences, Beijing 100005, China.

Abstract

RNA-binding proteins (RBPs) are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes. The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs (Che-RBPs). One of these proteins, KH-type splicing regulatory protein (KHSRP), is a multifunctional RBP that has been implicated in mRNA decay, alternative splicing, and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129. In this study, we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing. KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation. Of note, KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1. Taken together, our analyses revealed the dual DNA- and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.

Keywords: KHSRP; Monocytic differentiation; RNA-binding proteins; Transcriptional regulation.

Copyright © 2022 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).