REDH:A database of RNA editome in hematopoietic differentiation and malignancy

Background:The conversion of adenosine(A)to inosine(I)through deamination is the prevailing form of RNA editing,impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species.Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases,providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets.However,the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking.Methods:We downloaded RNA sequencing(RNA-seq)data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information(NCBI)Gene Expression Omnibus(GEO)database,and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used.We performed sequence alignment,identified RNA editing sites,and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases.Results:We established a new database,"REDH",represents RNA editome in hematopoietic differentiation and malignancy.REDH is a curated database of associations between RNA editome and hematopoiesis.REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts(human).Through the Differentiation,Disease,Enrichment,and knowledge modules,each A-to-I editing site is systematically integrated,including its distribution throughout the genome,its clinical information(human sample),and functional editing sites under physiological and pathological conditions.Furthermore,REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control.Conclusions:REDH is accessible at http://www.redhdatabase.com/.This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies.It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

RNA and hematopoiesis

Hematopoietic stem cells(HSCs)can differentiate into all mature functional blood cells via hematopoiesis,but can also self-renew to replenish the progenitor cell pool.Both hema-topoiesis and HSC renewal are strictly orchestrated processes to guard against dysregulation that could lead to life-threat-ening blood malignancies,such as leukemia.RNA regulatory networks have essential roles in ensuring normal hematopoi-esis.Now,state-of-the-art,high-throughput sequencing tech-nologies,including RNA-seq,CLIP-seq,ChIP-seq,ChIRP-seq,MeRIP-seq,are allowing us to gain comprehensive insights into the contribution of RNA regulatory networks to hema-topoiesis and how they might be perturbed to promote malignancies.

Multifaced regulator: RNA binding proteins and their roles in hematopoiesis

Despite the conventional definition of RNA binding proteins(RBPs)as controlling the metabolism of their bound RNAs,more and more RBPs are found to function via distinct ways in complex biological processes.With the recent discovery of transcriptional regulation activity of some RBPs,a hypothesis that RBPs could be multilayered regulators orchestrating gene expression has emerged.Hematopoiesis is a stepwise process that needs to be fine-tuned to keep the subtle balance between hematopoietic stem cell(HSC)stemness maintenance and downstream lineage commitment.Although the classic RBPs account for the posttranscriptional regulation in hematopoiesis,the importance and multiple regulatory capacities of RBPs have not been wellcharacterized.In this review,we summarize the recent findings of large-scale screening of novel RBPs and their novel transcriptional regulation potentials.In hematopoietic system,this kind of multifaced regulators account for nearly a half of functional RBPs.Therefore,further studies on identifying this new kind of multifaced RBPs and clarifying their regulatory mechanisms would help us better understand the precise and complex regulatory networks of gene expression in hematopoiesis.

KHSRP combines transcriptional and posttranscriptional mechanisms to regulate monocytic differentiation

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.