秀丽隐杆线虫RNA结合蛋白复合物AMG-1/SLRP-1通过线粒体稳态维持实现调控生殖腺发育和精子发生

RNA结合蛋白(mtRBP)介导的mRNA转录后调节对精子发生必不可少但却鲜有报道.在本文中,我们鉴定到一个在生殖腺中特异性表达的线粒体RNA结合蛋白AMG-1,它是秀丽隐杆线虫精子发生过程中必需的蛋白,同时与哺乳动物LRPPRC蛋白同源.amg-1突变会阻碍生殖腺的发育,最终导致生殖细胞的线粒体形态和结构异常以及线粒体功能障碍.通过测序鉴定RNA结合蛋白的靶点发现,AMG-1更倾向于与mtDNA编码的参与线粒体核糖体组装的12S和16S核糖体RNA(rRNA)结合,12S rRNA对于维持生殖细胞线粒体蛋白稳态至关重要,而12S rRNA的表达却受AMG-1蛋白调节.此外,哺乳动物SLIRP在秀丽线虫中的同源蛋白SLRP-1蛋白与AMG-1在遗传上存在互作关系,它们可共同调节秀丽线虫的精子发生和育性.综上所述,这些发现揭示了mtRBP蛋白AMG-1在线粒体调控中的新机制,这可能为由线粒体功能障碍引发的男性不育治疗提供新的理论基础.

RBM46 is essential for gametogenesis and functions in post-transcriptional roles affecting meiotic cohesin subunits

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis,but the targets and molecular functions of RBM46 remain unknown.Here,we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation.Using a recently reported,high-resolution technique known as LACE-seq and working with low-input cells,we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes.We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions.In Rbm46 knockout mice,the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation,resulting in the failed assembly of axial elements,synapsis disruption,and meiotic arrest.Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.

ADAR1:a mast regulator of aging and immunity

Recently,Nature and Nature Cell Biology published five papers on the function and molecular mechanism of ADAR1(adenosine deaminases acting on RNA)in aging,cancer,and autoimmune diseases.1,2,3,4,5 Among them,four papers published in Nature revealed that ADAR1 regulates autoimmune disease and cancer immunotherapy through canonical adenosine-to-inosine(A-to-I)RNA editing.

RNA biology and therapeutics

Eukaryotic genomes undergo pervasive transcription,generating vast amounts of noncoding RNAs alongside protein-coding mRNAs[1].These noncoding RNAs,including small noncoding RNAs,long noncoding RNAs(lncRNAs),and circular RNAs,have been shown to play critical roles in gene regulation,chromatin remodeling,assembly of membraneless organelles,and other essential biological processes.They function through a diverse range of mechanisms[2],[3],[4],[5].Dysregulation of noncoding RNAs contributes to human disease pathogenesis and affects plant development and stress response[6],[7],[8].Over the past decade,significant progress has been made in unraveling the functions of noncoding RNAs and elucidating the molecular mechanisms by which they operate.The involvement of noncoding RNAs in human disease pathogenesis and agronomic trait regulation has garnered increasing attention.

Emerging roles of non-coding RNAs in epigenetic regulation

Recent deep sequencing surveys of mammalian genomes have unexpectedly revealed pervasive and complex transcription and identified tens of thousands of RNA transcripts that do not code for proteins. These non-coding RNAs(nc RNAs) highlight the central role of RNA in gene regulation. nc RNAs are arbitrarily divided into two main groups: The first includes small RNAs, such as mi RNAs, pi RNAs, and endogenous si RNAs, that usually range from 20 to 30 nt, while the second group includes long non-coding RNAs(lnc RNAs), which are typically more than 200 nt in length. These nc RNAs were initially thought to merely regulate gene expression at the post-transcriptional level, but recent studies have indicated that nc RNAs, especially lnc RNAs, are extensively associated with diverse chromatin remodeling complexes and target them to specific genomic loci to alter DNA methylation or histone status. These findings suggest an emerging theme of nc RNAs in epigenetic regulation. In this review, we discuss the wide spectrum of nc RNAs in the regulation of DNA methylation and chromatin state, as well as the key questions that needs to be investigated and acknowledging the elegant design of these intriguing macromolecules.

Noncoding RNA:from dark matter to bright star

The central dogma states that genes encoded in the DNA should be first transcribed into messenger RNA(mRNA)and then translated into functional proteins(Crick,1970).This dogma has been written in numerous textbooks and learned by myriad students.However,along with the completion of the human genome project in June 2000,an astonishing fact was revealed:only 1.5%of the human genome encodes for proteins(Lander et al.,2001;Venter et al.,2001).This fact raised three fundamental questions:(i)why does the human genome have so few protein-coding genes?(ii)how to explain the apparent differences between humans and other species using the limited coding genes?(iii)what are the roles of the noncoding regions in our genome?

SRSF1 plays a critical role in invariant natural killer T cell development and function

Invariant natural killer T(iNKT)cells are highly conserved innate-like T lymphocytes that originate from CD4^(+)CD8^(+)double-positive(DP)thymocytes.Here,we report that serine/arginine splicing factor 1(SRSF1)intrinsically regulates iNKT cell development by directly targeting Myb and balancing the abundance of short and long isoforms.Conditional ablation of SRSF1 in DP cells led to a substantially diminished iNKT cell pool due to defects in proliferation,survival,and TCRαrearrangement.The transition from stage 0 to stage 1 of iNKT cells was substantially blocked,and the iNKT2 subset was notably diminished in SRSF1-deficient mice.SRSF1 deficiency resulted in aberrant expression of a series of regulators that are tightly correlated with iNKT cell development and iNKT2 differentiation,including Myb,PLZF,Gata3,ICOS,and CD5.In particular,we found that SRSF1 directly binds and regulates pre-mRNA alternative splicing of Myb and that the expression of the short isoform of Myb is substantially reduced in SRSF1-deficient DP and iNKT cells.Strikingly,ectopic expression of the Myb short isoform partially rectified the defects caused by ablation of SRSF1.Furthermore,we confirmed that the SRSF1-deficient mice exhibited resistance to acute liver injury uponα-GalCer and Con A induction.Our findings thus uncovered a previously unknown role of SRSF1 as an essential post-transcriptional regulator in iNKT cell development and functional differentiation,providing new clinical insights into iNKT-correlated disease.

Recent advances in RNA structurome

RNA structures are essential to support RNA functions and regulation in various biological processes. Recently, a range of novel technologies have been developed to decode genome-wide RNA structures and novel modes of functionality across a wide range of species. In this review, we summarize key strategies for probing the RNA structurome and discuss the pros and cons of representative technologies. In particular, these new technologies have been applied to dissect the structural landscape of the SARS-CoV-2 RNA genome. We also summarize the functionalities of RNA structures discovered in different regulatory layers-including RNA processing, transport, localization, and mRNA translation-across viruses, bacteria, animals, and plants. We review many versatile RNA structural elements in the context of different physiological and pathological processes(e.g., cell differentiation, stress response, and viral replication). Finally, we discuss future prospects for RNA structural studies to map the RNA structurome at higher resolution and at the single-molecule and single-cell level, and to decipher novel modes of RNA structures and functions for innovative applications.