Piwi Is Required to Limit Exhaustion of Aging Somatic Stem Cells

Please see the graphical abstract in the supplemental files

Macrophage development and activation involve coordinated intron retention in key inflammatory regulators

Monocytes and macrophages are essential components of the innate immune system. Herein, we report that intron retention (IR) plays an important role in the development and function of these cells. Using Illumina mRNA sequencing, Nanopore direct cDNA sequencing and proteomics analysis, we identify IR events that affect the expression of key genes/proteins involved in macrophage development and function. We demonstrate that decreased IR in nuclear-detained mRNA is coupled with increased expression of genes encoding regulators of macrophage transcription, phagocytosis and inflammatory signalling, including ID2, IRF7, ENG and LAT. We further show that this dynamic IR program persists during the polarisation of resting macrophages into activated macrophages. In the presence of proinflammatory stimuli, intron-retaining CXCL2 and NFKBIZ transcripts are rapidly spliced, enabling timely expression of these key inflammatory regulators by macrophages. Our study provides novel insights into the molecular factors controlling vital regulators of the innate immune response

The absence of core piRNA biogenesis factors does not impact efficient transposon silencing in Drosophila

Organisms require mechanisms to distinguish self and non-self-RNA. This distinction is crucial to initiate the biogenesis of Piwi-interacting RNAs (piRNAs). In Drosophila ovaries, PIWI-guided slicing and the recognition of piRNA precursor transcripts by the DEAD-box RNA helicase Yb are the 2 known mechanisms to licence an RNA for piRNA biogenesis in the germline and the soma, respectively. Both the PIWI proteins and Yb are highly conserved across most Drosophila species and are thought to be essential to the piRNA pathway and for silencing transposons. However, we find that species closely related to Drosophila melanogaster have lost the yb gene, as well as the PIWI gene Ago3. We show that the precursor RNA is still selected in the absence of Yb to abundantly generate transposon antisense piRNAs in the soma. We further demonstrate that Drosophila eugracilis, which lacks Ago3, is completely devoid of ping-pong piRNAs and exclusively produces phased piRNAs in the absence of slicing. Thus, core piRNA pathway genes can be lost in evolution while still maintaining efficient transposon silencing. Organisms need to distinguish self and non-self RNA when initiating the biogenesis of piRNAs to target transposons. This study reveals that some Drosophila species have lost the PIWI gene Ago3 and/or the helicase RNA Yb - highly conserved components of the piRNA biogenesis pathway - yet still retain piRNA abundance and specificity

The absence of core piRNA biogenesis factors does not impact efficient transposon silencing in Drosophila.

Organisms require mechanisms to distinguish self and non-self-RNA. This distinction is crucial to initiate the biogenesis of Piwi-interacting RNAs (piRNAs). In Drosophila ovaries, PIWI-guided slicing and the recognition of piRNA precursor transcripts by the DEAD-box RNA helicase Yb are the 2 known mechanisms to licence an RNA for piRNA biogenesis in the germline and the soma, respectively. Both the PIWI proteins and Yb are highly conserved across most Drosophila species and are thought to be essential to the piRNA pathway and for silencing transposons. However, we find that species closely related to Drosophila melanogaster have lost the yb gene, as well as the PIWI gene Ago3. We show that the precursor RNA is still selected in the absence of Yb to abundantly generate transposon antisense piRNAs in the soma. We further demonstrate that Drosophila eugracilis, which lacks Ago3, is completely devoid of ping-pong piRNAs and exclusively produces phased piRNAs in the absence of slicing. Thus, core piRNA pathway genes can be lost in evolution while still maintaining efficient transposon silencing

哺乳類ミトコンドリア翻訳因子の転写制御機構に関する研究

University of Tokyo (東京大学

Mechanistic insights into RNA surveillance by the canonical poly(A) polymerase Pla1 of the MTREC complex

The S. pombe orthologue of the human PAXT connection, Mtl1-Red1 Core (MTREC), is an eleven-subunit complex that targets cryptic unstable transcripts (CUTs) to the nuclear RNA exosome for degradation. It encompasses the canonical poly(A) polymerase Pla1, responsible for polyadenylation of nascent RNA transcripts as part of the cleavage and polyadenylation factor (CPF/CPSF). In this study we identify and characterise the interaction between Pla1 and the MTREC complex core component Red1 and analyse the functional relevance of this interaction in vivo. Our crystal structure of the Pla1-Red1 complex shows that a 58-residue fragment in Red1 binds to the RNA recognition motif domain of Pla1 and tethers it to the MTREC complex. Structure-based Pla1-Red1 interaction mutations show that Pla1, as part of MTREC complex, hyper-adenylates CUTs for their efficient degradation. Interestingly, the Red1-Pla1 interaction is also required for the efficient assembly of the fission yeast facultative heterochromatic islands. Together, our data suggest a complex interplay between the RNA surveillance and 3’-end processing machineries