Focus on regulatory RNAs

Yao et al. review functions of lncRNAs in controlling chromatin architecture, transcription and nuclear bodies in the nucleus and in modulating mRNA stability, translation and protein modifications in the cytoplasm.

Sylvain et al. review cellular functions of various RNA modifications and their roles in regulating cell fate in normal and cancer tissues.

RNA molecules are more than messengers between DNA and protein and exhibit rich regulatory functions in development and disease. In this issue, we present a Focus on regulatory RNAs with specially commissioned Review articles that discuss recent advances in this fast-growing area.

MicroRNAs (miRNAs) repress target mRNAs, often with exquisite tissue specificity. Wang et al. exploit the specific expression of miRNAs to regulate guide production for Cas9. Their method enables novel strategies to simultaneously measure the activity of multiple miRNAs and restrict Cas9 binding or genome editing to precisely defined cell types.

Stressed eukaryotic cells store mRNAs in protein-rich condensates called stress granules. Using single-molecule tracking techniques to examine how mRNAs enter stress granules, a new study shows that mRNAs make transient contacts with the granule surface before stable association, and become largely immobile after entry.

The intestinal crypt has become the prototype compartment to investigate adult stem cell biology, and the list of identified intestinal stem cell (ISC) markers is already extensive. A comprehensive study now uncovers an additional layer in ISC regulation by introducing long noncoding RNA lncGata6 to the stem cell repertoire.

Paraspeckles are nuclear bodies built on the long noncoding RNA, NEAT1, that regulate cellular homeostasis, but how they sense and help under stress is unclear. A study now shows mitochondrial stress modulates paraspeckles by altering NEAT1 expression with a feedback loop that influences mitochondrial homeostasis.

How the metabolic crosstalk between cancer and stromal cells affects tumour growth is incompletely defined. MYC-activated cancer cells are now shown to secrete exosomal miR-105, which fuels tumour growth by inducing a MYC-dependent metabolic programme in cancer-associated fibroblasts.

A coordinated DNA damage response mediated by p53 to repair DNA lesions or to promote apoptosis is essential for maintenance of genome stability. A study now unveils the long non-coding RNA GUARDIN as a component of this pathway, which protects genome integrity in a pleiotropic fashion.

N⁶-methyladenosine (m⁶A) mRNA modification influences mRNA fate by stimulating recruitment of m⁶A reader proteins. A previously unappreciated class of m⁶A reader proteins is now shown to use a common RNA-binding domain and flanking regions to selectively bind m⁶A-containing mRNAs, increasing their translation and stability.

The unfolded protein response (UPR) regulates cell metabolism and survival in response to stress, yet how the UPR is connected to other signalling pathways is poorly understood. PERK is now shown to regulate Bmal1 and Clock proteins to promote cancer cell survival, revealing a link between growth regulation and circadian rhythms.

Small RNAs generated at DNA break sites are implicated in mammalian DNA repair. Now, a study shows that following the formation of DNA double-strand breaks, bidirectional transcription events adjacent to the break generate small RNAs that trigger the DNA damage response by local RNA:RNA interactions.

A variety of non-coding RNAs have been reported as endogenous sponges for cancer-modulating miRNAs. However, miRNA trapping by transcripts with protein-coding functions is less understood. The mRNA of TYRP1 is now found to sequester the tumour suppressor miR-16 on non-canonical miRNA response elements in melanoma, thereby promoting malignant growth.

The mechanism of action of oncogenes in acute myeloid leukaemia is poorly understood. A study now shows that the fusion oncoprotein AML1-ETO regulates leukaemogenesis by increasing the expression of small nucleolar RNAs through post-transcriptional mechanisms, resulting in increased ribosomal RNA methylation, protein translation, and promotion of leukaemic-cell self-renewal and growth.

Little is known regarding how the interactions of stem cells with the immune system regulate their plasticity. A study now describes a mechanism by which normal breast and cancer stem cells utilize miR-199a to downregulate the corepressor LCOR and minimize responses to type I interferon.

Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in cancer progression. The previously uncharacterized lncRNA MAYA is now shown to promote bone metastasis by bridging ROR1–HER3 and Hippo–YAP pathways. Neuregulin-induced HER3 phosphorylation by ROR1 recruits a MAYA-containing protein complex to methylate Hippo/MST1 and activate YAP target genes that are essential for bone metastasis.

Xia and colleagues provided a map for transcriptome-wide distribution of m⁶A RNA methylation in eight human fetal tissue types.

Chen et al. show that tumour-associated macrophages transmit HIF-1α-stabilizing long noncoding RNA through extracellular vesicles to breast cancer cells, thereby enhancing tumour glycolysis and chemoresistance.

Wang et al. developed an inducible CRISPR–Cas9 system, in which guide RNA release is controlled by specific microRNAs, and demonstrated its application as a microRNA sensor and cell-type-specific genome regulator.

Moro et al. discover an Argonaute 2 (Ago2)-dependent miRNA network that, in response to substrate stiffness, regulates genes involved in tissue mechanics, and show that Ago2 restrains stiffness and contributes to regeneration in the zebrafish fin fold.

By using multicolour single-molecule live imaging, Moon et al. show that the dynamics of the interaction between mRNAs and ribonucleoprotein granules are affected by translational status, mRNA length and granule size.

Wang et al. show that mitochondrial stress alters paraspeckle number and morphology through regulating the transcription and processing of lncRNA NEAT1, retaining mRNAs of mitochondrial proteins in paraspeckles.

Zhu et al. show that the long noncoding RNA lncGata6 enhances Wnt signalling in intestinal stem cells by recruiting the NURF remodelling complex onto the Ehf promoter and initiating its transcription, which triggers expression of Lgr4/5.

Liu et al. show that reduced m⁶A mRNA methylation in endometrial cancer is oncogenic. Mechanistically, the AKT pathway is activated in these tumours due to altered expression of AKT regulators carrying m⁶A on their transcripts.

Zhang et al. report that tRNA methyltransferase Dnmt2 is required for sperm small-non-coding-RNA-mediated transmission of paternal metabolic disorders to the offspring.

Choi et al. find that KLHL6, which is mutated in diffuse large B-cell lymphoma, is part of a ubiquitin ligase complex that targets the mRNA decay factor roquin2 for degradation and that loss of KLHL6 enhances cell survival through loss of TNFAIP3.

Consistent crosstalk between cancer cells and stromal cells exists in the tumour microenvironment. Yan et al. show that exosomal miR-105 derived from cancer cells confers metabolic plasticity in recipient cancer-associated fibroblasts to adapt to nutrient-replete and -deplete conditions, thereby sustaining tumour growth.

Hu et al. report that the long non-coding RNA GUARDIN is transcriptionally induced by p53 and promotes genome stability through a dual mechanism to maintain TRF2 expression and BRCA1 stability.

Huang et al. identify IGF2BPs as an additional class of N⁶-methyladenosine (m⁶A) reader proteins. They find that IGF2BPs selectively bind to m⁶A-containing mRNAs and promote their stability.

PERK regulates tumour cell survival. Bu et al. show that the unfolded protein response protein PERK induces miR-211 repression of the circadian factor Bmal1 to regulate protein synthesis and stress responses, contributing to tumour progression.

Michelini et al. show that RNA polymerase II is recruited to double-strand breaks to induce long non-coding RNAs and the generation of small DNA damage response RNAs that promote recruitment of DNA repair factors and repair.

Gilot et al. have found that TYRP1 mRNA, in addition to coding for TYRP1 protein, can promote melanoma by sequestering the tumour suppressor miR-16, thus de-repressing the mRNA transcription of miR-16 target RAB17, which is involved in melanoma cell proliferation.

Wu et al. find that tumour hypoxic conditions increase miR25/93 levels, which via targeting Ncoa3 downregulate the expression of the innate immune regulator cGAS, thus allowing escape of the anti-tumour immune response.

Grelet et al. find that hnRNP E1 release from PNUTS pre-RNA in response to TGFβ generates a lncRNA that acts as competitive sponge for miR-205, promoting epithelial–mesenchymal transition in cancer.

Zhou et al. show that in the context of AML1-ETO-driven leukaemia, AES and DDX21 induce small nucleolar RNA (snoRNA)–ribonucleoprotein (RNP) formation and this is important for self-renewal of leukaemic cells.

Yuan et al. show that the MBNL3 splicing factor promotes alternative splicing of the lncRNA-PXN-AS1 antisense transcript of PXN, leading to the stabilization of PXN mRNA and increasing its protein levels to promote liver cancer growth.

Celià-Terrassa et al. find that by repressing LCOR, a modulator of the interferon response, miR-199a allows both normal and cancer mammary stem cells to evade senescence and differentiation, thus promoting tumorigenesis.

Tavernier et al. show that loss of the protective IRE1–XBP1 stress sensor results in the death of conventional dendritic cells in the lung, whereas those in the intestine survive due to a stronger ATF4-dependent stress response and RIDD activation.

Yang and colleagues report that the LINK-A lncRNA binds to the PIP₃ phospholipid, leading to enhanced AKT signalling, tumorigenesis and resistance to AKT inhibitors.

Li et al. show that ROR1–HER3 receptor tyrosine kinase signalling in breast cancer cells inhibits the MST1/2 Hippo pathway kinases through a lncRNA termed MAYA. The resulting activation of YAP promotes osteoclast differentiation for bone metastasis.

Daley and colleagues report that MAPK signalling controls pluripotency in embryonic stem cells and during somatic cell reprogramming by enhancing the stability and effects of LIN28 on direct mRNA targets through its phosphorylation by ERK.