bims-micpro 2020-06-28 papers

Issue of 2020‒06‒28
three papers selected by
Thomas Martinez
Salk Institute for Biological Studies

Aging (Albany NY). 2020 Jun 23. 12

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan.

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer's disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.

Keywords: aging; humanin; mitochondria; peptides

DOI: https://doi.org/10.18632/aging.103534

Mol Cell. 2020 Jun 18. pii: S1097-2765(20)30390-7. [Epub ahead of print]

Selective 40S Footprinting Reveals Cap-Tethered Ribosome Scanning in Human Cells.

Jonathan Bohlen, Kai Fenzl, Günter Kramer, Bernd Bukau, Aurelio A Teleman.

Translation regulation occurs largely during the initiation phase. Here, we develop selective 40S footprinting to visualize initiating 40S ribosomes on endogenous mRNAs in vivo. This reveals the positions on mRNAs where initiation factors join the ribosome to act and where they leave. We discover that in most human cells, most scanning ribosomes remain attached to the 5' cap. Consequently, only one ribosome scans a 5' UTR at a time, and 5' UTR length affects translation efficiency. We discover that eukaryotic initiation factor 3B (eIF3B,) eIF4G1, and eIF4E remain bound to 80S ribosomes as they begin translating, with a decay half-length of ∼12 codons. Hence, ribosomes retain these initiation factors while translating short upstream open reading frames (uORFs), providing an explanation for how ribosomes can reinitiate translation after uORFs in humans. This method will be of use for studying translation initiation mechanisms in vivo.

Keywords: cap-tethering; eukaryotic initiation factor; mRNA cap; reinitiation; ribosome footprinting; scanning; translation initiation; translational regulation

DOI: https://doi.org/10.1016/j.molcel.2020.06.005

Int J Cancer. 2020 Jun 23.

Multi-omics analysis reveals the functional transcription and potential translation of enhancers.

Yingcheng Wu, Yang Yang, Hongyan Gu, Baorui Tao, Erhao Zhang, Jinhuan Wei, Zhou Wang, Aifen Liu, Rong Sun, Miaomiao Chen, Yihui Fan, Renfang Mao.

Enhancer can transcribe RNAs, however, most of them were neglected in traditional RNA-seq analysis workflow. Here, we developed a Pipeline for Enhancer Transcription (PET, http://fun-science.club/PET) for quantifying enhancer RNAs (eRNAs) from RNA-seq. By applying this pipeline on lung cancer samples and cell lines, we show that the transcribed enhancers are enriched with histone marks and transcription factor motifs (JUNB, Hand1-Tcf3, and GATA4). By training a machine learning model, we demonstrate that enhancers can predict prognosis better than their nearby genes. Integrating the Hi-C, ChIP-seq, and RNA-seq data, we observe that transcribed enhancers associate with cancer hallmarks or oncogenes, among which LcsMYC-1 (Lung cancer-specific MYC eRNA-1) potentially supports MYC expression. Surprisingly, a significant proportion of transcribed enhancers contain small protein-coding open reading frames (sORFs) and can be translated into microproteins. Our study provides a computational method for eRNA quantification and deepens our understandings of the DNA, RNA, and protein nature of enhancers. This article is protected by copyright. All rights reserved.

Keywords: Enhancer RNA; eRNA pipeline; sORF; transcription factor

DOI: https://doi.org/10.1002/ijc.33132